Cyclophosphamide in refractory autoimmune hepatitis and autoimmune hepatitis coexisting extrahepatic autoimmune disorders: A review.

INTRODUCTION AND OBJECTIVES: Despite tacrolimus (TAC) or mycophenolate mofetil (MMF) for alternate approaches, a proportion of patients still required further exploration of other therapeutic options due to uncontrolled autoimmune hepatitis(AIH). The role of cyclophosphamide (CYC) for AIH has been explored in isolated case reports and small series. We present a review of CYC therapy in AIH patients. MATERIALS AND METHODS: A search for studies with keywords 'autoimmune hepatitis' and 'cyclophosphamide' was performed. Data recorded included gender, age, laboratory parameters and histological findings at the time of AIH diagnosis and before initiation of CYC therapy. RESULTS: We identified 13 patients across 7 studies who met criteria for study inclusion, of whom around 69.2% (9/13) were primary refractory; 30.8% (4/13) patients used CYC as rescue therapy due to their coexisting autoimmune complications. The main findings of the study were that CYC appears to have an acceptable safety profile in difficult-to-treat AIH patients, with an overall remission rate of 88.9% (8/9). The other four patients with AIH accompanied by extrahepatic autoimmune disorders also achieved remission of transaminase levels and stability of liver function after the addition of CYC. A positive response to CYC treatment was seen in 12(92.3%) patients and none of them relapsed during the follow-up. CONCLUSIONS: We cautiously recommend that CYC could be a conditioning alternative to starting second-line therapy after unsuccessful intensification of first-line treatment. Pharmacogenetic methods may play a role in guiding cyclophosphamide therapy. Given our small sample size, results should be considered preliminary.

Nonlinear Relationship Between Low Density Lipoprotein and the Probability of Diabetic Macular Edema.

Purpose: Previous studies simply linearized the relationship between low density lipoprotein (LDL) and diabetic macular edema's (DME) probability, ignoring the possibility of a nonlinear relationship between them. We aimed to investigate the nonlinear relationship between LDL and DME probability in patients with type 2 diabetes mellitus (T2DM). Patients and methods: The study recruited 431 T2DM patients who attended Guangdong Provincial People's Hospital from December 2017 to November 2018. A multivariate logistic regression model was conducted to evaluate the association between LDL and DME probability. The nonlinear relationship was identified by generalized additive model. Subgroup analyses were performed to assess the consistency of the association in different subgroups. Results: LDL was positively associated with DME probability (OR=1.60, 95% CI: 1.10~2.34, P=0.0145) after adjusting for covariates. A nonlinear relationship between LDL and DME probability was discovered, with an inflection point for LDL around 4.85 mmol/L (95% CI: 4.18~4.93, P=0.037). The effect sizes and the confidence intervals on the left and right sides of inflection point were 2.17 (1.31 to 3.58) and 0.26 (0.04 to 1.77), respectively. Subgroup analyses revealed other variables had no effect on the association between them. Conclusion: Our finding suggested LDL was positively correlated with DME probability in T2DM patients. And the relationship between LDL and DME probability was nonlinear. Our findings need to be confirmed by further causal researches.

The non-linear relationship between serum albumin and diabetic retinopathy in type 2 diabetes mellitus: a secondary analysis based on a cross-sectional study.

BACKGROUND: Most studies had shown a linear relationship between serum albumin (sALB) and the prevalence of diabetic retinopathy (DR). Thus, the purpose of this study is to investigate whether their relationship is non-linear. METHODS: We included 426 patients with type 2 diabetes who were hospitalized in Guangdong Provincial People's Hospital from December 2017 to November 2018. The outcome was the prevalence of DR. A two-piecewise logistics regression model was performed to identify the non-linear relationship between sALB and the prevalence of DR. The inflection point was calculated to determine the saturation effect through the maximum likelihood ratio and a recursive algorithm. RESULTS: DR was diagnosed in 167 of 426 type 2 diabetic patients. The relationship between sALB and DR was nonlinear. When sALB was less than 38.10 g/L, a significant negative association was observed (OR = 0.82; 95% CI, 0.72-0.94; P = 0.0037), while no significant association was observed when sALB was greater than 38.10 g/L (OR = 1.12; 95% CI, 0.92-1.35; P = 0.2637). CONCLUSIONS: The relationship between sALB and the prevalence of DR is non-linear. sALB is negatively associated with the prevalence of DR when sALB is less than 38.10 g/L. Our findings need to be confirmed by further prospective research.

