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Pulmonary aspergilloma is chronic and invasive, potentially leading to life-threatening massive hemoptysis. The role of surgery for treating pulmonary aspergilloma and its effect on long-term survival needs more study.We reviewed 166 patients with aspergillomas treated at Shanghai Pulmonary Hospital from 2004 to 2017. Surgery indications included destroyed lung parenchyma, recurrent hemoptysis, despite appropriate medical treatment, and isolated pulmonary nodules suspected to be aspergilloma. Pulmonary aspergillomas are classified as simple (in an isolated thin-walled cavity, ≤3 mm) or complex (a thick-walled cyst,3 mm) based on computed tomographic scan findings.Aspergilloma was complex in 100 patients (60.2%) and simple in 66 (39.8%). The median (interquartile range) size of complex aspergillomas (2.5 [0.3-8.0] cm) was larger than that (2.0 [0.2-6.0] cm) of simple types (P.001). Hemoptysis occurred in 72 patients (72%) with complex disease and in 35 (53%) with simple disease (P = .014). Video-assisted thoracoscopic surgery was performed in 42 patients (63.6%) with simple aspergillomas, and 75 patients (75%) with of complex aspergillomas underwent thoracotomy. Prolonged air leakage (7 days) was the most common (17 [10.2%]) postoperative complication. A bronchopleural fistula developed postoperatively in 1 patient (0.6%). One patient (0.6%) died of respiratory failure within 30 days postoperatively. Two patients (1.2%) experienced recurrence during follow-up. The overall 10-year survival rates were 87.7% for complex aspergillomas and 94.97% for simple aspergillomas (P = .478). Diabetes (12 [7.2%]; hazard ratio, 13.15; 95% CI, 1.12-154.46) was associated with a worse prognosis.The perioperative morbidity and mortality of pulmonary aspergillomas are acceptable. Overall survival rates of simple and complex types are comparable.

Hypoxic pulmonary hypertension (HPH) is a progressive and irreversible disease that reduces survival. Echinacoside is a phenylethanoid glycoside from Tibetan herbs known for its vasorelaxant effect and for inhibiting the proliferation of rat pulmonary arterial smooth muscle cells. This study aimed to investigate the effect of echinacoside on HPH. Sprague Dawley rats were housed in a hypobaric hypoxia chamber (4500 m) for 28 days to obtain the HPH model. Echinacoside (3.75, 7.5, 15, 30 and 40 mg/kg) was administered by intraperitoneal injection from the 1st to the 28th day. The mean pulmonary artery pressure (mPAP), right ventricular hypertrophy index, hemoglobin, hematocrit, red blood cell concentration and morphological change of pulmonary arteries were evaluated. Vascular perfusion assay was used to assess the pulmonary artery function. Echinacoside reduced mPAP, hemoglobin, hematocrit, right ventricular hypertrophy index and mean wall thickness% of pulmonary arteries in HPH rats. It significantly increased maximum vasoconstriction percentage of pulmonary arteries induced by noradrenaline in a dose-dependent manner. In addition, it improved the responsiveness of pulmonary arteries to acetylcholine and sodium nitroprusside. Therefore, Echinacoside might be an effective treatment against HPH, since it regulated pulmonary artery endothelium and smooth muscle layer function and improved the remodeling of pulmonary artery.

Diabetes mellitus (DM) is a highly prevalent chronic systemic disease, which may cause cognitive decline and degenerative change of the brain. Neuronal differentiation defects of neural stem cells (NSCs) played an important role in the development and progression of diabetes-associated cognitive decline (DACD), but the intrinsic pathological mechanism remains largely unclear. In the present study, we demonstrated that expression level of HDAC3 was upregulated in diabetic mice with reduced learning and memory abilities and in cultured NSCs after advanced glycation end products (AGEs) induction. In addition, AGEs interfered with normal differentiation of the cultured NSCs, and knocking down the expression of HDAC3 could partially attenuate the inhibitory effect of AGEs on NSCs differentiation. Findings in this study demonstrate that HDAC3 may serve as an experimental clue for revealing the pathogenesis of DACD.

Diffuse leptomeningeal glioneuronal tumor with the first symptom of acute rapid blindness in both eyes are rare in adolescents. We present a case of an adolescent female without a history of cancer who developed a dramatic loss of vision and eventually blindness, and was diagnosed as diffuse leptomeningeal glioneuronal tumor by cerebrospinal fluid cytology and enhanced MRI. In order to save vision, under the condition of ineffective dehydration treatment, timely emergency surgery to implant Ommaya sac drainage cerebrospinal fluid. According to the pathophysiological mechanism of cerebral edema, we added Edaravone to scavenge oxygen free radicals, Alprostadil to improve microcirculation, Monosialotetrahexosylganglioside nutrient nerve, Butylphthalide to promote collateral circulation, combined with hyperbaric oxygen and acupoint injection of Anisodine. Finally, the patient's vision returned to normal. Conclusion: when dehydration treatment is ineffective, timely surgery to reduce intracranial pressure, combined with comprehensive treatment, can effectively save vision.

Juanfen Mo,1 Li Zheng,1 Zhenzhen Gao,2 Jiayuan Wu,1 Yi Bao1,2 1The Key Laboratory, The Second Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang, 314000, People’s Republic of China; 2Department of Oncology, The Second Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang, 314000, People’s Republic of ChinaCorrespondence: Yi BaoThe Key Laboratory, The Department of Oncology, The Second Hospital of Jiaxing, 1518 Huanchen North Road, Zhejiang, 314000, People’s Republic of ChinaTel +865 738 207 3185Fax +865 738 208 2936Email ybao2011@gmail.comIntroduction: Mucosal-associated invariant T (MAIT) cells are a group of unconventional T cells, which strongly express CD161 and are involved in defending against infectious pathogens and inflammatory diseases. They are activated by inflammatory cytokines, secrete various cytokines and cytotoxic molecules, and express chemokine receptors and integrins. However, the underlying mechanisms of MAIT cells in colon cancer are still not fully understood.Methods: The phenotype and frequency of circulating MAIT cells were investigated by flow cytometry in colon cancer patients and healthy donors. CD161 was examined in cancerous and paracancerous nontumor tissues of colon cancer patients by immunohistochemistry. The serum levels of IFN-γ and IL-17A were analyzed by ELISA. Finally, MAIT cells were also detected in peripheral blood and tumor tissues in a CT26 tumor-bearing mice model.Results: The percentages of CD4+CD8− MAIT cells, CD4−CD8+ MAIT cells, and CD4−CD8− MAIT cells increased in the peripheral blood of colon cancer patients compared with healthy donors. The expression of CD161 protein in colon cancer cancerous tissues was higher than that in the paracancerous nontumor tissues. The killer cell lectin-like receptor B1 (KLRB1), a coding gene for CD161, was positively associated with the gene expressions of immune inhibitory receptors, such as CTLA4, HAVCR2, PDCD1, and CD274 in colon cancer. Furthermore, the serum levels of IFN-γ and CEA were positively correlated with CD8+ MAIT cells in the peripheral blood of colon cancer patients.Conclusion: Taken together, our data suggest that the circulating MAIT cells and the expression of CD161 protein in the tumor tissues increased in colon cancer patients, and MAIT cells may participate immune activities in colon cancer.Keywords: MAIT cells, colon cancer, KLRB1, inflammation, immune activities

BackgroundPyroptosis is essential for tumorigenesis and progression of neoplasm. However, the heterogeneity of pyroptosis and its relationship with the tumor microenvironment (TME) in clear cell renal cell carcinoma (ccRCC) remain unclear. The purpose of the present study was to identify pyroptosis-related subtypes and construct a prognosis prediction model based on pyroptosis signatures.MethodsFirst, heterogenous pyroptosis subgroups were explored based on 33 pyroptosis-related genes and ccRCC samples from TCGA, and the model established by LASSO regression was verified by the ICGC database. Then, the clinical significance, functional status, immune infiltration, cell–cell communication, genomic alteration, and drug sensitivity of different subgroups were further analyzed. Finally, the LASSO-Cox algorithm was applied to narrow down the candidate genes to develop a robust and concise prognostic model.ResultsTwo heterogenous pyroptosis subgroups were identified: pyroptosis-low immunity-low C1 subtype and pyroptosis-high immunity-high C2 subtype. Compared with C1, C2 was associated with a higher clinical stage or grade and a worse prognosis. More immune cell infiltration was observed in C2 than that in C1, while the response rate in the C2 subgroup was lower than that in the C1 subgroup. Pyroptosis-related genes were mainly expressed in myeloid cells, and T cells and epithelial cells might influence other cell clusters via the pyroptosis-related pathway. In addition, C1 was characterized by MTOR and ATM mutation, while the characteristics of C2 were alterations in SPEN and ROS1 mutation. Finally, a robust and promising pyroptosis-related prediction model for ccRCC was constructed and validated.ConclusionTwo heterogeneous pyroptosis subtypes were identified and compared in multiple omics levels, and five pyroptosis-related signatures were applied to establish a prognosis prediction model. Our findings may help better understand the role of pyroptosis in ccRCC progression and provide a new perspective in the management of ccRCC patients.

