Circ_0011058 alleviates RA pathology through the circ_0011058/miR-335-5p/CUL4B signal axis.

Our previous study found that Cullin 4B (CUL4B) inhibited rheumatoid arthritis (RA) pathology through glycogen synthase kinase-3beta (GSK3ß)/canonical Wnt signalling pathway. In this work, pre-experiment and bioinformatics analysis suggested that circ_0011058 may lead to the up-regulation of CUL4B expression by inhibiting miR-335-5p. Therefore, we studied whether circ_0011058 can promote the expression of CUL4B through sponging the miR-335-5p and further promote the pathological development of RA. Bioinformatics prediction, real-time quantitative PCR (RT-qPCR), western blot (WB), double luciferase reporter gene and other relevant methods were used to study the inhibition of circ_0011058 on RA pathology and its molecular mechanism. Results showed that the expression of circ_0011058 was significantly increased in adjuvant arthritis (AA) rats and RA fibroblast-like synoviocytes (FLS). The knockout of circ_0011058 inhibited the proliferation of AA FLS and RA FLS, decreased the levels of interleukin-1 beta (IL-1ß), interleukin 6 (IL-6), interleukin 8 (IL-8), and inhibited the expression of matrix metalloproteinase 3 (MMP3), fibronectin, which showed that circ_0011058 had a strong role in promoting RA pathology. Furthermore, miR-335-5p expression was reduced in AA rats and RA FLS. The highly expressed circ_0011058 directly sponged the miR-335-5p, which led to the increase of CUL4B expression and promoted the activation of the GSK3ß/canonical signalling pathway. Finally, we confirmed that miR-335-5p mediated the roles of circ_0011058 in promoting RA pathological development, which showed that the circ_0011058/miR-335-5p/CUL4B signal axis was involved in RA pathology. This work was of great significance for clarifying the roles of circ_0011058 in RA pathology, and further work was needed to establish whether circ_0011058 was a potential therapeutic target or diagnostic marker for RA.

Forgetfulness as the primary presenting symptom of type A acute aortic dissection.

Acute aortic dissection (AAD) is the most common lethal disease affecting the aorta. Neurological symptoms have been linked to AAD in some patients. Although aortic dissection patients have previously been shown to present with neurological symptoms, AAD with forgetfulness as the first manifestation is extremely rare. To increase the awareness of AAD among clinicians, we report the first case of a male Chinese patient with AD presenting with forgetfulness as the initial symptom. A 53-year-old man presented to the emergency department with forgetfulness. Based on the concept that "time is brain," stroke was initially considered in the differential diagnosis. The patient underwent emergency coronary angiography and was diagnosed with acute myocardial infarction. After contrast-enhanced computed tomography angiography, the patient was finally diagnosed with AAD. Because valuable time was lost in diagnosis rather than treatment, optimal timing for surgery missed. The patient died following an aortic dissection rupture while waiting for emergency surgery. When forgetfulness cannot be completely accounted for in patients presenting with acute myocardial infarction, AAD should be considered. We believe that this case report contains a worthwhile clinical lesson for clinicians.

Phosphatase and Tensin Homolog (PTEN) Expression as a Surrogate Biomarker Correlated With the Depth of Invasion in Cutaneous Malignant Melanoma.

Objective The aim of this study is to evaluate the expression of the phosphatase and tensin homolog (PTEN), which is a tumor suppressor gene that is implicated in the pathogenesis of cutaneous malignant melanoma, in normal skin and melanoma tissue samples. The study also aimed to correlate PTEN expression levels with various clinicopathological parameters of melanoma lesions, thus highlighting the utility of PTEN expression as a prognostic biomarker for melanoma. Study design Immunohistochemistry (IHC) staining was performed on tissue microarray samples representing normal skin and melanoma biopsies of different clinicopathological parameters. Tissue photomicrographs were evaluated with Aperio ImageScope, which has a positive-pixel-counting algorithm built in. Subsequently, a histochemical score (H-score) was derived from the percentage of positive cells (%-staining) and their staining intensity. The H-scores were averaged in groups of tissue samples representing the different melanomas' tumor (T), node (N), and distant metastasis (M), also known as TNM parameters, as set forth by the American Joint Committee on Cancer (AJCC) classification. The mean H-scores were statistically compared using a two-tailed unpaired t-test. Results The PTEN protein expression was measured by IHC and found to be correlated with tumor thickness (T), which is a reliable indicator for survival rates. Specifically, PTEN was significantly downregulated in tumors with a thickness over 2 mm (T3+T4) compared to tumors with a thickness at or below 2 mm (T1+T2). Conclusions The PTEN protein expression, as measured by immunohistochemistry, helped differentiate between tumors with a thickness over 2 mm and tumors with a thickness at or below 2 mm, suggesting PTEN as a potential surrogate marker for the melanoma's invasion depth along with possible prognostic implications. Longitudinal studies evaluating risk stratification based on the expression of PTEN are needed to establish the utility of this promising biomarker in the clinic as an adjunct for pathological examination.

