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Lung squamous cell carcinoma (LUSC) is a primary subtype of lung cancer with limited therapeutic options and poor prognosis, and tumour-infiltrating myeloid cells (TIMs) are key regulators of LUSC. However, the correlation between the abundance of TIM subtypes and clinical outcomes of LUSC remains unexplored. This study aimed to develop and validate a prognostic model for low- and high-risk patients with LUSC based on myeloid cell microenvironments. TIM markers in the tumoural (T) and stromal (S) regions were quantified using immunohistochemistry for 502 LUSC patients. L1-penalized Cox regression was used to develop a myeloid survival score (MSS) model based on the training cohort, followed by validation in distinct cohorts from multiple centres. RNA sequencing and immunostaining were used to examine the mechanisms of myeloid cells in LUSC progression and predict potential drug targets and therapeutic agents. Of the 12 myeloid markers, CD163T, CD163S, and S100A12T were highly associated with overall survival (OS) in LUSC patients. The MSS of the three myeloid signatures accurately categorized LUSC patients into risk categories, with an observable difference in OS between the training and validation cohorts. Tumours with high MSS were associated with enhanced antioxidative ability and hedgehog signalling and a shift to a more pro-tumorigenic microenvironment, accompanied by a reduced tumour cell immunogenicity and increased CD8

Lung adenocarcinoma (LUAD) is the most common type of lung cancers, which remains the leading cause of cancer-related death worldwide. Drebrin can promote cell migration and invasion with poor prognosis, but its roes in LUAD tumor progression remains unknown. We showed that the expression of Drebrin was upregulated in clinical LUAD samples. A Kaplan-Meier survival analysis showed that a high expression of Drebrin predicated poor prognosis in LUAD. In vitro, Drebrin promoted anchorage-independent growth and migration of LUAD cells. Drebrin interacted with dynamin through CT domain, and served as an adaptor to promote LUAD cell migration through inducing integrin β1 endocytosis. Thus, this study demonstrated the critical role of Drebrin in LUAD and associated mechanism.

Background Despite the established association between obesity and cancer risk, it remains unclear whether visceral obesity is causally related to cancer risk and whether it is more pro-oncogenic than total body fat. Methods We conducted two-sample Mendelian randomization (MR) analysis to assess the causal effects of visceral adipose tissue (VAT) on six common cancers. For exposure data, 221 genetic variants associated with the predicted volume of VAT in 325 153 Europeans from UK Biobank were used as instrumental variables. Genetic association data of six common cancers (breast, lung, colorectal, ovarian, pancreatic and prostate cancers) were obtained from large-scale consortia with an average of 19 576 cases and 43 272 controls. We performed univariable MR with five MR methods [inverse-variance weighted (IVW), MR-Egger regression, weighted median, MR-Pleiotropy Residual Sum and Outlier (MR-PRESSO) and Radial MR] and multivariable MR to estimate the effect of VAT independent of body mass index (BMI). Finally, we performed a series of sensitivity analyses as validation of primary MR results. Results Two associations survived the false discovery rate correction for multiple testing (q-value Conclusion Our findings suggest that lifelong exposure to elevated volumes of VAT might increase the risk of pancreatic cancer and lung squamous-cell carcinoma, highlighting the importance of revealing the underlying mechanisms for intervention targets.

Supplementary data contains additional methods and figures. The figures contain the following information: Supplementary Figure 1 extends Figure 1 providing evidence that Meflin is expressed in BM MSCs and PSCs in mice. Supplementary Figure 2 supports Figure 1 showing the development of the Meflin-ZDC mice. Supplementary Figure 3-5 extend Figure 1 providing additional evidence that Meflin is specifically expressed in PSCs and CAFs and its expression is regulated by calcipotriol. Supplementary Figure 6-9 support Figure 2 showing the detection of Meflin expression at the protein and mRNA levels in human and mouse PDAC. Supplementary Figure 10 and 11 support Figure 2 showing the data of single-cell RNA sequencing of CAFs isolated from PDAC and breast cancer mouse models. Supplementary Figure 12 supports Figure 3 showing the effects of Meflin depletion on the global gene expression profiles in mouse MSCs. Supplementary Figure 13 supports Figure 3 showing the analysis of tumors developed in WT and Meflin-KO KPC mice. Supplementary Figure 14 supports Figure 6 showing the development of the Meflin-CreERT2 mice. Supplementary Figure 15 and 16 support Figure 7 showing the effect of exogenous Meflin expression on MSC gene expression and the growth of xenograft tumors. Supplementary Figure 17 support Figure 7 showing the role of Meflin in collagen remodeling in mouse and human PDAC. Supplementary Table 1 and 2 show the description of the cohort of PDAC patients included in the analysis and univariate and multivariate Cox regression analysis of human PDAC cases.

