Fourth Affiliated Hospital of Harbin Medical University

In recent decades, with the continuous development of high-throughput sequencing technology, data volume in medical research has increased, at the same time, almost all clinical researchers have their own independent omics data, which provided a better condition for data mining and a deeper understanding of gene functions. However, for these large amounts of data, many common and cutting-edge effective bioinformatics research methods still cannot be widely used. This has encouraged the establishment of many analytical platforms, a portion of databases or platforms were designed to solve the special analysis needs of users, for instance, MG RAST, IMG/M, Qiita, BIGSdb, and TRAPR were developed for specific omics research, and some databases or servers provide solutions for special problems solutions. Metascape was designed to only provide functional annotations of genes as well as function enrichment analysis; BioNumerics and RidomSeqSphere+ perform multilocus sequence typing; CARD provides only antimicrobial resistance annotations. Additionally, some web services are outdated, and inefficient interaction often fails to meet the needs of researchers, such as our previous versions of the platform. Therefore, the demand to complete massive data processing tasks urgently requires a comprehensive bioinformatics analysis platform. Hence, we have developed a website platform, Sangerbox 3.0 (http://vip.sangerbox.com/), a web-based tool platform. On a user-friendly interface that also supports differential analysis, the platform provides interactive customizable analysis tools, including various kinds of correlation analyses, pathway enrichment analysis, weighted correlation network analysis, and other common tools and functions, users only need to upload their own corresponding data into Sangerbox 3.0, select required parameters, submit, and wait for the results after the task has been completed. We have also established a new interactive plotting system that allows users to adjust the parameters in the image; moreover, optimized plotting performance enables users to adjust large-capacity vector maps on the web site. At the same time, we have integrated GEO, TCGA, ICGC, and other databases and processed data in batches, greatly reducing the difficulty to obtain data and improving the efficiency of bioimformatics study for users. Finally, we also provide users with rich sources of bioinformatics analysis courses, offering a platform for researchers to share and exchange knowledge.

Chemodynamic therapy (CDT) employs Fenton catalysts to kill cancer cells by converting intracellular H2O2 into hydroxyl radical (•OH), but endogenous H2O2 is insufficient to achieve satisfactory anticancer efficacy. Despite tremendous efforts, engineering CDT agents with specific and efficient H2O2 self-supplying ability remains a great challenge. Here, we report the fabrication of copper peroxide (CP) nanodot, which is the first example of a Fenton-type metal peroxide nanomaterial, and its use as an activatable agent for enhanced CDT by self-supplying H2O2. The CP nanodots were prepared through coordination of H2O2 to Cu2+ with the aid of hydroxide ion, which could be reversed by acid treatment. After endocytosis into tumor cells, acidic environment of endo/lysosomes accelerated the dissociation of CP nanodots, allowing simultaneous release of Fenton catalytic Cu2+ and H2O2 accompanied by a Fenton-type reaction between them. The resulting •OH induced lysosomal membrane permeabilization through lipid peroxidation and thus caused cell death via a lysosome-associated pathway. In addition to pH-dependent •OH generation property, CP nanodots with small particle size showed high tumor accumulation after intravenous administration, which enabled effective tumor growth inhibition with minimal side effects in vivo. Our work not only provides the first paradigm for fabricating Fenton-type metal peroxide nanomaterials, but also presents a new strategy to improve CDT efficacy.