Non-targeted Profiling of Sea Buckthorn Fruit Oil Fingerprints from 3 Regions and Study on Its Antioxidant Activity.

This study investigated the chemical and volatile characteristics of sea buckthorn fruits from three different regions in China. The chemical composition of the volatile oil was determined by using a non-targeted gas chromatography and mass spectrometry (GC/MS) method and the differences in chemical composition among the three producing areas were compared by heatmap providing a visual basis for researchers. A total of 93 compounds were identified, including 52 compounds from the Northeast China, 51 from the Xinjiang region, and 37 from Inner Mongolia region. Then, the in vitro antioxidant activity of sea buckthorn fruit oil was measured using DPPH, ABTS, and SOD inhibition tests, and the results showed that sea buckthorn fruit oil in northeast China was the strongest antioxidant, followed by Inner Mongolia and Xinjiang. The results of the CCK-8 experiment indicated that within the tested concentration, there is no cell cytotoxicity of the essential oil in human umbilical vein endothelial cells (HUVECs) cells. The results could supply reference to distinguish sea buckthorn fruit from different production areas and, meanwhile, clarify the activity and safety of sea buckthorn oil.

Gastrodia elata Blume: A review of its mechanisms and functions on cardiovascular systems.

Gastrodia elata Blume (GEB), commonly called Tianma in Chinese, is a valuable and extensively used herbal Traditional Chinese Medicine with a wide range of clinical applications. It has been used to treat headaches, dizziness, stroke, epilepsy, amnesia, spasm, and other disorders since ancient times. Hundreds of compounds, including phenols, glycosides, polysaccharides, steroids, organic acids, and others, have been isolated and identified from this plant. Modern pharmacological studies have shown that its active ingredients possess many pharmacological effects, such as neuroprotective, analgesic, sedation and hypnosis, anti-anxiety, anti-depressant, anti-convulsant, anti-dizziness, blood pressure lowering, blood lipids lowering, liver protection, anti-tumor, and immunity enhancement effects. The present review discusses the pharmacological actions and mechanisms of various components of GEB in cardiovascular diseases to provide a reference for further study of GEB.

Clinical evidence comparing bridging and direct endovascular thrombectomy: progress and controversies.

Clinical evidence comparing bridging endovascular thrombectomy (bEVT) with intravenous thrombolysis and direct endovascular thrombectomy (dEVT) without thrombolysis for patients with acute ischemic stroke (AIS) presented directly to an EVT-capable center is overwhelming but inconsistent. This study aimed to analyze the progress and controversies in clinical evidence based on current meta-analyses. Three databases, including MEDLINE, EMBASE, and the Cochrane Library, were searched. Relevant data were extracted and reviewed from the pooled studies. The Assessment of Multiple Systematic Review (AMSTAR-2) was used for quality assessment. Twenty-five meta-analyses were finally included. There were 56% (14/25) from Asian countries, 20% (5/25) from North America, and 24% (6/25) from Europe. The majority (72%, 18/25) of evidence arose in a short period from 2020 to 2022 with the serial publication of four randomized controlled trials (RCTs). Among the 25 meta-analyses, 11 pooled at least three RCTs but there is substantial overlap among seven (five recruited the same four RCTs solely and two recruited the same three RCTs solely). Meanwhile, quality rating based on AMSTAR-2 showed 16 'high' rated studies (64%). For functional independence, 40% (10/25) of studies favored bEVT and 60% showed neutral results. For symptomatic intracerebral hemorrhage, most studies (82.6%, 19/23) showed no significant difference. Non-RCT studies contributed to evidence favoring bEVT. Current RCTs provide an update of clinical evidence comparing bEVT and dEVT. However, they simultaneously contribute to an unnecessary overlap among studies. Contemporary observational studies demonstrated different but possibly confounded evidence. Thus, this issue still requires more clinical evidence under standard procedures.