Cancer-associated fibroblasts (CAF) constitute a major component of the tumor microenvironment. Recent observations in genetically engineered mouse models and clinical studies have suggested that there may exist at least two functionally different populations of CAFs, that is, cancer-promoting CAFs (pCAF) and cancer-restraining CAFs (rCAF). Although various pCAF markers have been identified, the identity of rCAFs remains unknown because of the lack of rCAF-specific marker(s). In this study, we found that Meflin, a glycosylphosphatidylinositol-anchored protein that is a marker of mesenchymal stromal/stem cells and maintains their undifferentiated state, is expressed by pancreatic stellate cells that are a source of CAFs in pancreatic ductal adenocarcinoma (PDAC). In situ hybridization analysis of 71 human PDAC tissues revealed that the infiltration of Meflin-positive CAFs correlated with favorable patient outcome. Consistent herewith, Meflin deficiency led to significant tumor progression with poorly differentiated histology in a PDAC mouse model. Similarly, genetic ablation of Meflin-positive CAFs resulted in poor differentiation of tumors in a syngeneic transplantation model. Conversely, delivery of a Meflin-expressing lentivirus into the tumor stroma or overexpression of Meflin in CAFs suppressed the growth of xenograft tumors. Lineage tracing revealed that Meflin-positive cells gave rise to α-smooth muscle actin-positive CAFs that are positive or negative for Meflin, suggesting a mechanism for generating CAF heterogeneity. Meflin deficiency or low expression resulted in straightened stromal collagen fibers, which represent a signature for aggressive tumors, in mouse or human PDAC tissues, respectively. Together, the data suggest that Meflin is a marker of rCAFs that suppress PDAC progression.Significance:Meflin marks and functionally contributes to a subset of cancer-associated fibroblasts that exert antitumoral effects.

Colitis-associated colorectal cancer (CAC) arises due to prolonged inflammation and has distinct molecular events compared with sporadic colorectal cancer (CRC). Although inflammatory NF-κB signaling was activated by pro-inflammatory cytokines (such as TNFα) in early stages of CAC, Wnt/β-catenin signaling later appears to function as a key regulator of CAC progression. However, the exact mechanism responsible for the cross-regulation between these 2 pathways remains unclear. Here, we found reciprocal inhibition between NF-κB and Wnt/β-catenin signaling in CAC samples, and the Dvl2, an adaptor protein of Wnt/β-catenin signaling, is responsible for NF-κB inhibition. Mechanistically, Dvl2 interacts with the C-terminus of tumor necrosis factor receptor 1 (TNFRI) and mediates TNFRI endocytosis, leading to NF-κB signal inhibition. In addition, increased infiltration of the pro-inflammatory cytokine interleukin-13 (IL-13) is responsible for upregulating Dvl2 expression through STAT6. Targeting STAT6 effectively decreases Dvl2 levels and restrains colony formation of cancer cells. These findings demonstrate a unique role for Dvl2 in TNFRI endocytosis, which facilitates the coordination of NF-κB and Wnt to promote CAC progression.