Investigation of biogenic volatile organic compounds emissions in the Qinghai-Tibetan Plateau.

Biogenic volatile organic compounds (BVOCs), which are produced and emitted by plants, have significant chemical reactivity in the atmosphere and impacting climate change. Qinghai Province, a vital component of the plateau, has abundant vegetation resources, primarily grasslands and forests, yet BVOCs emissions and their impact on air quality remain understudied. In this study, the emissions rates and compositions of BVOCs from seven dominant vegetation types in Qinghai Province were sampled and analyzed using a closed-loop stripping dynamic headspace sampling approach combined with GC-MS, and the total emissions of BVOCs in Qinghai province in 2021 were estimated by using G95 model. At the same time, the emission characteristics of various vegetation types were also analyzed. The results showed that the emissions rates and compositions of BVOCs differed significantly among vegetation types, with monoterpenes being the dominant emission composition in coniferous forests, which accounted for >70 % of the total BVOCs emissions, while isoprene being the main composition in alpine meadow, accounting for 84.96 %. The emissions of three typical vegetation types, Picea asperata, alpine meadow and alpine steppe, were monitored daily, revealing significant diurnal and clear unimodal patterns. The study also found that the annual average BVOCs emissions from vegetation sources in Qinghai Province were estimated to be 1550.63 Gg yr-1, with isoprene contributing the highest proportion of emissions, accounting for 56.94 %. Grassland was the largest BVOCs emission source in Qinghai Province, with an annual average emission of 1438.52 Gg yr-1. Additionally, BVOCs emissions in Qinghai Province showed strong seasonal and daily variation patterns, with the highest emissions occurring in summer, with the peak in July. These findings provide the characteristics of BVOCs emissions from vegetation sources in the Tibetan Plateau, which will contribute to a better understanding of their impact on atmospheric chemistry and climate change.

A closer association between blood urea nitrogen and the probability of diabetic retinopathy in patients with shorter type 2 diabetes duration.

Blood urea nitrogen (BUN) is an indicator of renal function and catabolic status in human body. Diabetic retinopathy (DR) is a major microvascular complication of diabetes mellitus (DM) and a serious threat to the vision of diabetic patients. We included 426 type 2 diabetic patients who visited the endocrinology department of Guangdong Provincial People's Hospital and received an ophthalmology consultation from December 2017 to November 2018. The outcome was the probability of DR in participants. Multivariable logistics analysis was used to confirm the relationship between BUN and the probability of DR. And interaction tests were conducted to find the effects of DM duration on their association. A total of 167 of 426 patients with type 2 diabetes had DR, with a probability of 39.20%. After adjusting for potential confounders, a positive association between BUN and the probability of DR (OR = 1.12; 95% CI 1.03-1.21; P = 0.0107). And a test for interaction between DM duration and BUN on the probability of DR was significant (P = 0.0295). We suggested that in patients with type 2 diabetes, BUN was positively associated with the probability of DR and the association was influenced by DM duration.

Extracellular Vesicles Derived circSH3PXD2A Inhibits Chemoresistance of Small Cell Lung Cancer by miR-375-3p/YAP1.