Abstract There exist differences in the epidemiological characteristics, clinicopathological features, tumor biological characteristics, treatment patterns, and drug selections between gastric cancer patients from the Eastern and Western countries. The Chinese Society of Clinical Oncology (CSCO) has organized a panel of senior experts specializing in all sub‐specialties of gastric cancer to compile a clinical guideline for the diagnosis and treatment of gastric cancer since 2016 and renews it annually. Taking into account regional differences, giving full consideration to the accessibility of diagnosis and treatment resources, these experts have conducted expert consensus judgment on relevant evidence and made various grades of recommendations for the clinical diagnosis and treatment of gastric cancer to reflect the value of cancer treatment and meeting health economic indexes in China. The 2021 CSCO Clinical Practice Guidelines for Gastric Cancer covers the diagnosis, treatment, follow‐up, and screening of gastric cancer. Based on the 2020 version of the CSCO Chinese Gastric Cancer guidelines, this updated guideline integrates the results of major clinical studies from China and overseas for the past year, focused on the inclusion of research data from the Chinese population for more personalized and clinically relevant recommendations. For the comprehensive treatment of non‐metastatic gastric cancer, attentions were paid to neoadjuvant treatment. The value of perioperative chemotherapy is gradually becoming clearer and its recommendation level has been updated. For the comprehensive treatment of metastatic gastric cancer, recommendations for immunotherapy were included, and immune checkpoint inhibitors from third‐line to the first‐line of treatment for different patient groups with detailed notes are provided.

Importance: Late recurrence (more than 2 years) after liver resection for hepatocellular carcinoma (HCC) is generally considered as a multicentric tumor or a de novo cancer. Objective: To investigate the risk factors, patterns, and outcomes of late recurrence after curative liver resection for HCC. Design, Setting, and Participants: This study was a multicenter retrospective analysis of patients who underwent curative liver resection for HCC at 6 hospitals in China from January 2001 to December 2015. Among 734 patients who were alive and free of recurrence at 2 years after resection, 303 patients developed late recurrence. Data were analyzed from June 2017 to February 2018. Interventions: Liver resection for HCC. Main Outcomes and Measures: Risk factors of late recurrence as well as patterns, treatments, and long-term outcomes of patients with late recurrence. Univariate and multivariate Cox regression analyses were performed to identify independent risk factors of late recurrence. Results: Of the included 734 patients, 652 (88.8%) were male, and the mean (SD) age was 51.0 (10.3) years. At a median (interquartile range) follow-up of 78.0 (52.8-112.5) months, 303 patients (41.3%) developed late recurrence. Multivariate analysis revealed that male sex, cirrhosis, multiple tumors, satellite nodules, tumor size greater than 5 cm, and macroscopic and microscopic vascular invasion were independent risk factors of late recurrence. Of the 303 patients with late recurrence, 273 (90.1%) had only intrahepatic recurrence, 30 (9.9%) had both intrahepatic and extrahepatic recurrence, and none had only extrahepatic recurrence. Potentially curative treatments were given to 165 of 303 patients (54.5%) with late recurrence, which included reresection, transplant, and local ablation. Multivariate Cox regression analysis showed that regular surveillance for postoperative recurrence (hazard ratio [HR], 0.470; 95% CI, 0.310-0.713; P = .001), cirrhosis (HR, 1.381; 95% CI, 1.049-1.854; P = .02), portal hypertension (HR, 2.424; 95% CI, 1.644-3.574; P < .001), Child-Pugh grade of B or C (HR, 1.376; 95% CI, 1.153-1.674; P < .001), Barcelona Clinic Liver Cancer stage B (HR, 1.304; 95% CI, 1.007-1.708; P = .04) and stage C (HR, 2.037; 95% CI, 1.583-2.842; P < .001), and potentially curative treatment (HR, 0.443; 95% CI, 0.297-0.661; P < .001) were independent predictors of overall survival for patients with late recurrence. Conclusions and Relevance: Late recurrence after HCC resection was associated with sex, cirrhosis, and several aggressive tumor characteristics of the initial HCC. The patterns of late recurrence suggested surveillance for recurrence after 2 years of surgery should be targeted to the liver. Postoperative surveillance improved the chance of potentially curative treatments, with improved survival outcomes in patients with late recurrence.