Outcomes after endovascular thrombectomy for acute ischemic stroke patients with active cancer: A systematic review and meta-analysis.

Background: Active cancer (AC) is a known risk factor for stroke and a common comorbidity among patients being considered for treatment with endovascular thrombectomy (EVT). This systematic review and meta-analysis aimed to evaluate the current evidence for the feasibility, efficacy, and safety of EVT for patients with AC. Methods: MEDLINE, EMBASE, and the Cochrane Library were searched for relevant randomized controlled trials (RCTs) and observational studies which met the inclusion criteria for EVT in patients with AC. Studies were excluded due to the mismatch of data format, article type, and group design. The risk of bias was assessed through different scales according to the study design. I 2 statistics were used to evaluate the heterogeneity. Funnel plots were used to evaluate publication bias. Results: A total of six studies and 3,657 patients were included. Compared to without active cancer (WC) patients, patients with AC had a significantly higher proportion of in-hospital mortality (OR 3.24; 95% CI, 1.03-10.15). The estimated rate of favorable outcome of six studies was lower in patients with AC than in patients with WC (OR 0.47; 95% CI, 0.35-0.65). For 90-day mortality of four studies, the AC group had a higher proportion when compared with the WC group (OR 3.87; 95% CI, 2.64-5.68). There was no difference between rate of six studies of successful recanalization (OR 1.24; 95% CI, 0.90-1.72) and four studies of symptomatic ICH (OR 1.09; 95% CI, 0.61-1.97) comparing AC and WC. Conclusion: Patients with AC are less likely to have a favorable outcome and have a higher risk of mortality after EVT. Further studies are warranted for this unique patient population.

Assessment of the Effect on Thromboprophylaxis with Multifaceted Quality Improvement Intervention based on Clinical Decision Support System in Hospitalized Patients: A Pilot Study.

Background: To explore the feasibility and effectiveness of multifaceted quality improvement intervention based on the clinical decision support system (CDSS) in VTE prophylaxis in hospitalized patients. Methods: A randomized, department-based clinical trial was conducted in the department of respiratory and critical care medicine, orthopedic, and general surgery wards. Patients aged ≥18 years, without VTE in admission, were allocated to the intervention group and received regular care combined with multifaceted quality improvement intervention based on CDSS during hospitalization. VTE prophylaxis rate and the occurrence of hospital-associated VTE events were analyzed as primary and secondary outcomes. Results: A total of 3644 eligible residents were enrolled in this trial. With the implementation of the multifaceted quality improvement intervention based on the CDSS, the VTE prophylaxis rate of the intervention group increased from 22.93% to 34.56% (p < 0.001), and the incidence of HA-VTE events increased from 0.49% to 1.00% (p = 0.366). In the nonintervention group, the VTE prophylaxis rate increased from 24.49% to 27.90% (p = 0.091), and the incidence of HA-VTE events increased from 0.47% to 2.02% (p = 0.001). Conclusions: Multifaceted quality improvement intervention based on the CDSS strategy is feasible and expected to facilitate implementation of the recommended VTE prophylaxis strategies and reduce the incidence of HA-VTE in hospital. However, it is necessary to conduct more multicenter clinical trials in the future to provide more reliable real-world evidence.

Prognostic value and potential mechanism of long non-coding RNA Lnc-SMIM20-1 in acute myeloid leukemia.