OBJECTIVE This meta-analysis aimed to assess the diagnostic accuracy of lung ultrasonography in pneumonia-affected pediatric patients. METHODS Literature search of published articles in Medline, Web of Science, Scopus, Embase and Journal of Web till September 2020 were reviewed for the predescribed accuracy assessors. In compliance with the inclusion and exclusion criteria, two researchers independently screened the literature, collected the results and assessed the risks of bias using the quality assessment of diagnostic accuracy studies-2 tool. The pooled sensitivity and specificity, pooled positive likelihood ratio, negative likelihood ratio and diagnostic odds ratio were estimated for the meta-analysis. The overall efficiency of LUS was evaluated using a summary receiver operating characteristic curve. Q and I2 statistics were used to determine heterogeneity. Meta disc software was used for the analysis of the study. RESULTS Out of 1182 studies, only 29 articles were chosen; 25 of them were prospective studies and 4 studies were retrospective. The overall pooled sensitivity was 0.83 [95% confidence intervals (CI), 0.81-0.84] and specificity was 0.84 (95% CI, 0.81-0.86), depicting good diagnostic performance. CONCLUSION LUS is an efficient imaging technique for detecting childhood pneumonia with a high accuracy rate. It is an appealing alternative to chest X rays to detect and follow-up pneumonia in children because it is simple to do, widely available, comparatively cheap and free of radiation hazards.

BackgroundPatients with systemic lupus erythematosus (SLE) are at increased risk of cardiovascular disease (CVD) compared to the general population. However, little is known about the effects of tobacco smoking on CVD in patients with SLE.ObjectiveTo systematically review and summarize the available literature regarding the effects of tobacco smoking on developing CVD in patients with SLE.MethodsWe retrieved relevant studies from the following databases: PubMed, EMBASE, Web of Science and China National Knowledge Internet (CNKI) database. Two reviewers independently reviewed the eligible studies, assessed their validity, and extracted relevant data. Sensitivity and subgroup analyses were performed to distinguish sources of heterogeneity.ResultsA total of 10 studies, which comprised 6984 participants, were included in the analysis. The overall quality of evidence was rated as moderate to low. The smoking prevalence among CVD patients was 39.28% (271/690), which was higher than 31.36% (1974/6294) among non-CVD patients. Compared with never-smokers, the risk of developing CVD in current smokers was 1.42 (95% CI: 1.21–1.66). No significant publication bias was found in our meta-analysis.ConclusionsIn spite of the several negative results, this study found that current smokers with SLE have an increased risk of developing CVD, although most of the included studies were in low-to-moderate quality.Systematic Review Registrationhttps://www.crd.york.ac.uk/prospero/, identifier CRD42022338109.

Stromal invasion is considered an important prognostic factor in patients with lung adenocarcinoma. The mechanisms underlying the formation of tumor stroma and stromal invasion have been studied in the lung; however, they are still unclear. CD109 is a glycosylphosphatidylinositol‐anchored glycoprotein highly expressed in several types of human malignant tumors including lung cancers. In this study, we investigated the in vivo functions of CD109 protein in malignant lung tumors. Initially, we identified an association between higher expression of CD109 protein in human lung adenocarcinoma and a significantly worse prognosis, according to immunohistochemical analysis. We also showed that CD109 deficiency significantly reduced the area of stromal invasive lesions in a genetically engineered CD109‐deficient lung adenocarcinoma mouse model, which correlated with the results observed in human lung adenocarcinoma. Furthermore, we identified latent TGF‐β binding protein‐1 (LTBP1) as a CD109‐interacting protein using mass spectrometry and confirmed their interaction by co‐immunoprecipitation. Importantly, increased CD109 expression enhanced stromal TGF‐β activation in the presence of LTBP1. Therefore, these data suggest the significance of the regulation of TGF‐β signaling through CD109 and LTBP1 interaction in tumor stroma and also reveal the importance of CD109 expression levels in promoting lung cancer cell proliferation, migration, and invasion, and thus predicting the outcome of patients suffering from lung adenocarcinoma. Therefore, CD109 protein could be a potential therapeutic target for this disease., Stromal invasion is considered an important prognostic factor in patients with lung adenocarcinoma. We determined that CD109 deficiency significantly reduced stromal invasion and prolonged survival of the lung adenocarcinoma mouse model. Furthermore, we identified latent TGF‐β binding protein‐1 as a CD109‐interacting stromal protein, highlighting the significance of interaction between tumor cells and stroma in lung adenocarcinoma progression.