RationalePatients with clear cell renal cell cancer (ccRCC) may have completely different treatment choices and prognoses due to the wide range of heterogeneity of the disease. However, there is a lack of effective models for risk stratification, treatment decision making and prognostic prediction of renal cancer patients. The aim of the present study was to establish a model to stratify ccRCC patients in terms of prognostic prediction and drug selection based on multi-omics data analysis.MethodsThis study was based on the multi-omics data (including mRNA, lncRNA, miRNA, methylation and WES) of 258 ccRCC patients from TCGA database. Firstly, we screened the feature values that had impact on the prognosis and obtained two subtypes. Then, we used 10 algorithms to achieve multi-omics clustering, and conducted pseudo-timing analysis to further validate the robustness of our clustering method, based on which the two subtypes of ccRCC patients were further subtyped. Meanwhile, the immune infiltration was compared between the two subtypes, and drug sensitivity and potential drugs were analyzed. Furthermore, to analyze the heterogeneity of patients at the multi-omics level, biological functions between two subtypes were compared. Finally, Boruta and PCA methods were used for dimensionality reduction and cluster analysis to construct a renal cancer risk model based on mRNA expression.ResultsA prognosis predicting model of ccRCC was established by dividing patients into high- and low-risk groups. It was found that overall survival (OS) and progression-free interval (PFI) were significantly different between the two groups (pConclusionThe model could precisely predict the prognosis of ccRCC patients and may have implications for drug selection for ccRCC patients.

BackgroundPytoptosis is essential for tumorigenesis and progression of clear cell renal cell carcinoma (ccRCC). However, the heterogeneity of pyroposis and its relationship with the tumor microenvironment (TME) remain unclear. The aim of the present study was to identify proptosis-related subtypes and construct a prognosis prediction model based on pyroptosis signatures.MethodsFirst, heterogenous pyroptosis subgroups were explored based on 33 pyroptosis-related genes and ccRCC samples from TCGA, and the model establsihed by LASSO regression was verified by ICGC database. Then, the clinical significance, functional status, immune infiltration, cell-cell communication, genomic alteration and drug sensitivity of different subgroups were further analyzed. Finally, the LASSO-Cox algorithm was applied to narrow down the candidate genes to develop a robust and concise prognostic model.ResultsTwo heterogenous pyroptosis subgroups were identified: pyroptosis-low immunity-low C1 subtype, and pyroptosis-high immunity-high C2 subtype. Compared with C1, C2 was associated with a higher clinical stage or grade and a worse prognosis. More immune cell infiltration was observed in C2 than that in C1, while the response rate in C2 subgroup was lower than that in C1 subgroup. Pyroptosis related genes were mainly expressed in myeloid cells, and T cells and epithelial cells might influence other cell clusters via Pyroptosis related pathway. In addition, C1 was characterized by MTOR and ATM mutation, while C2 was characterized by more significant alterations in SPEN and ROS1 mutation. Finally, we constructed and validated a robust and promising signature based on the pyroptosis-related risk score for assessing the prognosis in ccRCC.ConclusionWe identified two heterogeneous pyroptosis subtypes and 5 reliable risk signatures to establish a prognosis prediction model. Our findings may help better understand the role of pyroptosis in ccRCC progression and provide a new perspective in the management of ccRCC patients.

Purpose Previous studies have shown that the presence of EGFR T790M mutation may reduce the treatment efficacy of tyrosine kinase inhibitors (TKIs) in EGFR-mutant lung cancer. However, little is known about the clinical features and outcomes of EGFR T790M mutation in pretreated patients with NSCLC. Patients and methods The clinical features of EGFR-activating and T790M mutations were assessed in a large cohort of patients with EGFR-TKI-naive NSCLC (all/EGFR mutations, n=16,347/7,687). The correlation between the pretreatment T790M mutation status and clinical outcomes was evaluated using univariate and multivariate analyses. Results Pretreatment T790M mutation was reported in 1.39% of the patients and coexisted with an EGFR-activating or uncommon mutation. The dual EGFR T790M and common EGFR-activating mutations were more likely to be detected in lung adenocarcinoma, whereas single T790M mutation was more prevalent in non-adenocarcinomas. The presence of de novo T790M mutation correlated with reduced recurrence-free survival (RFS) in patients with NSCLC (odds ratio [OR] 3.37, 95% confidence interval [CI] 1.67-6.79, P = 0.001). After molecular stratification, T790M mutation was shown to exert adverse effects on the RFS of EGFR 19-del group (OR 2.89, 95% CI 1.10-7.91, P = 0.028) and EGFR L858R group (OR 3.43, 95% CI 1.33-8.88, P = 0.013). Furthermore, pretreatment T790M mutation promoted tumor metastasis to different sites. Conclusion T790M-positive tumors presented special clinical features, and the coexistence of T790M and common EGFR-activating mutations was associated with poor prognosis in patients with NSCLC.

Ischemia and reperfusion injury following severe trauma or cardiac arrest are major causes of organ damage in intensive care patients. The brain is particularly vulnerable because hypoxia rapidly damages neurons due to their heavy reliance on oxidative phosphorylation. Therapeutic hypothermia can reduce ischemia-induced brain damage, but cooling procedures are slow and technically difficult to perform in critical care settings. It has been previously reported that injection of naturally occurring adenosine 5’-monophosphate (AMP) can rapidly induce hypothermia in mice. We studied the underlying mechanisms and found that AMP transiently reduces the heart rate, respiratory rate, body temperature, and the consciousness of adult male and female C57BL/6J mice. Adding AMP to mouse or human neuronal cell cultures dose-dependently reduced the membrane potential (ΔΨm) and Ca(2+) signaling of mitochondria in these cells. AMP treatment increased intracellular AMP levels and activated AMP-activated protein kinase (AMPK), which resulted in the inhibition of mammalian target of rapamycin complex 1 (mTORC1) and of mitochondrial and cytosolic Ca(2+) signaling in resting and stimulated neurons. Pretreatment with an intraperitoneal injection of AMP almost doubled the survival time of mice under hypoxic (6% O(2)) or anoxic (

The incidence of synchronous multiple primary lung cancer (SMPLC) has been increased in recent years. Because of a variance in clinical management and outcome, it is important to distinguish SMPLC from a primary tumor with intrapulmonary metastases. Here, we reported a diagnosis and treatment procedure regarding a case of a 58-year-old woman who presented with synchronous multiple tumor lesions in separate lungs. Using a next generation sequencing technology, a discordant EGFR gene profile from the separate lungs was revealed for this patient. After standard treatment procedures, the therapeutic effects were evaluated by response evaluation criteria in solid tumors (RECIST). This case shows an essential role in the combination of molecular features, together with pathological analysis, during the management of SMPLC, but challenges still required considering during dealing the cases of SMPLC.