OBJECTIVES: Acute myeloid leukemia (AML) is a common hematologic malignancy with high heterogeneity and poor prognosis. Although long non-coding RNAs (lncRNAs) have been used as biomarkers for tumors, the clinical relevance of numerous lncRNAs in AML remains to be investigated. RESEARCH DESIGN AND METHODS: Differentially expressed lncRNAs between AML and normal peripheral blood samples were identified using DESeq2. Pan-cancer analysis was performed by GEPIA tool. Kaplan-Meier survival curve was applied for prognosis analysis. KEGG pathway analysis and GSEA were used for functional enrichment. The ceRNA network was constructed by GDCRNAtools. RESULTS: Lnc-SMIM20-1 was most highly expressed in AML and up-regulated in the TCGA-AML cohort compared to normal tissues. Patients with high expression of Lnc-SMIM20-1 had poor overall prognosis both in the TCGA adult AML cohort and the TARGET pediatric AML cohort, no matter whether they were treated with chemotherapy or allo-HSCT. Lnc-SMIM20-1 might participate in cancer-associated signaling pathways and immune-related signaling pathways by interacting with four microRNAs and 20 mRNAs. CONCLUSION: Lnc-SMIM20-1 was up-regulated in AML acting as a stable poor prognostic factor. The prognostic impact of Lnc-SMIM20-1 cannot be overcome by allo-HSCT. Our findings provide insight into the clinical relevance of Lnc-SMIM20-1 in AML; aiming to progress the development of novel therapeutics.

Long non-coding RNA LOC644135 is a potential prognostic indicator in cytogenetically normal acute myeloid leukemia.

OBJECTIVES: Acute myeloid leukemia (AML) is a hematological malignancy with highly clinical heterogeneity resulting in poor outcomes. We aim to identify novel prognostic lncRNA in AML expecting to provide new clues for therapy in AML. METHODS: Three cohorts were enrolled in this study. Differentially expressed lncRNAs between TCGA-AML cohort and GTEx cohort was identified by DESeq2. The relationship between expression level of LOC644135 and prognosis in AML was analyzed by multiple methods. RESULTS: Pan-cancer analysis indicated that LOC644135 was most highly expressed in AML across 33 types of cancer. Patients with high expression of LOC644135 had poor overall prognosis in both TCGA-AML cohort and the TARGET-AML cohort. Especially, high expression of LOC644135 indicated inferior overall survival and event-free survival in CN-AML patients in the TCGA-AML cohort. Besides, CN-AML patients had higher expression of LOC644135 than normal samples. Multivariable analysis suggested that LOC644135 was an independent prognostic factor in AML. GSEA analysis showed that LOC644135 was associated with some immune-related pathways. Besides, high expression of LOC644135 was associated with less infiltration of CD8+ T cell. CONCLUSION: Our findings indicated that LOC644135 was an independent prognostic factor in AML and provided a new idea in the development of therapy in AML.

[Screening of differentially expressed genes for colorectal cancer and prediction of potential traditional Chinese medicine: based on bioinformatics].

This study screened and analyzed the differentially expressed genes(DEGs) between colorectal cancer(CRC) tissues and normal tissues with bioinformatics techniques to predict biomarkers and Chinese medicinals for the diagnosis and treatment of CRC. The microarray data sets GSE21815, GSE106582, and GSE41657 were downloaded from the Gene Expression Omnibus(GEO), and the DEGs were screened by GEO2 R, followed by the Gene Ontology(GO) tern enrichment and Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway enrichment analysis of the DEGs based on DAVID. The protein-protein interaction network was constructed by STRING, and MCODE and Cytohubba plug-ins were used to screen the significant modules and hub genes in the network. UCSC, cBioPortal, and Oncomine were employed for hierarchical clustering, survival analysis, Oncomine analysis, and correlation analysis of clinical data. Coremine Medical was applied to predict the Chinese medicinals acting on hub genes. A total of 284 DEGs were screened out, with 146 up-regulated and 138 down-regulated. The up-regulated genes were mainly involved in cell cycle, NLRs pathway, and TNF signaling pathway, and the down-regulated genes were related to mineral absorption, nitrogen metabolism, and bicarbonate reabsorption in proximal tubules. The 15 hub genes were CDK1, CDC20, AURKA, MELK, TOP2 A, PTTG1, BUB1, CDCA5, CDC45, TPX2, NEK2, CEP55, CENPN, TRIP13, and GINS2, among which CDK1 and CDC20 were regarded as core genes. The high expression of CDK1 and CDC20 suggested poor prognosis, and they significantly expressed in many cancers, especially breast cancer, lung cancer, and CRC. The expression of CDK1 and CDC20 was correlated with gender, tumor type, TNM stage, and KRAS gene mutation. The potential effective medicinals against CRC were Scutellariae Radix, Scutellariae Barbatae Herba, Arnebiae Radix, etc. The significant expression of CDK1 and CDC20 can help distinguish tumor tissues from normal tissues, and is related to survival prognosis. Thus, the two can be used as biomarkers for the diagnosis and treatment of CRC. This study provides a reference for related drug development.