The actin‐binding protein Girdin is a hub protein that interacts with multiple proteins to regulate motility and Akt and trimeric G protein signaling in cancer cells. Girdin expression correlates with poor outcomes in multiple human cancers. However, those findings are not universal, as they depend on study conditions. Those data suggest that multiple aspects of Girdin function and its role in tumor cell responses to anticancer therapeutics must be reconsidered. In the present study, we found that Girdin is involved in DNA damage‐induced cancer cell apoptosis. An esophageal cancer cell line that exhibited high Girdin expression showed a marked sensitivity to UV‐mediated DNA damage compared to a line with low Girdin expression. When transcriptional activation of endogenous Girdin was mediated by an engineered CRISPR/Cas9 activation system, sensitivity to DNA damage increased in both stationary and migrating HeLa cancer cells. High Girdin expression was associated with dysregulated cell cycle progression and prolonged G1 and M phases. These features were accompanied by p53 activation, which conceivably increases cancer cell vulnerability to UV exposure. These data highlight the importance of understanding complex Girdin functions that influence cancer cell sensitivity to therapeutics., The present study suggests that Girdin overexpression perturbs cell cycle distribution with prolonged G1 and M phases and aberrant p53 activation, which leads to an increase in sensitivity to DNA damage. It also showed that the upregulation of the spindle checkpoint protein Mad2 in Girdin‐overexpressing cells could be involved in dysregulated cell cycle progression.

Aging is a main risk factor for a number of debilitating diseases and contributes to an increase in mortality. Previous studies have shown that Ginkgo biloba extract (EGb) can prevent and treat aging-related diseases, but its pharmacological effects need to be further clarified. This study aimed to propose a network pharmacology-based method to identify the therapeutic pathways of EGb for aging. The active components of EGb and targets of sample chemicals were obtained from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) database. Information on aging-related genes was obtained from the Human Ageing Genomic Resources database and JenAge Ageing Factor Database. Subsequently, a network containing the interactions between the putative targets of EGb and known therapeutic targets of aging was established, which was used to investigate the pharmacological mechanisms of EGb for aging. A total of 24 active components, 154 targets of active components of EGb, and 308 targets of aging were obtained. Network construction and pathway enrichment were conducted after data integration. The study found that flavonoids (quercetin, luteolin, and kaempferol) and beta-sitosterol may be the main active components of EGb. The top eight candidate targets, namely, PTGS2, PPARG, DPP4, GSK3B, CCNA2, AR, MAPK14, and ESR1, were selected as the main therapeutic targets of EGb. Pathway enrichment results in various pathways were associated with inhibition of oxidative stress, inhibition of inflammation, amelioration of insulin resistance, and regulation of cellular biological processes. Molecular docking results showed that PPARG had better binding capacity with beta-sitosterol, and PTGS2 had better binding capacity with kaempferol and quercetin. The main components of EGb may act on multiple targets, such as PTGS2, PPARG, DPP4, and GSK3B, to regulate multiple pathways, and play an antiaging role by inhibiting oxidative stress, inhibiting inflammation, and ameliorating insulin resistance.

Bladder cancer is the most prevalent cancer of the urinary system, but its pathogenesis is still poorly understood. Several reports have suggested that gene damage repair is highly correlated with tumor development and drug resistance, in which homologous recombination repair gene Rad54L, seems to play an important role, through yet unclear mechanisms. Therefore, this study stratified cancer patients by Rad54L expression in bladder cancer tissue, and high Rad54L expression was associated with a poor prognosis. Mechanistically, we demonstrate that high Rad54L expression promotes abnormal bladder tumor cell proliferation by changing the cell cycle and cell senescence. In addition, this study also suggests that Rad54L may be associated with p53, p21, and pRB in bladder cancer tissue. In summary, this study exposes Rad54L as potential a prognostic biomarker and precision treatment target in bladder cancer.