Introduction: Small cell lung cancer (SCLC) is a subtype of lung cancer with high malignancy and poor prognosis. Rapid acquisition of chemoresistance is one of the main reasons leading to clinical treatment failure of SCLC. Studies have indicated that circRNAs participate in multiple processes of tumor progression, including chemoresistance. However, the molecular mechanisms of circRNAs driving the chemoresistance of SCLC are not well specified. Methods: The differentially expressed circRNAs were screened by transcriptome sequencing of chemoresistant and chemosensitive SCLC cells. The EVs of SCLC cells were isolated and identified by ultracentrifugation, Western blotting, transmission electron microscopy, nanoparticle tracking analysis and EVs uptake assays. The expression levels of circSH3PXD2A in serum and EVs of SCLC patients and healthy individuals were detected by qRT‒PCR. The characteristics of circSH3PXD2A were detected by Sanger sequencing, RNase R assay, nuclear-cytoplasmic fraction assay, and fluorescence in situ hybridization assay. The mechanisms of circSH3PXD2A inhibiting SCLC progression were studied by bioinformatics analysis, chemoresistance assay, proliferation assay, apoptosis assay, transwell assay, pull-down assay, luciferase reporting assay, and mouse xenograft assay. Results: It was identified that the circSH3PXD2A was a prominently downregulated circRNA in chemoresistant SCLC cells. The expression level of circSH3PXD2A in EVs of SCLC patients was negatively associated with chemoresistance, and the combination of EVs-derived circSH3PXD2A and serum ProGRP (Progastrin-releasing peptide) levels had better indications for DDP-resistant SCLC patients. CircSH3PXD2A inhibited the chemoresistance, proliferation, migration, and invasion of SCLC cells through miR-375-3p/YAP1 axis in vivo and in vitro. SCLC cells cocultured with EVs secreted by circSH3PXD2A-overexpressing cells exhibited decreased chemoresistance and cell proliferation. Conclusion: Our results manifest that EVs-derived circSH3PXD2A inhibits the chemoresistance of SCLC through miR-375-3p/YAP1 axis. Moreover, EVs-derived circSH3PXD2A may serve as a predictive biomarker for DDP-resistant SCLC patients.

The diagnosis and treatment of central retinal artery occlusion with severe cardio-cerebrovascular disease: a case report.

Background: Central retinal artery occlusion (CRAO) is an acute eye disease that seriously damages vision. Patients with CRAO often have a combination of various cardio-cerebrovascular diseases (CCVDs), and CRAO patients often ignore their cardio-cerebrovascular disorders because of their ocular symptoms. In addition, there are few reports about CRAO patients with CCVDs received effective interventions implemented. We report the diagnosis and treatment of a Chinese CRAO patient with CCVD who received timely multidisciplinary interventional therapy to provide ideas for clinical ophthalmologists in the diagnosis and treatment of similar diseases. Case Description: A 76-year-old male patient, who had previously been diagnosed with hypertension, was admitted to hospital due to a sudden decrease in vision in his right eye for >2 days with a severe headache. After fundus photography, he was diagnosed with CRAO in the right eye. His cerebral angiography revealed multiple stenoses at arteries of his neck and brain included the right ophthalmic artery. Neurosurgery was attempted to perform a thrombolysis of the right ophthalmic artery while performing the angiography, but failed to find the opening of the right ophthalmic artery. However, through electrocardiogram (ECG) monitoring during the operation, we found that the patient had frequent ventricular premature beats, so the Department of Cardiology performed coronary arteriography for him which revealed severe stenosis of the left anterior descending (LAD) artery. The cardiologists performed a percutaneous coronary intervention (PCI) at the same time as the coronary angiography. Some 2 months later, the patient was admitted to the Neurosurgery Department to implant stent at the left vertebral artery. After stent implantation, his headache symptom improved significantly and his right eye vision improved. Conclusions: Through timely cerebral angiography and ophthalmic examinations, the patient was diagnosed with CRAO combined with CCVD, and after received multidisciplinary interventional therapy, the patient's right eye vision and headache symptom improved and more severe cardio-cerebrovascular adverse events were avoided. In treating CRAO patients, in addition to aggressive eye treatment, the systemic cardio-cerebrovascular situation of each patient should also be assessed, a timely diagnosis made, and effective interventions implemented to reduce morbidity- and mortality-related cardio-cerebrovascular events.

Gastrointestinal microbiome and primary Sjögren's syndrome: a review of the literature and conclusions.

The recognition of the profound impact of the human gastrointestinal microbiome (GM) on human autoimmune diseases has gradually increased thanks to deeper research efforts. As a systemic autoimmune disease, primary Sjögren's syndrome (pSS) cannot be completely cured. Human studies have revealed that GM species and diversity are altered in patients with pSS compared with healthy individuals. Animal studies have provided possible mechanisms for the association between pSS and GM. The potential role of GM in pSS is exerted through several mechanisms. GM dysbiosis leads to increased intestinal permeability, which increases the risk of GM antigen exposure and activates specific autoreactive T lymphocytes via "molecular mimicry". In addition, GM antigen exposure and intestinal immune tolerance loss caused by GM dysbiosis together induce chronic local gut mucosal inflammation, which deteriorates to systemic chronic non-specific inflammation with the circulation of pro-inflammatory lymphocytes and cytokines. These factors eventually activate autoreactive B lymphocytes and lead to pSS. If GM plays a key role in the pathogenesis of pSS, clarifying the underlying mechanisms will be helpful for the development of new therapies targeting GM for dry eye associated with pSS. This review summarizes the latest knowledge about the relationship between GM and pSS, with the aim of contributing to future research and to the development of new clinical applications.