BACKGROUND: In December 2019, a series of pneumonia cases of unknown cause emerged in Wuhan, Hubei, China. In this study, we investigate the clinical and laboratory features and short-term outcomes of patients with coronavirus disease 2019 (COVID-19). METHODS: All patients with COVID-19 admitted to Wuhan University Zhongnan Hospital in Wuhan, China, between 3 January and 1 February 2020 were included. All those patients were with laboratory-confirmed infections. Epidemiological, clinical, and radiological characteristics; underlying diseases; laboratory tests; treatments; complications; and outcomes data were collected. Outcomes were followed up at discharge until 15 February 2020. RESULTS: The study cohort included 102 adult patients. The median age was 54 years (interquartile ranger, 37-67 years), and 48.0% were female. A total of 34 patients (33.3%) were exposed to a source of transmission in the hospital setting (as health-care workers, patients, or visitors) and 10 patients (9.8%) had a familial cluster. There were 18 patients (17.6%) who were admitted to the intensive care unit (ICU), and 17 patients died (mortality, 16.7%; 95% confidence interval, 9.4-23.9%). Those patients who survived were younger, were more likely to be health-care workers, and were less likely to suffer from comorbidities. They were also less likely to suffer from complications. There was no difference in drug treatment rates between the survival and nonsurvival groups. Those patients who survived were less likely to require admission to the ICU (14.1% vs 35.3% of those admitted). Chest imaging examinations showed that patients who died were more likely to have ground-glass opacity (41.2% vs 12.9% in survivors). CONCLUSIONS: The mortality rate was high among the COVID-19 patients described in our cohort who met our criteria for inclusion in this analysis. The patient characteristics seen more frequently in those who died were the development of systemic complications following onset of the illness and a severity of disease requiring admission to the ICU. Our data support those described by others indicating that COVID-19 infection results from human-to-human transmission, including familial clustering of cases, and from nosocomial transmission. There were no differences in mortality among those who did or did not receive antimicrobial or glucocorticoid drug treatments.

The effect of nanoparticle size (30-120 nm) on magnetic resonance imaging (MRI) of hepatic lesions in vivo has been systematically examined using polyvinylpyrrolidone (PVP)-coated iron oxide nanoparticles (PVP-IOs). Such biocompatible PVP-IOs with different sizes were synthesized by a simple one-pot pyrolysis method. These PVP-IOs exhibited good crystallinity and high T(2) relaxivities, and the relaxivity increased with the size of the magnetic nanoparticles. It was found that cellular uptake changed with both size and surface physiochemical properties, and that PVP-IO-37 with a core size of 37 nm and hydrodynamic particle size of 100 nm exhibited higher cellular uptake rate and greater distribution than other PVP-IOs and Feridex. We systematically investigated the effect of nanoparticle size on MRI of normal liver and hepatic lesions in vivo. The physical and chemical properties of the nanoparticles influenced their pharmacokinetic behavior, which ultimately determined their ability to accumulate in the liver. The contrast enhancement of PVP-IOs within the liver was highly dependent on the overall size of the nanoparticles, and the 100 nm PVP-IO-37 nanoparticles exhibited the greatest enhancement. These results will have implications in designing engineered nanoparticles that are optimized as MR contrast agents or for use in therapeutics.

CircRNAs are a class of endogenous RNA that regulates gene expression at the post-transcriptional or transcriptionallevel through interacting with other molecules or microRNAs. Increasing studies have demonstrated that circRNAs play a crucial role in biology processes. CircRNAs are proved as potentialbiomarkers in many diseases including cancers. However, the role of Cdr1as in Hepatocellular carcinoma (HCC) remains to be elucidated. We demonstrated that Cdr1as expression was upregulated in HCC tissues compared with the adjacent non-tumor tissues. In addtion, miR-7 expression was downregulated in HCC tissues compared with the adjacent non-tumor tissues. Moreover, the expression level of miR-7 was inversely correlated with that in HCC tissues. Knockdown of Cdr1as suppressed the HCC cell proliferation and invasion. Overexpression of miR-7 inhibited the HCC cell proliferation and invasion. Overexpression of miR-7 could suppress the direct target gene CCNE1 and PIK3CD expression. Knockdown of Cdr1as suppressed the expression of miR-7 and also inhibited the CCNE1 and PIK3CD expression. Furthermore, knockdown of Cdr1as suppressed the HCC cell proliferation and invasion through targeting miR-7. These data suggested that Cdr1as acted as an oncogene partly through targeting miR-7 in HCC.