Background. Acute myocardial infarction (AMI) remains a leading cause of morbidity and mortality worldwide. The idea of therapeutic angiogenesis in ischemic myocardium is a promising strategy for MI patients. Buyang Huanwu decoction (BHD), a famous Chinese herbal prescription, exerted antioxidant, antiapoptotic, and anti-inflammatory effects, which contribute to cardio-/cerebral protection. Here, we aim to investigate the effects of BHD on angiogenesis through the caveolin-1 (Cav-1)/vascular endothelial growth factor (VEGF) pathway in MI model of mice. Materials and Methods. C57BL/6 mice were randomly divided into 3 groups by the table of random number: (1) sham-operated group (sham, n=15), (2) AMI group (AMI+sham, n=20), and (3) BHD-treated group (AMI+BHD, n=20). 2,3,5-Triphenyltetrazolium chloride solution stain was used to determine myocardial infarct size. Myocardial histopathology was tested using Masson staining and hematoxylin-eosin staining. CD31 immunofluorescence staining was used to analyze the angiogenesis in the infarction border zone. Western blot analysis, immunofluorescence staining, and/or real-time quantitative reverse transcription polymerase chain reaction was applied to test the expression of Cav-1, VEGF, vascular endothelial growth factor receptor 2 (VEGFR2), and/or phosphorylated extracellular signal-regulated kinase (p-ERK). All statistical analyses were performed using the SPSS 20.0 software and GraphPad Prism 6.05. Values of P<0.05 were considered as statistically significant. Results and Conclusion. Compared with the AMI group, the BHD-treated group showed a significant improvement in the heart weight/body weight ratio, echocardiography images, cardiac function, infarct size, Mason staining of the collagen deposition area, and density of microvessel in the infarction border zone (P<0.05). Compared with the AMI group, BHD promoted the expression of Cav-1, VEGF, VEGFR2, and p-ERK in the infarction border zone after AMI. BHD could exert cardioprotective effects on the mouse model with AMI through targeting angiogenesis via Cav-1/VEGF signaling pathway.

Diffuse leptomeningeal glioneuronal tumor has various clinical manifestations and is easily misdiagnosed. This article aims to describe the clinical features of a patient with diffuse leptomeningeal glioneuronal tumor misdiagnosed as optic neuromyelitis lineage disease (NMOSD), analyze the causes of misdiagnosis, and identify the disease with similar clinical manifestations. Adolescent women with decreased vision and headache, nausea, and vomiting were initially diagnosed as NMOSD. Immunotherapy was ineffective; enhanced MRI and cerebrospinal fluid cytology examination were completed and compared with classic meningeal carcinoma, NMOSD, multiple sclerosis, and Vogt-Koyanagi-Harada (VKH) syndrome. Diffuse leptomeningeal glioneuronal tumor was finally diagnosed in adolescent women with no history of tumor. Compared with NMOSD: no history of infection, no AQP4, MOG antibody, no spinal segmental abnormalities, immunotherapy was ineffective; compared with multiple sclerosis: no history of infection, no plaque, no oligoclonal antibody, immunotherapy was ineffective; compared with VKH syndrome: no history of infection, no fever, no treatment for immunotherapy; and compared with classic meningeal carcinoma: adolescents, no extracranial tumor lesions, super high protein, more different sugar excess. Patients with acute visual impairment should consider not only NMOSD, but also diffuse leptomeningeal glioneuronal tumor (DLGNT) and other diseases. DLGNT could not be excluded when CSF cytology and MRI plain scan were negative. The positive rate of malignant cells can only be increased by repeatedly sending fresh cerebrospinal fluid for examination; DLGNT needs to be differentiated from NMOSD, multiple sclerosis, VKH syndrome, and other diseases. Early diagnosis and molecular targeted therapy can improve the quality of life and prolong life.

Long noncoding RNAs (lncRNAs) are implicated in renal cell carcinoma (RCC), but remain largely unclear. Using publicly available transcriptome sequencing data from renal cancer (n = 703) and integrating bioinformatics analyses, we screened and identified a valuable lncRNA, EGFR-AS1. In our validation cohort (n = 204), EGFR-AS1 was significantly upregulated in RCC tissues (P < 0.001). Gain-of-function and loss-of-function studies showed that EGFR-AS1 promoted cell proliferation and invasion in vitro and in vivo. Based on previous studies and sequence complementarity of EGFR with EGFR-AS1, we demonstrated that EGFR-AS1 directly bound to EGFR mRNA and inhibited its degradation. Furthermore, RNA pull-down and mass spectrometry analyses showed that EGFR-AS1 interacted with HuR, which was responsible for the mRNA stability of EGFR. Multivariate analysis suggested that higher EGFR-AS1 expression predicted a poor prognosis in RCC patients (high vs low: P = 0.018, HR = 2.204, 95% CI: 1.145–4.241). In conclusion, EGFR-AS1 enhances the malignant phenotype of RCC cells by enhancing HuR-mediated mRNA stability of EGFR. Our data also provide biological rationales for EGFR-AS1 as a prognostic biomarker and a potential therapeutic target for RCC.

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DEAD-box protein 39 (DDX39) has been demonstrated to be a tumorigenic gene in multiple tumor types, but its role in the progression and immune microenvironment of clear cell renal cell cancer (ccRCC) remains unclear. The aim of the present study was to investigate the role of DDX39 in the ccRCC tumor progression, immune microenvironment and efficacy of immune checkpoint therapy. The DDX39 expression level was first detected in tumors in the public data and then verified in ccRCC samples from Changzheng Hospital. The prognostic value of DDX39 expression was assessed in the Cancer Genome Atlas (TCGA) and ccRCC patients from Changhai Hospital. The role of DDX39 in promoting ccRCC was analyzed by bioinformatic analysis and in vitro experiments. The association between DDX39 expression and immune cell infiltration and immune inhibitory markers was analyzed, and its value in predicting the immune checkpoint therapy efficacy in ccRCC were evaluated in the public database. DDX39 expression was elevated in Oncomine, GEO and TCGA ccRCC databases, as well as in Changzheng ccRCC samples. In TCGA ccRCC patients, increased DDX39 expression predicted worse overall survival (OS) (p

Microglia-mediated neuroinflammation is tightly correlated with the etiology and progression of neurodegenerative disorders, including Parkinson's disease (PD). Nilotinib, a c-Abl inhibitor used for chronic myeloid leukemia, has been proven effective in relieving PD progression. However, whether nilotinib could affect neuroinflammation is largely unknown. In this current study, we investigated the role of nilotinib in microglia-mediated neuroinflammatory response in Parkinson's disease. Lipopolysaccharide (LPS)-induced neuroinflammation in BV2 microglial cells and mouse brains were used as models for Parkinson's disease. Our results demonstrated that nilotinib significantly suppressed LPS-induced neuroinflammation by reducing the production of pro-inflammatory factors including iNOS, COX-2, IL-1β, IL-6 and TNF-α in BV2 cells. Moreover, pretreatment of nilotinib attenuated the neurotoxicity of LPS-treated microglial conditioned medium to MES23.5 dopaminergic (DA) neurons. Mechanismly, nilotinib inhibited NF-κB signaling pathway and suppressed the nuclear translocation of p65 upon LPS stimulation. In LPS-injected mouse brains, nilotinib administration markedly suppressed the activation of microglia and down-regulated COX-2 as well as IL-1β expression. Most importantly, nilotinib effectively protected against microglial activation-mediated mouse DA neuronal loss. Taken together, our study suggests that nilotinib exerts anti-neuroinflammatory effect and protects DA neurons from activated microglia-induced inflammatory damage through suppressing NF-κB signaling pathway, indicating its potential application in further clinical trials.

BACKGROUND: Tribbles pseudokinase 3 (TRIB3) is a member of the tribbles-related family, which has been determined in various cancers, including renal cell carcinoma, acute promyelocytic leukemia, colorectal cancer, endometrial cancer, and glioma. However, its role in retinoblastoma (RB) has not yet been explored. METHODS: The expression level of TRIB3 was detected in RB tissues and cell lines using qRT-PCR. The effects of TRIB3 on cell proliferation and invasion capacities were analyzed with MTT, crystal violet, and transwell assays. Western blot and rescue assays were conducted to explore the underlying mechanism. RESULTS: This study found that TRIB3 was upregulated in human RB tissues compared to adjacent normal tissues both at the mRNA and protein levels. Overexpression of TRIB3 significantly promoted cell proliferation and invasion of RB cells, while TRIB3 knockdown inhibited these processes. Moreover, the mechanism deciphering experiments showed that TRIB3 overexpression can increase AKT and mTOR phosphorylation. Conversely, TRIB3 knockdown decreased the phosphorylation of AKT and mTOR. Additionally, MK2206, a potent AKT inhibitor, blocked the promotive effects of TRIB3 in RB cells. CONCLUSION: This study demonstrated that TRIB3 acts as an oncogene and plays a crucial role in the proliferation and invasion of RB cells via regulating the AKT/mTOR signaling pathway. Therefore, TRIB3 may serve as a potential target in the diagnosis and/or treatment of RB.