Cholesterol affects the relationship between albumin and major adverse cardiac events in patients with coronary artery disease: a secondary analysis.

We aimed to examine whether the efficacy of the risk of poor prognosis in patients with coronary artery disease is jointly affected by total cholesterol and baseline serum albumin in a secondary analysis of previous study. We analyzed the data of 204 patients from October 2014 to October 2017 for newly diagnosed stable CAD. The outcome was major adverse cardiac events (MACE; defined as all cause mortality, non fatal myocardial infarction, and non fatal stroke). The median duration of follow-up was 783 days. Multivariable COX model was performed to revalidate the relationship between the sALB and MACE and interaction tests were conducted to find the effects of total cholesterol on their association. A total of 28 MACE occurred among the 204 participants. The risk of MACE varied by baseline serum albumin and total cholesterol. Specifically, lower serum albumin indicated higher risk of MACE (HR 3.52, 95% CI 1.30-9.54), and a test for interaction between baseline serum albumin and total cholesterol on MACE was significant (P = 0.0005). We suggested that baseline serum albumin and total cholesterol could interactively affect the risk of poor prognosis of patients with coronary artery diseases. Our findings need to be confirmed by further randomized trials.

Interferon-mediated repression of miR-324-5p potentiates necroptosis to facilitate antiviral defense.

Mixed lineage kinase domain-like protein (MLKL) is the terminal effector of necroptosis, a form of regulated necrosis. Optimal activation of necroptosis, which eliminates infected cells, is critical for antiviral host defense. MicroRNAs (miRNAs) regulate the expression of genes involved in various biological and pathological processes. However, the roles of miRNAs in necroptosis-associated host defense remain largely unknown. We screened a library of miRNAs and identified miR-324-5p as the most effective suppressor of necroptosis. MiR-324-5p downregulates human MLKL expression by specifically targeting the 3'UTR in a seed region-independent manner. In response to interferons (IFNs), miR-324-5p is downregulated via the JAK/STAT signaling pathway, which removes the posttranscriptional suppression of MLKL mRNA and facilitates the activation of necroptosis. In influenza A virus (IAV)-infected human primary macrophages, IFNs are induced, leading to the downregulation of miR-324-5p. MiR-324-5p overexpression attenuates IAV-associated necroptosis and enhances viral replication, whereas deletion of miR-324-5p potentiates necroptosis and suppresses viral replication. Hence, miR-324-5p negatively regulates necroptosis by manipulating MLKL expression, and its downregulation by IFNs orchestrates optimal activation of necroptosis in host antiviral defense.

Extracellular vesicles containing PD-L1 contribute to CD8+ T-cell immune suppression and predict poor outcomes in small cell lung cancer.

Programmed death ligand-1 (PD-L1) is expressed on the surface of tumor cells and binds to programmed cell death protein-1 (PD1) on the surface of T cells, leading to cancer immune evasion via inhibition of T-cell function. One of the characteristics of small cell lung cancer (SCLC) is its ineffective anti-tumor immune response and highly immunosuppressive status in the tumor microenvironment. SCLC cells have been shown to generate extracellular vesicles (EVs), which may play an important role in tumor progression. We thus hypothesized that SCLC EVs may be important mediators of immunosuppression and that PD-L1 could play a role. Herein, we showed that PD-L1 was expressed on the surface of SCLC-derived EVs, with the potential to directly bind to PD1. Experimentally, we further showed that EVs secreted by SCLC cells can inhibit CD8+ T-cell activation and cytokine production in vitro in response to T-cell receptor stimulation. Importantly, an anti-PD-L1 blocking antibody significantly reversed the EV-mediated inhibition of CD8+ T-cell activation. Furthermore, we performed a retrospective study of patients with SCLC to determine the prognostic value of PD-L1 harvested from plasm circulating EVs. The results showed that EVs containing PD-L1 was an independent prognostic factor and significantly correlated with progression-free survival. Together, these results indicate that EVs containing PD-L1 can be served as a diagnostic biomarker for predicting the effectiveness of therapy, as well as a new strategy to enhance T-cell-mediated immunotherapy against SCLC cancers.