An open-like conformation of the sigma-1 receptor reveals its ligand entry pathway.

The sigma-1 receptor (σ1R) is a non-opioid transmembrane receptor which has been implicated in many diseases, including neurodegenerative disorders and cancer. After more than forty years of research, substantial progress has been made in understanding this unique receptor, yet the molecular mechanism of its ligand entry pathway remains uncertain. Published structures of human σ1R reveal its homotrimeric organization of a cupin-fold ß-barrel body that contains the ligand binding site, a carboxy-terminal V-shaped two-helix bundle, and a single amino-terminal transmembrane helix, while simulation studies have suggested a ligand entry pathway that is generated by conformational rearrangements of the cupin-fold domain. Here, we present multiple crystal structures, including an open-like conformation, of σ1R from Xenopus laevis. Together with functional binding analysis our data suggest that access to the σ1R ligand binding site is likely achieved by protein conformational changes that involve the carboxy-terminal two-helix bundle, rather than structural changes in the cupin-fold domain.

Functional maturation of immature ß cells: A roadblock for stem cell therapy for type 1 diabetes.

Type 1 diabetes mellitus (T1DM) is a chronic autoimmune disease caused by the specific destruction of pancreatic islet ß cells and is characterized as the absolute insufficiency of insulin secretion. Current insulin replacement therapy supplies insulin in a non-physiological way and is associated with devastating complications. Experimental islet transplantation therapy has been proven to restore glucose homeostasis in people with severe T1DM. However, it is restricted by many factors such as severe shortage of donor sources, progressive loss of donor cells, high cost, etc. As pluripotent stem cells have the potential to give rise to all cells including islet ß cells in the body, stem cell therapy for diabetes has attracted great attention in the academic community and the general public. Transplantation of islet ß-like cells differentiated from human pluripotent stem cells (hPSCs) has the potential to be an excellent alternative to islet transplantation. In stem cell therapy, obtaining ß cells with complete insulin secretion in vitro is crucial. However, after much research, it has been found that the ß-like cells obtained by in vitro differentiation still have many defects, including lack of adult-type glucose stimulated insulin secretion, and multi-hormonal secretion, suggesting that in vitro culture does not allows for obtaining fully mature ß-like cells for transplantation. A large number of studies have found that many transcription factors play important roles in the process of transforming immature to mature human islet ß cells. Furthermore, PDX1, NKX6.1, SOX9, NGN3, PAX4, etc., are important in inducing hPSC differentiation in vitro. The absent or deficient expression of any of these key factors may lead to the islet development defect in vivo and the failure of stem cells to differentiate into genuine functional ß-like cells in vitro. This article reviews ß cell maturation in vivo and in vitro and the vital roles of key molecules in this process, in order to explore the current problems in stem cell therapy for diabetes.

An engineered disulfide bridge traps and validates an outward-facing conformation in a bile acid transporter.

Apical sodium-dependent bile acid transporter (ASBT) mediates the uptake of bile acids from the ileum lumen into enterocytes and presents a potential target for the treatment of several metabolic diseases, including type 2 diabetes. It has been proposed that the underlying mechanism for transport by ASBT is an elevator-style alternating-access model, which was deduced mainly by comparing high-resolution structures of two bacterial ASBT homologs (ASBTNM from Neisseria meningitides and ASBTYf from Yersinia frederiksenii) in different conformations. However, one important issue is that the only outward-facing structure (PDB entry 4n7x) was obtained with an Na+-binding site mutant of ASBTYf, which severely cripples its transport function, and therefore the physiological relevance of the conformation in PDB entry 4n7x requires further careful evaluation. Here, another crystal structure is reported of ASBTYf that was captured in a state closely resembling the conformation in PDB entry 4n7x using an engineered disulfide bridge. The introduced cysteine mutations avoided any proposed Na+- or substrate-binding residues, and the resulting mutant retained both structural and functional integrity and behaved similarly to wild-type ASBTYf. These data support the hypothesis that the PDB entry 4n7x-like structure represents a functional outward-facing conformation of ASBTYf in its transport cycle.