Background: The intracerebral hemorrhagic stroke (ICH) is associated with high mortality and severe disability in survivors, which causing about 42% of the disability-adjusted life years lost and 50% of all stroke patients dead within 1 year. Although early functional training is recommended to facility rehabilitation after the stroke, the benefit and safety are still controversial. Introduction: This systematic review aims to investigate whether early physical rehabilitation could have a beneficial effect for the patients with ICH compared with standard rehabilitation care. Methods and analysis: Pubmed, Embase, and Cochrane library will be searched to include randomized control trials which investigate the rehabilitation effective of the early mobilization for patients with ICH compared with routine nursing or standard care. Rev-Man version 5.3 will be used to perform all calculations related to the meta-analysis. Dichotomous data will be calculated in terms of a fixed or random effect model and expressed by the relative risk (RR) with 95% confidence interval (CI). The Cochrane collaborations tool in the following aspects was used to assess the risk of bias (ROB) in included studies. The inconsistency index (I2) and Chi-Squared will be applied for heterogeneity detection between clinical trials. A value of P

Diabetic coronary heart disease (DM-CHD) poses a major threat to the world. The newly described T cell subset-Th9 cells and related cytokine interleukin (IL)-9 play important roles in the pathogenesis of diabetes and atherosclerosis. B lymphocyte-induced maturation protein 1 (Blimp-1) has been indicated to negatively regulate Th9 development in allergic asthma, but its role in DM-CHD remains unclear. Hence, this study was designed to investigate the role of Blimp-1 in DM-CHD and to elucidate whether the mechanism was associated with regulation of Th9 cell differentiation. Our results showed that serum Blimp-1 mRNA level was decreased whereas proportion of Th9 cells (IL-9+ CD4+ T cells) and serum level of Th9-related IL-9 were increased in DM-CHD patients. Furthermore, serum Blimp-1 mRNA level was negatively correlated with IL-9 level in DM-CHD patients. Importantly, administration of lentiviruses expressing Blimp-1 (LV-Blimp-1) significantly inhibited Th9 cell differentiation and alleviated the severity of atherosclerotic lesions in the aorta and coronary artery, dyslipidemia, inflammation, vascular endothelial dysfunction, and oxidative stress in DM-CHD model rats. Collectively, Blimp-1 exerts a protective effect in DM-CHD rats and the mechanism might involve inhibition of Th9 cell differentiation.

Diffuse leptomeningeal glioneuronal tumor has a high degree of malignancy and high mortality. The purpose of this paper is to describe the characteristics of atypical diffuse leptomeningeal glioneuronal tumor and analyze the causes of misdiagnosis as viral meningoencephalitis. An adolescent female patient presented with headache, nausea, vomiting, sharp vision loss and cognitive dysfunction. After poor therapeutic effect of standard antiviral treatment, further inspection found that malignant cells were detected by cerebrospinal fluid (CSF) cytology; and enhanced magnetic resonance imaging (MRI) showed extensive enhancement of the leptomeningeal. In conclusions, when patient with unexplained high intracranial pressure, it is necessary to be alert to the diagnosis of diffuse leptomeningeal glioneuronal tumor. Multiple examinations of fresh CSF are helpful to increase the positive detection rate of tumor cells. Early diagnosis and active treatment are conducive to improving survival rate.

Stroke is one of the major diseases that endanger the physical health life of middle-aged and old people. It has the characteristics of high incidence, mortality and disability rate. Atherosclerosis is the main intervention target for stroke prevention and treatment. MiRNAs are highly expressed in the cerebral vasculature and play an important regulatory role in the pathogenesis of neuronal damage and ischemic stroke. This article reviews the mechanism of action between miRNAs and atherosclerosis, stroke, ischemia-reperfusion injury, collateral circulation and circRNA molecular networks, providing theoretical support for miRNA in gene diagnosis and drug therapy of atherosclerotic stroke.

Long non-coding RNAs (lncRNAs) can be used as prognostic biomarkers in many types of cancer.We sought to establish an lncRNA signature to improve postoperative risk stratification for patients with localized clear cell renal cell carcinoma (ccRCC).Based on the RNA-seq data of 444 stage I-III ccRCC tumours from The Cancer Genome Atlas project, we built a four-lncRNA-based classifier using the least absolute shrinkage and selection operation (LASSO) Cox regression model in 222 randomly selected samples (training set) and validated the classifier in the remaining 222 samples (internal validation set). We confirmed this classifier in an external validation set of 88 patients with stage I-III ccRCC from a Japan cohort and using quantitative reverse transcription polymerase chain reaction (RT-PCR) in another three independent sets that included 1869 patients from China with stage I-III ccRCC.Univariable and multivariable Cox regression, Harrell's concordance index (c-index), and time-dependent receiver operating characteristic curves were used to evaluate the association of the classifier with overall survival, disease-specific survival, and disease-free survival.Using the LASSO Cox regression model, we built a classifier named RCClnc4 based on four lncRNAs: ENSG00000255774, ENSG00000248323, ENSG00000260911, and ENSG00000231666. In the RNA-seq and RT-PCR data sets, the RCClnc4 signature significantly stratified patients into high-risk versus low-risk groups in terms of clinical outcome across and within subpopulations and remained as an independent prognostic factor in multivariate analyses (hazard ratio range, 1.34 [95% confidence interval {CI}: 1.03-1.75; p=0.028] to 1.89 [95% CI, 1.55-2.31; p0.001]) after adjusting for clinical and pathologic factors. The RCClnc4 signature achieved a higher accuracy (mean c-index, 0.72) than clinical staging systems such as TNM (mean c-index, 0.62) and the stage, size, grade, and necrosis (SSIGN) score (mean c-index, 0.64), currently reported prognostic signatures and biomarkers for the estimation of survival. When integrated with clinical characteristics, the composite clinical and lncRNA signature showed improved prognostic accuracy in all data sets (TNM + RCClnc4 mean c-index, 0.75; SSIGN + RCClnc4 score mean c-index, 0.75). The RCClnc4 classifier was able to identify a clinically significant number of both high-risk stage I and low-risk stage II-III patients.The RCClnc4 classifier is a promising and potential prognostic tool in predicting the survival of patients with stage I-III ccRCC. Combining the lncRNA classifier with clinical and pathological parameters allows for accurate risk assessment in guiding clinical management.The RCClnc4 classifier could facilitate patient management and treatment decisions.

CXC chemokine receptor 4 (CXCR4) has been suggested to play a critical role in cancer metastasis. Some studies have described CXCR4 nuclear localization in metastatic lesions of renal cell carcinoma (RCC), which has been suggested to be correlated with cancer metastasis. However, the underlying mechanism and clinical significance of CXCR4 nuclear localization remains unknown. Here, we show that CXCR4 nuclear localization is more likely to occur in RCC tissues, especially in metastases, and is associated with poor prognosis. CXCR4 nuclear localization requires its nuclear localization sequence (NLS, residues 146-RPRK-149). After the mutation of NLS in CXCR4, CXCR4 nuclear localization in RCC cells is lost. Nuclear localization of CXCR4 promoted RCC tumorigenicity both in vitro and in vivo. Mechanistically, we found that CXCR4 and hypoxia-inducible factor-1α (HIF-1α) colocalized in RCC cells and interacted with each other. Moreover, CXCR4 nuclear localization promoted nuclear accumulation of HIF-1α, thereby promoting the expression of genes downstream of HIF-1α. Reciprocally, nuclear HIF-1α promoted CXCR4 transcription, thus forming a feed-forward loop. Subcellular CXCR4 and HIF-1α expression levels were independent adverse prognostic factors and could be combined with TNM stage to generate a predictive nomogram of the clinical outcome of patients with RCC. Therefore, our findings indicate that CXCR4 nuclear translocation plays a critical role in RCC metastasis and may serve as a prognostic biomarker and potential therapeutic target.