Circ_0075804 promotes the malignant behaviors of retinoblastoma cells by binding to miR-138-5p to induce PEG10 expression.

BACKGROUND: It has been gradually recognized that circular RNAs (circRNAs) are important modulators in multiple malignancies. Here, we analyzed the function of circ_0075804 and explored its associated mechanism in regulating retinoblastoma (RB) progression. METHODS: Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and Western blot assay were utilized to measure RNA and protein expression, respectively. Cell proliferation was analyzed by Cell counting kit-8 (CCK8) assay and 5-Ethynyl-2'-deoxyuridine (EdU) assay. Cell apoptosis was assessed by flow cytometry. Cell migration and invasion abilities were analyzed by wound healing assay and transwell invasion assay. Dual-luciferase reporter assay and RNA immunoprecipitation (RIP) assay were applied to verify intermolecular target relations. Xenograft tumor model was used to analyze the role of circ_0075804 in tumor growth in vivo. RESULTS: Circ_0075804 expression was markedly up-regulated in RB tissues and cell lines. Circ_0075804 knockdown restrained the proliferation, migration and invasion whereas promoted the apoptosis of RB cells. Circ_0075804 acted as a molecular sponge for microRNA-138-5p (miR-138-5p), and circ_0075804 silencing-induced effects were partly reversed by miR-138-5p knockdown in RB cells. MiR-138-5p interacted with the 3' untranslated region (3'UTR) of paternally expressed 10 (PEG10). Circ_0075804 positively regulated PEG10 level by sponging miR-138-5p in RB cells. PEG10 overexpression largely overturned miR-138-5p overexpression-mediated effects in RB cells. Circ_0075804 knockdown blocked xenograft tumor growth in vivo. CONCLUSION: Circ_0075804 promoted RB progression via miR-138-5p-dependent regulation of PEG10, which provided new insight in RB therapy.

Two-field non-mydriatic fundus photography for diabetic retinopathy screening: a protocol for a systematic review and meta-analysis.

INTRODUCTION: Diabetic retinopathy (DR) is one of the most prevalent microvascular complications of diabetes mellitus. Guidelines for DR screening in different countries vary greatly, including fundus photography, slit-lamp biomicroscopy, indirect ophthalmoscopy, Optical Coherence Tomography (OCT), OCT-A and Fundus Fluorescein Angiography (FFA). Two-field non-mydriatic fundus photography (NMFP) is an effective screening method due to its low cost and less time-consuming process. However, it is controversial due to the sensitivity and specificity of two-field NMFP. This review intends to evaluate the performance of the two-field NMFP in diagnosing DR and helps clinicians determine the most optimal screening method. METHODS AND ANALYSIS: Two reviewers will independently search on the Medline, Embase, Cochrane databases, ProQuest, Opengrey, Chinese National Knowledge Infrastructure, Wanfang Data, VIP China Science and Technology Journal Database, Chinese BioMedical Literature Database, ISRCTN, ClinicalTrials.gov and the WHO ICTRP to identify relevant studies. There is no restriction posed on the language of the study. Included studies focus on the performance of two-field NMFP in detecting DR in diabetes patients. Analysis and evaluation of the studies will be examined by two reviewers independently using the Quality Assessment for Diagnostic Accuracy Studies-2 tool and later evaluated using the Population, Intervention, Comparison, Outcome, Study design criteria. A random-effect model will calculate the diagnostic indicators, including the sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, diagnostic OR, area under the curve and 95% CIs. We will also develop a summary receiver operating characteristic curve. We anticipate analysing subgroups according to the factors, which may lead to heterogeneity, including DR levels of patients, the reference standards, camera models, the interpretation criteria. The data will be analysed by STATA software. This study was registered with PROSPERO. ETHICS AND DISSEMINATION: This review will analyse the published data. Patients/the public were not involved in this research. The results of this study will be published in peer-reviewed journals. PROSPERO REGISTRATION NUMBER: CRD42020203608.

Exosomal miR-92b-3p Promotes Chemoresistance of Small Cell Lung Cancer Through the PTEN/AKT Pathway.