Photodynamic therapy is a promising treatment method, but its applications are limited by the shallow penetration of visible light. Here, we report a novel X-ray inducible photodynamic therapy (X-PDT) approach that allows PDT to be regulated by X-rays. Upon X-ray irradiation, the integrated nanosystem, comprised of a core of a nanoscintillator and a mesoporous silica coating loaded with photosensitizers, converts X-ray photons to visible photons to activate the photosensitizers and cause efficient tumor shrinkage.

The 2023 update of the Chinese Society of Clinical Oncology (CSCO) Clinical Guidelines for Gastric Cancer focuses on standardizing cancer diagnosis and treatment in China, reflecting the latest advancements in evidence-based medicine, healthcare resource availability, and precision medicine. These updates address the differences in epidemiological characteristics, clinicopathological features, tumor biology, treatment patterns, and drug selections between Eastern and Western gastric cancer patients. Key revisions include a structured template for imaging diagnosis reports, updated standards for molecular marker testing in pathological diagnosis, and an elevated recommendation for neoadjuvant chemotherapy in stage III gastric cancer. For advanced metastatic gastric cancer, the guidelines introduce new recommendations for immunotherapy, anti-angiogenic therapy and targeted drugs, along with updated management strategies for human epidermal growth factor receptor 2 (HER2)-positive and deficient DNA mismatch repair (dMMR)/microsatellite instability-high (MSI-H) patients. Additionally, the guidelines offer detailed screening recommendations for hereditary gastric cancer and an appendix listing drug treatment regimens for various stages of gastric cancer. The 2023 CSCO Clinical Guidelines for Gastric Cancer updates are based on both Chinese and international clinical research and expert consensus to enhance their applicability and relevance in clinical practice, particularly in the heterogeneous healthcare landscape of China, while maintaining a commitment to scientific rigor, impartiality, and timely revisions.

BACKGROUND: Circular RNAs (circRNAs) are a novel type of noncoding RNAs and play important roles in tumorigenesis, including gastric cancer (GC). However, the functions of most circRNAs remain poorly understood. In our study, we aimed to investigate the functions of a new circRNA circ-DONSON in GC progression. METHODS: The expression of circ-DONSON in gastric cancer tissues and adjacent normal tissues was analyzed by bioinformatics method, qRT-PCR, Northern blotting and in situ hybridization (ISH). The effects of circ-DONSON on GC cell proliferation, apoptosis, migration and invasion were measured by using CCK8, colony formation, EdU, immunofluorescence (IF), FACS and Transwell assays. qRT-PCR and Western blotting were utilized to validate how circ-DONSON regulates SOX4 expression. ChIP, DNA fluorescence in situ hybridization (DNA-FISH) and DNA accessibility assays were used to investigate how circ-DONSON regulates SOX4 transcription. The interaction between circ-DONSON and NURF complex was evaluated by mass spectrum, RNA immunoprecipitation (RIP), pulldown and EMSA assays. Xenograft mouse model was used to analyze the effect of circ-DONSON on GC growth in vivo. RESULTS: Elevated expression of circ-DONSON was observed in GC tissues and positively associated with advanced TNM stage and unfavorable prognosis. Silencing of circ-DONSON significantly suppressed the proliferation, migration and invasion of GC cells while promoting apoptosis. circ-DONSON was localized in the nucleus, recruited the NURF complex to SOX4 promoter and initiated its transcription. Silencing of the NURF complex subunit SNF2L, BPTF or RBBP4 similarly attenuated GC cell growth and increased apoptosis. circ-DONSON knockdown inhibited GC growth in vivo. CONCLUSION: circ-DONSON promotes GC progression through recruiting the NURF complex to initiate SOX4 expression.