Epstein-Barr virus (EBV) and human papillomavirus (HPV) infection is the risk factors for nasopharyngeal carcinoma and cervical carcinoma, respectively. However, clinical analyses demonstrate that EBV or HPV is associated with improved response of patients, although underlying mechanism remains unclear. Here, we reported that the oncoproteins of DNA viruses, such as LMP1 of EBV and E7 of HPV, inhibit PERK activity in cancer cells via the interaction of the viral oncoproteins with PERK through a conserved motif. Inhibition of PERK led to increased level of reactive oxygen species (ROS) that promoted tumor and enhanced the efficacy of chemotherapy in vivo. Consistently, disruption of viral oncoprotein-PERK interactions attenuated tumor growth and chemotherapy in both cancer cells and tumor-bearing mouse models. Our findings uncovered a paradoxical effect of DNA tumor virus oncoproteins on tumors and highlighted that targeting PERK might be an attractive strategy for the treatment of NPC and cervical carcinoma.

Background: Multiple studies have revealed that idiopathic pulmonary fibrosis (IPF) patients are more at risk for cardiovascular diseases and that many IPF patients receive cardiovascular medications like statins, angiotensin-converting enzyme inhibitor (ACEI), angiotensin receptor blocker (ARB), and anticoagulants. Existing studies have reported divergent findings on the link between cardiovascular medications and fibrotic disease processes. The aim of this study is to synthesize the evidence on the efficacy of cardiovascular medications in IPF.Methods: We searched studies reporting the effect of cardiovascular medications on IPF in the PubMed, Embase, Web of Science, Cochrane Library, and two Chinese databases (China National Knowledge Infrastructure database and China Wanfang database). We calculated survival data, forced vital capacity (FVC) decline, and IPF-related mortality to assess the efficacy of cardiovascular medications in IPF. We also estimated statistical heterogeneity by using I2 and Cochran Q tests, and publication bias was evaluated by risk of bias tools ROBINS-I.Results: A total of 12 studies were included in the analysis. The included studies had moderate-to-serious risk of bias. Statin use was associated with a reduction in mortality (hazard ratio (HR), 0.89; 95% CI 0.83–0.97). Meta-analysis did not demonstrate any significant relationship between statin use and the FVC decline (HR, 0.86; 95% CI 0.73–1.02), ACEI/ARB use, and survival data (HR, 0.92; 95% CI 0.73–1.15) as well as anticoagulant use and survival data (HR, 1.16; 95% CI 0.62–2.19).Conclusion: Our study suggested that there is a consistent relationship between statin therapy and survival data in IPF population. However, there is currently insufficient evidence to conclude the effect of ACEI, ARB, and anticoagulant therapy on IPF population especially to the disease-related outcomes in IPF.

Background: It remains controversial whether the application of chemotherapy has an impact on recurrent nasopharyngeal carcinoma (rNPC) patients with salvage radiotherapy. Here, we aimed to evaluate treatment outcomes of rNPC patients and derive a prognostic model to assess the benefit of chemotherapy in patients with re-radiotherapy. Methods: This study was conducted as a retrospective study. In total, 340 rNPC patients treated with salvage intensity-modulated radiotherapy (IMRT) or radiochemotherapy (RCT) from October 2006 to September 2019 were included in this study. Overall survival (OS) was the primary outcome. Kaplan-Meier method was employed to detect the prognostic difference with Log-rank tests. The Cox regression analysis was performed to explore the potential prognostic factors while the multivariate Cox analysis was used to identify candidate variables for the prognostic model of OS. Results: The 5-year actuarial rates of OS, progression-free survival, loco-regional progression-free survival, and distant metastases-free survival did not show significant difference between the IMRT and RCT groups ( P > .05). Age at recurrence and rT category were found to be the independent prognostic factors for OS. We found that rNPC patients suffered poor OS in the high-risk group (patients with higher age at recurrence and advanced rT category) (high-risk vs low-risk, HR = 1.87, 95% CI: 1.36-2.57, P