Resistance to first-line chemotherapy drugs has become an obstacle to improving the clinical prognosis of patients with small cell lung cancer (SCLC). Exosomal microRNAs have been shown to play pro- and anti-chemoresistant roles in various cancers, but their role in SCLC chemoresistance has never been explored. In this study, we observed that the expression of exosomal miR-92b-3p was significantly increased in patients who developed chemoresistance. Luciferase reporter analysis confirmed that PTEN was a target gene of miR-92b-3p. The PTEN/AKT regulatory network was related to miR-92b-3p-mediated cell migration and chemoresistance in vitro and in vivo in SCLC. Importantly, exosomes isolated from the conditioned medium of SBC-3 cells overexpressing miR-92b-3p could promote SCLC chemoresistance and cell migration. Furthermore, we found that plasma miR-92b-3p levels were significantly higher in patients with chemoresistant SCLC than in those with chemosensitive SCLC, but the levels were down-regulated in patients who achieved remission. Kaplan-Meier analysis showed that SCLC patients with high miR-92b-3p expression were associated with shorter progression-free survival. Overall, our results suggested that exosomal miR-92b-3p is a potential dynamic biomarker to monitor chemoresistance in SCLC and represents a promising therapeutic target for chemoresistant SCLC.

Single-Field Non-Mydriatic Fundus Photography for Diabetic Retinopathy Screening: A Systematic Review and Meta-Analysis.

PURPOSE: Single-field non-mydriatic fundus photography (NMFP) has been used to detect diabetic retinopathy (DR) in many studies; however, its value in a general clinical setting has not been established. Here we performed a meta-analysis to evaluate its diagnostic effectiveness. METHOD: We systematically searched PubMed, EMBASE, and Cochrane databases for candidate studies published through May 19, 2018. A random-effect model was used to calculate the diagnostic indicators including the sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), area under the curve (AUC), and 95% confidence intervals. RESULTS: Ten prospective studies were ultimately included. The pooled sensitivity, specificity, PLR, NLR, and DOR were 0.68, 0.94, 11.2, 0.34 and 33, respectively. The AUC was 0.88. Subgroup analysis showed that single-field NMFP had a respective sensitivity and specificity of 0.73 and 0.91 when compared to standard 7-field mydriatic stereoscopic photography (7SF), and 0.54 and 0.98 when compared to slit-lamp biomicroscopy as reference standard. CONCLUSIONS: Single-field NMFP is inadequate to detect DR. Additionally, it showed higher sensitivity and lower specificity when 7SF was used as reference standard, as compared to slit-lamp biomicroscopy, suggesting that different reference standards used in DR screening might have affected the diagnostic results.

Factors Determining Effective Orthokeratology Treatment for Controlling Juvenile Myopia Progression.

BACKGROUND: We aimed to identify factors influencing the therapeutic outcome of orthokeratology on controlling juvenile myopia progression, and the risk factors for complications. METHODS: Myopic patients (n=724) in Shenzhen Second Hospital from Jan 2011 to Jan 2016 fitted with orthokeratology lenses and followed-up for 6-65 months were reviewed retrospectively. Univariate and multivariate logistic regression analyses were used to screen for the factors that can improve treatment outcome and prevent the development of complications. RESULTS: Patients where the orthokeratology treatment was effective displayed a shorter myopia time, smaller diopter and corneal curvature, larger corneal endothelium density, high proportion of overnight wear and longer wearing times compared with patients whose treatments were ineffective. Additionally, wearing Ortho-k for 6 or 12 months yielded improved corrective effect and achieved higher comfort level. Logistic regression analyses showed that myopia time, diopter, corneal curvature e value, corneal endothelium density, time with Ortho-k and corrective effect after wearing Ortho-k for 6 or 12 months were all independent factors influencing the treatment effects. Results showed corneal curvature, anterior chamber depth and central corneal thickness were independent risk factors. CONCLUSION: This study systematically identified the factors leading to effective treatments, and those carrying a risk for complications, to provide guidance for the prescription and follow-up of orthokeratology in the treatment of juvenile myopia.

Downregulation of cell division cycle 25 homolog C reduces the radiosensitivity and proliferation activity of esophageal squamous cell carcinoma.