Despite showing promise against PIK3CA-mutant breast cancers in preclinical studies, PI3K/AKT pathway inhibitors demonstrate limited clinical efficacy as monotherapy. Here, we found that histone H3K27me3 demethylase KDM6B-targeted IGFBP5 expression provides a protective mechanism for PI3K/AKT inhibitor-induced apoptosis in breast cancer cells. We found that overexpression of KDM6B and IGFBP5 in luminal breast cancer are positively associated with poorer disease outcomes. Mechanistically, KDM6B promotes IGFBP5 expression by antagonizing EZH2-mediated repression, and pharmacologic inhibition of KDM6B augments apoptotic response to PI3K/AKT inhibitor treatment. Moreover, the IGFBP5 expression is upregulated upon acquired resistance to the PI3K inhibitor GDC-0941, which is associated with an epigenetic switch from H3K27me3 to H3K27Ac at the IGFBP5 gene promoter. Intriguingly, GDC-0941–resistant breast cancer cells remained sensitive to KDM6B or IGFBP5 inhibition, indicating the dependency on the KDM6B–IGFBP5 axis to confer the survival advantage in GDC-0941–resistant cells. Our study reveals an epigenetic mechanism associated with resistance to targeted therapy and demonstrates that therapeutic targeting of KDM6B-mediated IGFBP5 expression may provide a useful approach to mitigate both intrinsic and acquired resistance to the PI3K inhibitor in breast cancer. Mol Cancer Ther; 17(9); 1973–83. ©2018 AACR.

Polydatin (PD), a natural precursor of resveratrol, has been used to treat several diseases, such as cardiovascular diseases, hepatic diseases and various cancers. In this study, we aimed to investigate the protective effects and underlying mechanisms of PD on non-alcoholic fatty liver disease (NAFLD) using a high fat induced obese mice model. The studied subjects were randomly divided into a lean group, a high fat diet (HFD) group, and a high fat diet with PD (HFD + PD) group. The results showed that PD reduced the body weights in HFD mice. PD also downregulated the serum levels of triglyceride (TG), low density lipoprotein (LDL), aspartate aminotransferase (AST) and alanine aminotransferase (ALT), and upregulated high density lipoprotein (HDL). Moreover, PD significantly alleviated hepatocyte steatosis and reduced Gr-1+ cells in the liver tissues of HFD mice. The mRNA levels of pro-inflammatory factors, such as monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), S100A8 and S100A9 were significantly decreased in the liver tissues of HFD mice with PD treatment, and the downregulation of MCP-1 and S100A9 protein expressions was also observed. In conclusion, PD had beneficial roles in suppressing lipid accumulation in hepatocytes and anti-inflammatory responses in the liver tissue of obese associated NAFLD.

In the present study, knockdown of E2F1 impaired the migration and invasion of osteosarcoma cells. Further analysis showed that E2F1 knockdown decreased the expression of discoidin domain receptor 1 (DDR1) which plays a crucial role in many fundamental processes such as cell differentiation, adhesion, migration and invasion. Luciferase and ChIP assays confirmed that E2F1 silencing attenuated the expression of DDR1 through disrupting E2F1-mediated transcription of DDR1 in osteosarcoma cells. Similarly with the effect of E2F1 silencing, DDR1 knockdown weakened the migratory and invasive capabilities of osteosarcoma cells; while overexpression of DDR1 resulted in a significant increase of cell motility and invasiveness, even after knocking down E2F1. Interestingly, inactivation of E2F1/DDR1 pathway by shRNA weakened STAT3 signaling and subsequently suppressed the epithelial-mesenchymal transition (EMT) of osteosarcoma cells, as shown with decreased vimentin, MMP2, MMP9, and increased E‑cadherin. Consistently, high expressions of E2F1 and DDR1 observed in osteosarcoma tissues were related to TNM stage and metastasis. In addition, high level of E2F1 or DDR1 was associated with poor prognosis in osteosarcoma patients. These results suggest that E2F1/DDR1/STAT3 pathway is critical for malignancy of osteosarcoma, which may provide a novel prognostic indicator or approach for osteosarcoma therapy.

// Hai-Song Tan 1, * , Wei-Hua Jiang 2, * , Yi He 3, * , De-Sheng Wang 4, * , Zhen-Jie Wu 1 , Deng-Shuang Wu 1 , Li Gao 5 , Yi Bao 1 , Jia-Zi Shi 1 , Bing Liu 1 , Li-Jun Ma 2 and Lin-Hui Wang 1 1 Department of Urology, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China 2 Department of Oncology, Shanghai Tongren Hospital, Shanghai Jiaotong University, Shanghai 200336, China 3 Department of Urology, Jiaxing First Hospital, Zhejiang 314000, China 4 Department of Urology, Second People's Hospital of Bengbu City, Anhui 233000, China 5 Department of Pathology, Changhai Hospital, Second Military Medical University, Shanghai 200433, China * These authors have contributed equally to this work Correspondence to: Lin-Hui Wang, email: wanglinhuicz@163.com Li-Jun Ma, email: lijun.ma@shtrhospital.com Bing Liu, email: 13501616398@163.com Keywords: clear cell renal cell carcinoma, metastasis, KRT8, IL-11, biomarker Received: January 17, 2017 Accepted: June 19, 2017 Published: July 12, 2017 ABSTRACT Keratin 8 (KRT8) plays an essential role in the development and metastasis of multiple human cancers. However, its role in clear cell renal cell carcinoma (ccRCC) remains unexplored. Here, we investigated the expression pattern, clinical significance, and function of KRT8 in ccRCC. KRT8 mRNA and protein levels were determined in two large cohorts using quantitative real-time polymerase chain reaction (qRT-PCR) and tissue microarray (TMA) immunohistochemistry (IHC), respectively. We found that KRT8 expression was upregulated in ccRCC and vein tumor thrombi (VTTs). KRT8 overexpression in ccRCC was significantly correlated with aggressive characteristics and was predictive of a poor prognosis in ccRCC patients. Moreover, KRT8 overexpression in renal cancer cell lines promoted cell migration and invasion. In contrast, KRT8 knockdown suppressed ccRCC metastasis both in vitro and in vivo . In addition, our findings showed that KRT8 promoted ccRCC metastasis by increasing IL-11 expression, causing IL-11 autocrine induction, and triggering STAT3 signaling. Overall, this study established the significance of KRT8-IL-11 axis activation in aggressive ccRCC and defined a novel critical signaling mechanism that drives human ccRCC invasion and metastasis.

Background Recent evidences showed that long noncoding RNAs (lncRNAs) are frequently dysregulated and play important roles in various cancers. Clear cell renal cell carcinoma (ccRCC) is one of the leading cause of cancer-related death, largely due to the metastasis of ccRCC. However, the clinical significances and roles of lncRNAs in metastatic ccRCC are still unknown. Methods lncRNA expression microarray analysis was performed to search the dysregulated lncRNA in metastatic ccRCC. quantitative real-time PCR was performed to measure the expression of lncRNAs in human ccRCC samples. Gain-of-function and loss-of-function experiments were performed to investigate the biological roles of lncRNAs on ccRCC cell proliferation, migration, invasion and in vivo metastasis. RNA pull-down, RNA immunoprecipitation, chromatin immunoprecipitation, and western blot were performed to explore the molecular mechanisms underlying the functions of lncRNAs. Results The microarray analysis identified a novel lncRNA termed metastatic renal cell carcinoma-associated transcript 1 (MRCCAT1), which is highly expressed in metastatic ccRCC tissues and associated with the metastatic properties of ccRCC. Multivariate Cox regression analysis revealed that MRCCAT1 is an independent prognostic factor for ccRCC patients. Overexpression of MRCCAT1 promotes ccRCC cells proliferation, migration, and invasion. Depletion of MRCCAT1 inhibites ccRCC cells proliferation, migration, and invasion in vitro, and ccRCC metastasis in vivo. Mechanistically, MRCCAT1 represses NPR3 transcription by recruiting PRC2 to NPR3 promoter, and subsequently activates p38-MAPK signaling pathway. Conclusions MRCCAT1 is a critical lncRNA that promotes ccRCC metastasis via inhibiting NPR3 and activating p38-MAPK signaling. Our results imply that MRCCAT1 could serve as a prognostic biomarker and therapeutic target for ccRCC. Electronic supplementary material The online version of this article (doi:10.1186/s12943-017-0681-0) contains supplementary material, which is available to authorized users.