Efficacy of Joungal in preventing febrile neutropenia induced by platinum-based doublet chemotherapy in lung cancer.

BACKGROUND: Myelosuppressive chemotherapy often results in febrile neutropenia (FN) in patients with lung cancer, resulting in infection, prolonged hospitalization, higher economic and labor costs, and increased mortality rate. Colony-stimulating factor (CSF) is used to treat FN, but it exhibits limited efficacy and is often underused. We evaluated Joungal, a traditional Chinese medicine, for treatment of neutropenic complications in patients with lung cancer who received chemotherapy. METHODS: A total of 795 patients with lung cancer were treated with platinum-based chemotherapy from 2012 to 2017. Of these, 191 received Joungal during chemotherapy. Three hundred eighty-two patients were included in the control group. The primary end point was incidence of FN. The secondary end points were incidence of neutropenia, granulocyte colony-stimulating factor (G-CSF) use, hospitalization duration, and cost. RESULTS: There were no differences in clinicopathological characteristics such as gender, age, smoking status, stage of disease, hemoglobin, or histologic type between two groups. Joungal significantly decreased the incidence of chemotherapy-induced FN (2.1% vs. 9.4%, OR =0.21, P=0.002), grade 2/3/4 neutropenia (29.8 % vs. 55.8%, OR =0.34, P=0.000), and grade 3/4 neutropenia (13.1% vs. 23.8%, OR =0.48, P=0.013) compared with controls. Furthermore, Joungal decreased G-CSF use (0.68 vs. 1.34/patient/cycle, P=0.001), hospitalization duration (2.56 vs. 4.68 day/patient/cycle, P=0.002), and economic burden ($660 vs. $1,580/ patient/cycle, P=0.001). No drug-related toxicity was observed. CONCLUSIONS: Joungal safely and effectively decreased the incidence of neutropenia and FN induced by doublet platinum-based chemotherapy in patients with lung cancer, and may have potential as a supportive care agent for patients with lung cancer.

PIM1 inhibitor synergizes the anti-tumor effect of osimertinib via STAT3 dephosphorylation in EGFR-mutant non-small cell lung cancer.

BACKGROUND: An increasing amount of evidence has demonstrated that combined or multiple targeted therapies could bring about more durable clinical outcomes, and it is known that epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) resistance is related to bypass activation. This study aims to explore a specific solution for third-generation EGFR-TKI resistance caused by bypass activation, and to examine the antitumor effects of the combination of a novel inhibitor CX-6258 HCl with osimertinib, along with its underlining mechanisms. METHODS: A bioinformatics analysis was performed to detect the relations between the provirus integration site for Moloney murine leukemia virus 1 (PIM1) expression and prognosis of lung cancer. The EGFR-mutated lung cancer cell lines were treated with the combination of CX-6258 HCl and osimertinib to analyze cell proliferation using the Cell Counting Kit-8, colony formation, and in vivo experiments. Cell migration was analyzed using wound healing and Transwell assays. The apoptosis level was detected using Annexin V-propidium iodide flow cytometry. The expression levels of EGFR and STAT3 were determined using Western blot analysis. RESULTS: High expression level of PIM1 was related to the poor prognosis of non-small cell lung cancer (NSCLC). The combined administration of osimertinib and CX-6258 HCl significantly inhibited cell proliferation and migration and effectively induced apoptosis in lung cancer cells. It was more efficient in suppressing EGFR activation and phosphorylation of STAT3 compared with osimertinib treatment alone. Furthermore, it showed a durable efficacy in a xenograft model. CONCLUSIONS: This study showed that PIM1 is a poor prognostic factor for NSCLC. CX-6258 HCl is a potential molecular inhibitor to sensitize the antitumor effects of osimertinib through the inhibiting of the phosphorylation of STAT3 in NSCLC.