Radiation therapy is one of the most important methods of contemporary cancer treatment. Cells in the G2 and M phases are more sensitive to radiation therapy, and cell division cycle 25 homolog C (CDC25C) is essential in shifting the cell cycle between these two phases. In this study, the knockdown of CDC25C in human esophageal squamous carcinoma EC9706 cells was mediated by transfecting shRNA against human CDC25C-subcloning into pGV248. The levels of CDC25C mRNA and protein expression were assessed by reverse transcription-polymerase chain reaction (RT-PCR) and western blotting, respectively. Moreover, cell proliferation and radiosensitivity were measured. Stable CDC25C-knockdown EC9706 cell lines were successfully established. Furthermore, the proliferation of both control and CDC25C-shRNA-EC9706 cells was inhibited after the cells were treated with increasing X-ray doses, and the proliferation of the control cells was affected more significantly (p<0.05). Moreover, cell colony formation assays allowed us to reach the same conclusion. Taken together, our experiments demonstrated that the knockdown of CDC25C can reduce both the radiotherapy sensitivity and the proliferation activity of EC9706 cells. Thus, CDC25C might be a potential biomarker for radiotherapy treatment.

PBK/TOPK mediates geranylgeranylation signaling for breast cancer cell proliferation.

PDZ binding-kinase (PBK) (also named T-lymphokine-activated killer cell-originated protein kinase (TOPK)), a serine/threonine kinase, is tightly controlled in normal tissues but elevated in many tumors, and functions in tumorigenesis and metastasis. However, the signaling that regulates expression of PBK in cancer cells remains elusive. Here we show that atorvastatin (Lipitor), an inhibitor of hydroxymethylglutaryl co-enzyme A (HMG-CoA) reductase that is a rate-limiting enzyme of mevalonate pathway, down-regulates expression of PBK by impairing protein geranylgeranylation. The shRNA knockdown demonstrated that Yes-associated protein (YAP) mediates geranylgeranylation-regulated expression of PBK. Importantly, atorvastatin or the geranylgeranyltransferase I inhibitor GGTI-298 inhibited breast cancer cell proliferation through inactivation of YAP signaling and down-regulation of PBK. These findings have defined a new signaling pathway that regulated expression of PBK and identified PBK as a downstream target of the Hippo-YAP signaling, uncoverd a mechanism underlying the anti-cancer effect by inhibition of mevalonate pathway and geranylgeranylation, and provided a potential target for breast cancer targeted therapy.

Nedd4-1 is an exceptional prognostic biomarker for gastric cardia adenocarcinoma and functionally associated with metastasis.

BACKGROUND: Gastric cardia adenocarcinoma (GCA) is the most aggressive subtype of gastric carcinoma. New molecular markers and therapeutic targets are needed for diagnosis, prognosis and treatment of GCA. This study is to establish the E3 ubiquitin ligase Nedd4-1 as a prognostic biomarker to predict the survival and guide the treatment of GCA patients. METHODS: Expression of Nedd4-1 in 214 GCA tumor samples was detected by immunohistochemistry staining (IHC) using tissue microarray assay (TMA). Association of Nedd4-1 with cumulative survival of the TNM stages I-III patients and clinicopathological characteristics was statistically analyzed. The role of Nedd4-1 in gastric cancer cell migration and invasion were determined by transwell and wound healing assays. RESULTS: Nedd4-1 is overexpressed in 83% of the GCA tumors. The 5-year survival rate in Nedd4-1 negative GCA patients is as high as 96%. Log-rank analysis indicated that overexpression of Nedd4-1 is inversely correlated with cumulative survival (χ(2) = 21.885, p <0.001). Multivariate logistic regression analysis showed that overexpression of Nedd4-1 is associated with an extremely low GCA survival rate with a hazard ratio (HR) = 0.068 (p = 0.008) in TNM stages I-III patients. Statistical analysis of association of Nedd4-1 overexpression with clinicopathological characteristics revealed that overexpression of Nedd4-1 is tightly associated with TNM stage (p < 0.001). Knockdown of Nedd4-1 in gastric cancer cell lines AGS and N87 dramatically inhibited the gastric cancer cell migration and invasion. CONCLUSIONS: Our results indicate that Nedd4-1 is an exceptional prognostic biomarker for GCA and suggest that Nedd4-1 may play an essential role in GCA metastasis.