MitoTEMPO, a mitochondrial antioxidant, has protective effects on liver-related diseases. However, the role of MitoTEMPO on nonalcoholic fatty liver disease (NAFLD) and its possible mechanisms are largely unknown. Here, we investigated the effects of MitoTEMPO on NAFLD using high fat diet- (HFD-) induced obese mice as animal models. MitoTEMPO was intraperitoneally injected into HFD mice. Liver morphological changes were observed by H&E and Oil Red O staining, and the frequency of MDSCs in peripheral blood was analyzed by flow cytometry. Moreover, real-time quantitative PCR, western blot, and immunohistochemistry were conducted to detect the mRNA and protein expressions in the liver tissues. The results showed that the hepatic steatosis in liver tissues of HFD mice injected with MitoTEMPO was significantly ameliorated. Additionally, MitoTEMPO reduced the frequency of CD11b+Gr-1+ MDSCs in peripheral circulation and decreased Gr-1+ cell accumulation in the livers. Further studies demonstrated that MitoTEMPO administration suppressed the mRNA and protein expressions of MDSC-associated proinflammatory mediators, such as monocyte chemoattractant protein-1 (MCP-1), S100 calcium-binding protein A8 (S100A8), and S100 calcium-binding protein A9 (S100A9). Our results suggest that MitoTEMPO appears to be a potential chemical compound affecting certain immune cells and further ameliorates inflammation in obese-associated NAFLD.

Resistance is a major concern when administering chemotherapy to patients with non-small cell lung cancer (NSCLC). Chemosensitizer are agents that can reverse resistance to chemotherapeutic drugs, thereby enhancing the chemosensitivity of tumor cells. Thus, their development will improve therapeutic efficacy in cancer. However, few effective chemosensitizer have been identified to date. Piperlongumine (PL) has been shown to effectively reverse resistance to chemotherapeutic drugs in several types of cancers. However, the mechanisms associated with the chemotherapy resistance reversal effect of PL and its regulation of target factors in chemotherapy resistance cells are still unclear. This study investigated the reversal effect of PL both in vitro and in vivo, and provided evidence that PL inhibited the phosphorylation of Akt via the accumulation of reactive oxygen species in chemotherapy resistance cells. Consequently, various Akt activation-dependent genes caused a reduction of drug efflux and induction of apoptosis in cisplatin-resistant A549 NSCLC cells. Our results indicate that Akt phosphorylation may play a functional role in the reversal effect of PL and contribute, at least in part, to the treatment outcomes of patients with chemotherapy resistance.

Circular RNAs (circRNAs) are reported to act as important regulators in cancers. CircRNA RAPGEF5 (cRAPGEF5) is derived from exons 2-6 of the RAPGEF5 gene and may promote papillary thyroid cancer progression. However, the role of cRAPGEF5 in renal cell carcinoma (RCC) remains unclear. In this study, we found cRAPGEF5 to be significantly downregulated in RCC tissues. Among 245 RCC cases, cRAPGEF5 downregulation correlated positively with aggressive clinical characteristics and independently predicted poor overall survival and recurrence-free survival. Functional assays demonstrated that cRAPGEF5 suppresses RCC proliferation and migration in vitro and in vivo. Mechanistically, RNA Immunoprecipitation and circRNA in vivo precipitation assays showed that cRAPGEF5 functions as a sponge of oncogenic miR-27a-3p, which targets the suppressor gene TXNIP. Interactions between miR-27a-3p and cRAPGEF5 or TXNIP were confirmed by dual-luciferase reporter assays. In conclusion, cRAPGEF5 plays a role in suppressing RCC via the miR-27a-3p/TXNIP pathway and may serve as a promising prognostic biomarker and novel therapeutic target for RCC patients.

Angiopoietin-like proteins (ANGPTLs) comprise a group of proteins that are structurally similar to angiopoietins. In our previous studies, we found that ANGPTL3 can inhibit sorafenib resistance in renal cell carcinoma (RCC). According to bioinformatics analysis based on data in the Cancer Genome Atlas (TCGA), we found that expression of ANGPTL3 was significantly lower in RCC tissues than in adjacent tissues and that disease-free survival and overall survival were significantly shorter in patients with lower ANGPTL3 levels than in those with higher ANGPTL3 levels. Consistent with these results, we demonstrated that RCC tissues exhibited lower ANGPTL3 mRNA and protein expression levels than paired adjacent tissues. Moreover, we found that ANGPTL3 upregulation was associated with better clinical outcomes in RCC patients. ANGPTL3 overexpression inhibited the metastatic ability in RCC cells. Mechanistically, ANGPTL3 binds to vasodilator-stimulated phosphoprotein (VASP) and inhibits its phosphorylation at amino acid 157 in RCC cells. Finally, ANGPTL3 expression and VASP-157 phosphorylation may be combined to predict the prognosis of RCC patients. Overall, our findings describe the role of ANGPTL3 in inhibiting RCC metastasis and thus provide new molecular markers for RCC treatment and prognosis.

Hyperglycemia plays a major role in the development of diabetic macrovascular complications, including atherosclerosis and restenosis, which are responsible for the most of disability and mortality in diabetic patients. Osteopontin (OPN) is an important factor involved in atherogenesis, and hyperglycemia enhances the transcriptional activity of FoxO1 which is closely association with insulin resistance and diabetes. Here, we showed that plasma OPN levels were significantly elevated in type 2 diabetic patients and positively correlated with glycated albumin (GA). The more atherosclerotic lesions were observed in the aorta of diabetic ApoE−/− mice analyzed by Sudan IV staining. High glucose increased both the mRNA and protein expression levels of OPN and inhibited the phosphorylation of FoxO1 in RAW 264.7 cells. Overexpression of WT or constitutively active mutant FoxO1 promoted the expression levels of OPN, while the dominant-negative mutant FoxO1 decreased slightly the expression of OPN. Conversely, knockdown of FoxO1 reduced the expression of OPN. Luciferase reporter assay revealed that high glucose and overexpression of FoxO1 enhanced the activities of the OPN promoter region nt −1918 ~ −713. Furthermore, the interactions between FoxO1 and the OPN promoter were confirmed by electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation assay (ChIP). Our results suggest that high glucose upregulates OPN expression via FoxO1 activation, which would play a critical role in the development of diabetic atherogenesis.

Background Approximately 30-70% percent of patients with non-small cell lung cancer (NSCLC) still relapse after receiving complete resection and even suffer distant metastasis. Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have gradually replaced chemotherapy to become the first-line postoperative NSCLC treatment because they can effectively inhibit the postoperative recurrence of lung cancer. However, the clinical efficacy of neoadjuvant EGFR-TKIs in EGFR mutant NSCLC patients is still unclear. The purpose of this study was to evaluate their clinical efficacy and to further explore factors affecting recurrence in such patients. Methods EGFR-mutated patients receiving neoadjuvant EGFR-TKI treatment in our hospital from July 2016 to September 2020 were retrospectively included. These patients underwent radical tumor resection after treatment. The primary endpoint was the objective response rate (ORR). The secondary endpoints were the major pathological response (MPR), disease-free survival (DFS), and overall survival (OS). Results A total of 42 patients who met the inclusion criteria were included in this study. The ORR was 47.6% (20/42), and the MPR was 23.8% (10/42). The average follow-up time was 23.7 months. As of the final follow-up date, 18 (42.9%, 18/42) patients had experienced tumor recurrence. Of these, there were 11 (61.1%) cases of local recurrence and 7 (38.9%) cases of distant metastasis, including 5 bone metastases and 2 brain metastases. Multivariate Cox regression results showed that the high-risk subtype [P=0.012, hazard ratio (HR) =24.560; 95% confidence interval (CI), 2.016-299.227] was a risk factor for postoperative recurrence. Patients with a high-risk subtype (solid or micropapillary subtype) had significantly worse recurrence-free survival (RFS, log-rank P=0.032). Although patients with pathological remission had a similar RFS as patients who did not achieve pathological remission (log-rank P=0.069), the patients without pathological remission showed a tendency toward a worse prognosis. Conclusions Neoadjuvant EGFR-TKIs had good effects on EGFR-mutant NSCLC patients at different stages, especially those with MPR. Patients with high-risk subtypes (solid or micropapillary) should be closely followed up after surgery because of the high risk of recurrence.