Girdin, an Akt substrate, has been reported to promote tumorigenesis in various tumors. However, the role of Girdin in a spontaneous tumor model has not yet been explored. Here, we studied the role of Girdin in lung adenocarcinoma (LUAD) using the autochthonous mouse model and found that Girdin led to LUAD progression and chemoresistance by enhancing the Warburg effect. Mechanistically, Girdin interacted with pyruvate kinase M2 (PKM2), which played a vital role in aerobic glycolysis. Furthermore, Girdin impaired Platelet Derived Growth Factor Receptor Beta (PDGFRβ) degradation, which in turn, promoted PKM2 tyrosine residue 105 (Y105) phosphorylation and inhibited PKM2 activity, subsequently promoting aerobic glycolysis in cancer cells. Taken together, our study demonstrates that Girdin is a crucial regulator of tumor growth and may be a potential therapeutic target for overcoming the resistance of LUAD cells to chemotherapy.

Background: Administration of aspirin has the potential for significant side effects of gastrointestinal (GI) injury mainly caused by gastric acid stimulation, especially in long-term users or users with original gastrointestinal diseases. The debate on the optimal treatment of aspirin-induced gastrointestinal injury is ongoing. We aimed to compare and rank the different treatments for aspirin-induced gastrointestinal injury based on current evidence.Methods: We searched PubMed, EMBASE, Cochrane Library (Cochrane Central Register of Controlled Trials), and Chinese databases for published randomized controlled trials (RCTs) of different treatments for aspirin-induced gastrointestinal injury from inception to 1 May 2021. All of the direct and indirect evidence included was rated by network meta-analysis under a Bayesian framework.Results: A total of 10 RCTs, which comprised 503 participants, were included in the analysis. The overall quality of evidence was rated as moderate to high. Eleven different treatments, including omeprazole, lansoprazole, rabeprazole, famotidine, geranylgeranylacetone, misoprostol, ranitidine bismuth citrate, chili, phosphatidylcholine complex, omeprazole plus rebamipide, and placebo, were evaluated in terms of preventing gastrointestinal injury. It was suggested that omeprazole plus rebamipide outperformed other treatments, whereas geranylgeranylacetone and placebo were among the least treatments.Conclusion: This is the first systematic review and network meta-analysis of different treatments for aspirin-induced gastrointestinal injury. Our study suggested that omeprazole plus rebamipide might be considered the best option to treat aspirin-induced gastrointestinal injury. More multicenter, high quality, large sample size randomized controlled trials will confirm the advantages of these medicines in the treatment of aspirin-induced gastrointestinal injury in the future.

Breast cancer stem cells (BCSCs) are the main drivers of recurrence and metastasis. However, commonly used drugs rarely target BCSCs. Via screenings, we found that Salt-inducible kinase 2 (SIK2) participated in breast cancer (BC) stemness maintenance and zebrafish embryos development. SIK2 was upregulated in recurrence samples. Knockdown of SIK2 expression reduced the proportion of BCSCs and the tumor initiation of BC cells. Mechanistically, SIK2, phosphorylated by CK1α, directly phosphorylated LRP6 in a SIK2 kinase activity-dependent manner, leading to Wnt/β-catenin signaling pathway activation. ARN-3236 and HG-9-91-01, inhibitors of SIK2, inhibited LRP6 phosphorylation and β-catenin accumulation and disturbed stemness maintenance. In addition, the SIK2-activated Wnt/β-catenin signaling led to induction of IDH1 expression, causing metabolic reprogramming in BC cells. These findings demonstrate a novel mechanism whereby Wnt/β-catenin signaling pathway is regulated by different kinases in response to metabolic requirement of CSCs, and suggest that SIK2 inhibition may potentially be a strategy for eliminating BCSCs.