Detecting G protein-coupled receptor complexes in postmortem human brain with proximity ligation assay and a Bayesian classifier.

Despite the controversy regarding the existence and physiological relevance of class A G protein-coupled receptor dimerization, there is substantial evidence for functional interactions between the dopamine D2 receptor (D2R) and the adenosine A2A receptor (A2AR). A2AR-D2R complexes have been detected in rodent brains by proximity ligation assay; however, their existence in the human brain has not been demonstrated. In this study, we used Brightfield proximity ligation assay, combined with a systematic sampling and a parameter-free naive Bayesian classifier, and demonstrated proximity between the D2R and the A2AR in the adult human ventral striatum, consistent with their colocalization within complexes and the possible existence of D2R-A2AR heteromers. These methods are applicable to the relative quantification of proximity of two proteins, as well as the expression levels of individual proteins.

Mast cells induce epithelial-to-mesenchymal transition and migration in non-small cell lung cancer through IL-8/Wnt/ß-catenin pathway.

[This retracts the article DOI: 10.7150/jca.29953.].

Mast cells induce epithelial-to-mesenchymal transition and migration in non-small cell lung cancer through IL-8/Wnt/ß-catenin pathway.

Background: In the various cancer, mast cells (MCs) infiltration is correlated with a worse prognosis. There is an increasing evidence that MCs and their mediators are participated in remodeling of the tumor microenvironment and facilitate tumor growth, epithelial-to-mesenchymal transition (EMT) and metastasis. Methods: The transwell was conducted to evaluate the correlations between MCs and non-small cell lung cancer (NSCLC) cells in vitro. The RNA interference of ß-catenin was performed to further explore the signaling pathway. Lung adenocarcinoma cell line A549 and human MC (HMC-1) were subcutaneously injected into BALB/c nude mice. The conventional experiment methods (such as quantitative RT-PCR Western Blot, Immunofluorescence, and ELISA) were used in the present study. Results: We found that high density of MCs in NSCLC correlates with worse prognosis. The NSCLC cells could release CCL5 and recruit MCs to the tumor microenvironment. Then, we explored that HMC-1 transplantation accelerated the growth of A549 cell in nude mice. Moreover, the MCs-derived factors were responsible for tumor growth. When NSCLC cells were activated, MCs produced various factors that induced EMT and migration. We also identified that CXCL8/interleukin (IL)-8 served as the major modulator containing in the activated MC conditioned medium. Furthermore, MCs and exogenous IL-8 promoted ß-catenin phosphorylation in NSCLC cells. Inhibiting the Wnt/ß-catenin pathway by RNA interference could revert EMT and migration of NSCLC. Conclusions: Our study suggests that MCs are recruited into NSCLC microenvironment and improve the EMT and migration of cancer cells, thereby accelerating the growth of NSCLC.

Sertad1 promotes prostate cancer progression through binding androgen receptor ligand binding domain.

Androgen receptor (AR) signaling is involved in the initiation and progression of prostate cancer (PCa), which is the most frequently diagnosed nonskin cancer and remains a leading cause of cancer-related death in men. Further investigation of the involvement of AR signaling in PCa progression is urgently needed. In the present study, we performed a yeast two-hybrid screen and demonstrated that SERTA domain-containing protein 1 (Sertad1) is a novel AR-binding protein that binds to the AR ligand binding domain (LBD). The binding between AR-LBD and Sertad1 was confirmed by glutathione S-transferase (GST) pull-down assays and immunoprecipitation (IP) and confocal immunofluorescence co-localization experiments. Furthermore, we demonstrated that DHT inhibited Sertad1 protein degradation in prostate cancer cell lines and that Sertad1 knockdown inhibited the proliferation of prostate cancer cells in vitro. In human PCa tumor tissues, Sertad1 expression is positively correlated with AR expression and the Gleason score. Taken together, this report is the first to show that Sertad1 is a novel AR-LBD-binding protein, and DHT-liganded AR-LBD inhibits Sertad1 degradation. Thus, Sertad1 may represent a novel therapeutic target for the treatment of AR-positive PCa.