Sepsis remains an unresolved clinical problem. Therapeutic strategies focusing on inhibition of neutrophils (polymorphonuclear neutrophils) have failed, which indicates that a more detailed understanding of the underlying pathophysiology of sepsis is required. Polymorphonuclear neutrophil activation and chemotaxis require cellular adenosine triphosphate release via pannexin-1 channels that fuel autocrine feedback via purinergic receptors. In the current study, we examined the roles of endogenous and systemic adenosine triphosphate on polymorphonuclear neutrophil activation and host defense in sepsis. Prospective randomized animal investigation and in vitro studies. Preclinical academic research laboratory. Wild-type C57BL/6 mice, pannexin-1 knockout mice, and healthy human subjects used to obtain polymorphonuclear neutrophils for in vitro studies. Wild-type and pannexin-1 knockout mice were treated with suramin or apyrase to block the endogenous or systemic effects of adenosine triphosphate. Mice were subjected to cecal ligation and puncture and polymorphonuclear neutrophil activation (CD11b integrin expression), organ (liver) injury (plasma aspartate aminotransferase), bacterial spread, and survival were monitored. Human polymorphonuclear neutrophils were used to study the effect of systemic adenosine triphosphate and apyrase on chemotaxis. Inhibiting endogenous adenosine triphosphate reduced polymorphonuclear neutrophil activation and organ injury, but increased the spread of bacteria and mortality in sepsis. By contrast, removal of systemic adenosine triphosphate improved bacterial clearance and survival in sepsis by improving polymorphonuclear neutrophil chemotaxis. Systemic adenosine triphosphate impairs polymorphonuclear neutrophil functions by disrupting the endogenous purinergic signaling mechanisms that regulate cell activation and chemotaxis. Removal of systemic adenosine triphosphate improves polymorphonuclear neutrophil function and host defenses, making this a promising new treatment strategy for sepsis.

Purpose Sepsis remains an unresolved clinical problem with high in-hospital mortality. Despite intensive research over decades, no treatments for sepsis have become available. Here we explore the role of ATP in the pathophysiology of sepsis. ATP is not only a universal energy carrier but it also acts as an extracellular signaling molecule that regulates immune function. ATP stimulates a large family of purinergic receptors found on the cell surface of virtually all mammalian cells. In severe sepsis and septic shock, ATP is released in large amounts into the extracellular space where it acts as a “danger” signal. In this review, we focus on the roles of ATP as a key regulator of immune cell function and as a disruptive signal that contributes to immune dysfunction in sepsis. Methods We summarized the current understanding of the pathophysiology of sepsis, with special emphasis on the emerging role of systemic ATP as a disruptive force that promotes morbidity and mortality in sepsis. Findings Over the past two decades, the discovery that regulated ATP release and purinergic signaling represent a novel regulatory mechanism in immune cell physiology has opened up new possibilities in the treatment of sepsis. Immune cells respond to stimulation with the release of cellular ATP, which regulates cell functions in autocrine and paracrine fashions. In sepsis, large amounts of systemic ATP produced by tissue damage and inflammation disrupt these regulatory purinergic signaling mechanisms, leading to immune dysfunction that promotes the pathophysiologic processes involved in sepsis. Implications The knowledge of these ATP-dependent signaling processes is likely to reveal exciting new avenues in the treatment of the unresolved clinical problem of sepsis.

Sunitinib resistance is a major challenge for advanced renal cell carcinoma (RCC). Understanding the underlying mechanisms and developing effective strategies against sunitinib resistance are highly desired in the clinic. Here we identified an lncRNA, named lncARSR (lncRNA Activated in RCC with Sunitinib Resistance), which correlated with clinically poor sunitinib response. lncARSR promoted sunitinib resistance via competitively binding miR-34/miR-449 to facilitate AXL and c-MET expression in RCC cells. Furthermore, bioactive lncARSR could be incorporated into exosomes and transmitted to sensitive cells, thus disseminating sunitinib resistance. Treatment of sunitinib-resistant RCC with locked nucleic acids targeting lncARSR or an AXL/c-MET inhibitor restored sunitinib response. Therefore, lncARSR may serve as a predictor and a potential therapeutic target for sunitinib resistance.

Renal cell carcinoma (RCC) is one of the most common malignancies in the urinary system. The study aimed to identify genetic characteristics and reveal the underlying mechanisms in RCC. GSE53757, GSE46699, and TCGA KIRC database (n = 897) were analyzed to screen differentially expressed genes (DEGs) in RCC. The gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed, followed by the analysis of the protein-protein interaction (PPI) network of the DEGs by Cytoscape software. In all, 834 DEGs were identified in RCC, including 416 upregulated genes and 418 downregulated genes. The top 10 hub genes, VEGFA, EGFR, EGF, CD44, CD86, FN1, ITGAM, ITGB2, TLR2, and PTPRC, were identified from the PPI network according to the core degree. The following subnetwork revealed that these significant modules were enriched in positive regulation of response to external stimulus, regulation of leukocyte-mediated immunity, and regulation of exocytosis. The expressions of these hub genes were also validated using qRT-PCR and IHC in Changzheng RCC database (n = 160). We especially found that half of the top ten hub genes were cell adhesion-related molecules, which were associated with RCC progression and poor prognosis. In conclusion, these hub genes, particularly cell adhesion-related molecules, could be used as prognostic biomarkers and potential therapeutic targets for RCC.

Background: Danshensu (DSS) possesses unique bioactivity on the cardiovascular system. However, there is a lack of systematical summary of DSS for acute myocardial ischemia injury and no quality assessment tool for the systematical review of cell experiments. Here, we aimed to assess the preclinical evidences and possible mechanisms of DSS for myocardial ischemia injury, and to develop a quality assessment tool for the systematical review of cell experiments. Methods: Thirty-two studies with 473 animals and 134 cells were identified by searching seven databases. All data analysis was performed using RevMan 5.3. CAMARADES 10-item checklist was used to assess the methodological quality of animal experiments. A new 10-item checklist was first developed to assess the methodological quality of cell studies. Results: The score of study quality ranged from 3 to 7 points in animal studies, while the cell studies scored 3–6 points. Meta-analysis showed that DSS had significant effects on reducing myocardial infarct (MI) size in vivo, and increasing cell viability and reducing apoptosis rate in vitro compared with controls (P < 0.01). The possible mechanisms of DSS for MI are improving circulation, antioxidant, anti-apoptosis, anti-inflammatory, promoting angiogenesis, anti-excessive autophagy, anti-calcium overload, and improving energy metabolism. Conclusions: DSS could exert cardioprotective effect on myocardial ischemia injury, and thus is a probable candidate for further clinical trials andtreatment of AMI. In addition, the newly devloped 10-item checklist for assessing methodological quality of cell study that recommened to use the sysmatic review of cell studies.

With the aim of discovering novel cyclin-dependent kinase 8 (CDK8) inhibitors, a combined similarity search and molecular docking approach was employed, which led to 32 hits. Biological tests led to the discovery of several novel submicromolar inhibitors. In particular, compound C768-0769 (ZC0201) showed good CDK8 inhibitory activity, and compound ZC0201 effectively suppressed HCT-116 colorectal cancer cell proliferation by inducing G1/S transition arrest. Furthermore, modulation of phosphorylated signal transducer and activator of transcription 1 (Ser 727) (STAT1SER727), a pharmacodynamic biomarker of CDK8 activity, demonstrated that ZC0201 may cause G1/S transition arrest through CDK8 activity inhibition. Due to its good cellular activity, ZC0201 may be an ideal lead compound for further modification as a potential cancer therapeutic agent.

Multidrug resistance (MDR) is a major concern when using chemotherapy for the treatment of patients with colorectal cancer. MDR modulators are agents that can reverse MDR and, thus, enhance the chemosensitivity of tumor cells. The development of MDR modulators can improve the therapeutic efficacies of MDR in cancer. However, few effective MDR modulators have been identified so far. Curcumin has been reported to be an effective compound in the reversal of MDR in colorectal cancer cells. However, the mechanisms associated with the reversal effect of curcumin on MDR and its regulation of target factors in MDR cells remain to be fully elucidated. 3-(4,5-dimethyl-2-thiazol)-2,5-diphenyltetrazolium bromide assays, flow cytometer apoptosis assays as well as mRNA and protein expression assays were performed in the present study, and the results confirmed the reversal effect of curcumin on HCT-8/5-Fu cells and provided evidence that activated nuclear factor erythroid 2-related factor (Nrf2) deficiency induced by the curcumin altered the B-cell lymphoma 2 (Bcl-2) associated X protein/Bcl-2 expression ratio, which led to the induction of apoptosis in HCT-8/5-Fu cells. These results indicated that Nrf2 may have a functional in the reversal effect of curcumin and contribute, at least in part, to the outcomes of chemotherapy in patients with MDR.