Cancer-associated fibroblasts (CAF) constitute a major component of the tumor microenvironment. Recent observations in genetically engineered mouse models and clinical studies have suggested that there may exist at least two functionally different populations of CAFs, that is, cancer-promoting CAFs (pCAF) and cancer-restraining CAFs (rCAF). Although various pCAF markers have been identified, the identity of rCAFs remains unknown because of the lack of rCAF-specific marker(s). In this study, we found that Meflin, a glycosylphosphatidylinositol-anchored protein that is a marker of mesenchymal stromal/stem cells and maintains their undifferentiated state, is expressed by pancreatic stellate cells that are a source of CAFs in pancreatic ductal adenocarcinoma (PDAC). In situ hybridization analysis of 71 human PDAC tissues revealed that the infiltration of Meflin-positive CAFs correlated with favorable patient outcome. Consistent herewith, Meflin deficiency led to significant tumor progression with poorly differentiated histology in a PDAC mouse model. Similarly, genetic ablation of Meflin-positive CAFs resulted in poor differentiation of tumors in a syngeneic transplantation model. Conversely, delivery of a Meflin-expressing lentivirus into the tumor stroma or overexpression of Meflin in CAFs suppressed the growth of xenograft tumors. Lineage tracing revealed that Meflin-positive cells gave rise to α-smooth muscle actin-positive CAFs that are positive or negative for Meflin, suggesting a mechanism for generating CAF heterogeneity. Meflin deficiency or low expression resulted in straightened stromal collagen fibers, which represent a signature for aggressive tumors, in mouse or human PDAC tissues, respectively. Together, the data suggest that Meflin is a marker of rCAFs that suppress PDAC progression., ファイル公開：2020/10/01

Dysfunction of Girdin plays a crucial role in the development of a variety of tumors. Phosphorylated regulation of Girdin has been studied extensively. However, how Girdin is dephosphorylated remains unclear. In this study, we report a mechanism of Girdin dephosphorylation and the importance of this mechanism in the migration of breast cancer cells. We show that the protein phosphatase 2A (PP2A) complex can bind to Girdin via the modulating B subunit. Overexpression or knockdown of PP2A inhibits or increases the phosphorylation of Girdin at serine 1416, respectively. PP2Ac-induced Girdin dephosphorylation is involved in the inhibition of breast cancer cell migration. Furthermore, in human breast cancer samples, PP2Ac expression is negatively correlated with the phosphorylation of Girdin, and low expression of PP2Ac is correlated with tumor stage, grade and lymph node metastasis of breast cancer. These data indicate that PP2A regulates Girdin dephosphorylation and highlight the critical role of this pathway in breast cancer metastasis.

The Sick Sinus Syndrome (SSS) is a serious life-threatening heart disease. It is important to establish a credible and stable sinus node damage model. In this study, we use two methods to construct an SSS damage model in rats. One is to inject sodium hydroxide to the SSS area through internal jugular vein. Another is to cause ischemia-reperfusion injury on the SSS area. 43 healthy SD rats were randomly divided into 4 groups, namely ischemia-reperfusion injury group (IRIG), inject sodium hydroxide group (ISHG), and propranolol group (PG) and the control group (CG). The achievement ratio of modeling was 67% in the IRIG and 83% in the ISHG. The HR significantly decreased after operation in the IRIG and ISHG compared with pre-operation (P＜0.01). The HR was reduced by above 30% in these 2 groups after modeling, while the reduction was better maintained in IRIG. Additionally, the sinoatrial node recovery time (SNRT) and sinoatrial conduction time (SACT) were significantly prolonged compared with pre-modeling in 2 groups (P

Previous therapeutic attempts to deplete cancer-associated fibroblasts (CAFs) or inhibit their proliferation in pancreatic ductal adenocarcinoma (PDAC) were not successful in mice or patients. Thus, CAFs may be tumor suppressive or heterogeneous, with distinct cancer-restraining and -promoting CAFs (rCAFs and pCAFs, respectively). Here, we show that induced expression of the glycosylphosphatidylinositol-anchored protein Meflin, a rCAF-specific marker, in CAFs by genetic and pharmacological approaches improved the chemosensitivity of mouse PDAC. A chemical library screen identified Am80, a synthetic, non-natural retinoid, as a reagent that effectively induced Meflin expression in CAFs. Am80 administration improved the sensitivity of PDAC to chemotherapeutics, accompanied by increases in tumor vessel area and intratumoral drug delivery. Mechanistically, Meflin was involved in the suppression of tissue stiffening by interacting with lysyl oxidase to inhibit its collagen crosslinking activity. These data suggested that modulation of CAF heterogeneity may represent a strategy for PDAC treatment.