A growing body of evidence confirms that long non-coding RNAs (lncRNAs) have an important role in biological processes by regulating gene expression at multiple levels. Dysregulated lncRNAs may be potential prognostic biomarkers or targets for the development of cancer treatments. However, the prognostic role of an lncRNA signature in pancreatic cancer has not been investigated. Pancreatic cancer lncRNA expression profiles from The Cancer Genome Atlas (TCGA) were analyzed in the current study. The prognostic value of differentially expressed lncRNAs (DElncRNAs) was evaluated via the Kaplan-Meier method. A risk score model was established based on the potential prognostic lncRNAs. The biological functions of lncRNAs were predicted by functional enrichment analysis. Then, an lncRNA-mRNA co-expression network was established and predicted the function of the lncRNAs. Seven DElncRNAs that were significantly associated with the prognosis of pancreatic cancer were identified. Patients were classified into high-risk and low-risk groups using a risk score based on a three-lncRNA signature. There was a significant difference in overall survival (OS) between the groups (median OS 1.33 vs. 3.65 years; log-rank test, P=0.0000). Cox regression analysis and ROC curves demonstrated that the three-lncRNA signature may be an effective independent prognostic biomarker in patients with pancreatic. The functional enrichment analysis showed that lncRNA {"type":"entrez-nucleotide","attrs":{"text":"AL137789.1","term_id":"6982383","term_text":"AL137789.1"}}AL137789.1, one component of the three-lncRNA signature, may be associated with tumor immune responses. In the present study, a novel three-lncRNA signature that was established that may be useful in predicting survival among patients with pancreatic cancer. These lncRNAs may be involved in tumor immunity and thus affect the prognosis of patients.

Ligustrazine (Lig) is one of the main effective components of Ligusticum Chuanxiong Hort, which possesses a variety of biological activities in the cardiovascular system. Here, we conducted a preclinical systematic review to investigate the efficacy of Lig for animal models of myocardial ischemia/reperfusion injury and its possible mechanisms. Twenty-five studies involving 556 animals were identified by searching 6 databases from inception to August 2017. The methodological quality was assessed by using Collaborative Approach to Meta-Analysis and Review of Animal Data from Experimental Studies (CAMARADES) 10-item checklist. All the data were analyzed using Rev-Man 5.3 software. As a result, the score of study quality ranged from 2 to 6 points. Meta-analyses showed Lig can significantly decrease the myocardial infarct size, cardiac enzymes and troponin compared with control (P < 0.01). The possible mechanisms of Lig for myocardial infarction are antioxidant, anti-inflammatory, anti-apoptosis activities and improving coronary blood flow and myocardial metabolism. In conclusion, the findings indicated that Lig exerts cardio protection through multiple signaling pathways in myocardial ischemia/reperfusion injury.

Astragaloside IV (AS-IV), the major pharmacological extract from Astragalus membranaceus Bunge, possesses a variety of biological activities in the cardiovascular systems. Here, we aimed to evaluate preclinical evidence and possible mechanism of AS-IV for animal models of myocardial ischemia/reperfusion (I/R) injury. Studies of AS-IV in animal models with myocardial I/R injury were identified from 6 databases from inception to May, 2018. The methodological quality was assessed by using CAMARADES 10-item checklist. All the data were analyzed using Rev-Man 5.3 software. As a result, 22 studies with 484 animals were identified. The quality score of studies ranged from 3 to 6 points. Meta-analyses showed AS-IV can significantly decrease the myocardial infarct size and left ventricular ejection fraction, and increase shortening fraction compared with control group (P < 0.01). Significant decreasing of cardiac enzymes and cardiac troponin and increasing of decline degree in ST-segment were reported in one study each (P < 0.05). Additionally, the possible mechanisms of AS-IV for myocardial I/R injury are promoting angiogenesis, improving the circulation, antioxidant, anti-inflammatory and anti-apoptosis. Thus, AS-IV is a potential cardioprotective candidate for further clinical trials of myocardial infarction.

Colorectal cancer patients often relapse after chemotherapy, owing to the survival of stem or progenitor cells referred to as cancer stem cells (CSCs). Although tumor stromal factors are known to contribute to chemoresistance, it remains not fully understood how CSCs in the hypoxic tumor microenvironment escape the chemotherapy. Here, we report that hypoxia-inducible factor (HIF-1α) and cancer-associated fibroblasts (CAFs)-secreted TGF-β2 converge to activate the expression of hedgehog transcription factor GLI2 in CSCs, resulting in increased stemness/dedifferentiation and intrinsic resistance to chemotherapy. Genetic or small-molecule inhibitor-based ablation of HIF-1α/TGF-β2-mediated GLI2 signaling effectively reversed the chemoresistance caused by the tumor microenvironment. Importantly, high expression levels of HIF-1α/TGF-β2/GLI2 correlated robustly with the patient relapse following chemotherapy, highlighting a potential biomarker and therapeutic target for chemoresistance in colorectal cancer. Our study thus uncovers a molecular mechanism by which hypoxic colorectal tumor microenvironment promotes cancer cell stemness and resistance to chemotherapy and suggests a potentially targeted treatment approach to mitigating chemoresistance.

Stroke is the world's leading cause of physiological disability, but there are currently no available agents that can be delivered early after stroke to enhance recovery. Daidzein, a soy isoflavone, is a clinically approved agent that has a neuroprotective effectin vitro, and it promotes axon growth in an animal model of optic nerve crush. The current study investigates the efficacy of daidzein on neuroprotection and functional recovery in a clinically relevant mouse model of stroke recovery. In light of the fact that cholesterols are essential lipid substrates in injury-induced synaptic remodeling, we found that daidzein enhanced the cholesterol homeostasis genetic program, includingLxrand downstream transporters,Apoe,Abca1, andAbcg1genesin vitro. Daidzein also elevated the cholesterol homeostasis genes in the poststroke brain withApoe, the highest expressing transporter, but did not affect infarct volume or hemispheric swelling. Despite the absence of neuroprotection, daidzein improved motor/gait function in chronic stroke and elevated synaptophysin expression. However, the daidzein-enhanced functional benefits and synaptophysin expression were abolished inApoe-knock-out mice, suggesting the importance of daidzein-induced ApoE upregulation in fostering stroke recovery. Dissociation between daidzein-induced functional benefits and the absence of neuroprotection further suggest the presence of nonoverlapping mechanisms underlying recovery processes versus acute pathology. With its known safety in humans, early and chronic use of daidzein aimed at augmenting ApoE may serve as a novel, translatable strategy to promote functional recovery in stroke patients without adverse acute effect.SIGNIFICANCE STATEMENTThere have been recurring translational failures in treatment strategies for stroke. One underlying issue is the disparity in outcome analysis between animal and clinical studies. The former mainly depends on acute infarct size, whereas long-term functional recovery is an important outcome in patients. In an attempt to identify agents that promote functional recovery, we discovered that an FDA-approved soy isoflavone, daidzein, improved stroke-induced behavioral deficits via enhancing cholesterol homeostasis in chronic stroke, and this occurs without causing adverse effects in the acute phase. With its known safety in humans, the study suggests that the early and chronic use of daidzein serves as a potential strategy to promote functional recovery in stroke patients.

To evaluate intermediate-term oncologic and renal functional outcome of laparoendoscopic single-site radical nephrectomy (LESS-RN) in the treatment of localized kidney cancer.We performed a chart review of patients who underwent LESS-RN between 2009 and 2011 at our institution. Patients with a minimum of 3 years of follow-up were included in this study. The demographic data and main perioperative outcome variables were analyzed. Estimated glomerular filtration rate was calculated using the Modification of Diet Renal Disease equation. Upstaging of chronic kidney disease (CKD) was calculated. The Kaplan-Meier method was used to calculate overall survival (OS), cancer-specific survival (CSS), and cancer-free survival (CFS). Multivariate logistic regression was performed to show predicting factors for an undesirable outcome arbitrarily defined as any one or more of the following events: surgical conversion, complication of Clavien grade2, new onset of CKD stages ≥3 at the latest follow-up, or cancer recurrence or metastasis.A total of 51 patients were included with a median follow-up of 41 (interquartile range: 38-45) months. The OS, CSS, and CFS rates at 3 years were 100%, 100%, and 98%, respectively. There was a 74.5% (38/51) upstaging of CKD at the latest follow-up, with 22 patients (43.1%) who developed a new onset of CKD stages ≥3. Multivariate analysis showed that patient age, body mass index, Charlson comorbidity index, early surgeon experience, and follow-up duration (all p 0.05) have increased the odds of an undesirable outcome.For localized kidney cancer, LESS-RN is effective in oncologic control at an intermediate follow-up interval but, similar to other kinds of RN technique, it is associated with worsened renal functional outcomes.