Gliomas are the most common type of primary brain tumor in the central nervous system of adults. Maternally Expressed Gene 3 (MEG3) is an imprinted gene located at 14q32 that encodes a non-coding RNA (ncRNA) associated with tumorigenesis. However, little is known about whether and how MEG3 regulates glioma development. In the present study we assayed the expression of MEG3 in glioma tissue samples by real-time polymerase chain reaction assay, and defined the biological functions and target genes by CCK-8 assay, flow cytometry, and RNA immunoprecipitation. We first demonstrated that MEG3 expression was markedly decreased in glioma tissues compared with adjacent normal tissues. Moreover, ectopic expression of MEG3 inhibited cell proliferation and promoted cell apoptosis in U251 and U87 MG human glioma cell lines. We further verified that MEG3 was associated with p53 and that this association was required for p53 activation. These data suggest an important role of MEG3 in the molecular etiology of glioma and implicate the potential application of MEG3 in glioma therapy.

This article is the series of methodology of clinical prediction model construction (total 16 sections of this methodology series). The first section mainly introduces the concept, current application status, construction methods and processes, classification of clinical prediction models, and the necessary conditions for conducting such researches and the problems currently faced. The second episode of these series mainly concentrates on the screening method in multivariate regression analysis. The third section mainly introduces the construction method of prediction models based on Logistic regression and Nomogram drawing. The fourth episode mainly concentrates on Cox proportional hazards regression model and Nomogram drawing. The fifth Section of the series mainly introduces the calculation method of C-Statistics in the logistic regression model. The sixth section mainly introduces two common calculation methods for C-Index in Cox regression based on R. The seventh section focuses on the principle and calculation methods of Net Reclassification Index (NRI) using R. The eighth section focuses on the principle and calculation methods of IDI (Integrated Discrimination Index) using R. The ninth section continues to explore the evaluation method of clinical utility after predictive model construction: Decision Curve Analysis. The tenth section is a supplement to the previous section and mainly introduces the Decision Curve Analysis of survival outcome data. The eleventh section mainly discusses the external validation method of Logistic regression model. The twelfth mainly discusses the in-depth evaluation of Cox regression model based on R, including calculating the concordance index of discrimination (C-index) in the validation data set and drawing the calibration curve. The thirteenth section mainly introduces how to deal with the survival data outcome using competitive risk model with R. The fourteenth section mainly introduces how to draw the nomogram of the competitive risk model with R. The fifteenth section of the series mainly discusses the identification of outliers and the interpolation of missing values. The sixteenth section of the series mainly introduced the advanced variable selection methods in linear model, such as Ridge regression and LASSO regression.

BACKGROUND: Workplace violence (WPV) is a global public health problem and has caused a serious threat to the physical and mental health of healthcare workers. Moreover, WPV also has an adverse effect on the workplace behavior of healthcare workers. This study has three purposes: (1) to identify the prevalence of workplace violence against physicians; (2) to examine the association between exposure to WPV, job satisfaction, job burnout and turnover intention of Chinese physicians and (3) to verify the mediating role of social support. METHODS: A cross-sectional study adopted a purposive sampling method to collect data from March 2017 through May 2017. A total of nine tertiary hospitals in four provinces, which provide healthcare from specialists in a large hospital after referral from primary and secondary care, were selected as research sites based on their geographical locations in the eastern, central and western regions of China. Descriptive analyses, a univariate analysis, a Pearson correlation, and a mediation regression analysis were used to estimate the prevalence of WPV and impact of WPV on job satisfaction, job burnout, and turnover intention. RESULTS: WPV was positively correlated with turnover intention (r = 0.238, P < 0.01) and job burnout (r = 0.150, P < 0.01), and was negatively associated with job satisfaction (r = - 0.228, P < 0.01) and social support (r = - 0.077, P < 0.01). Social support was a partial mediator between WPV and job satisfaction, as well as burnout and turnover intention. CONCLUSIONS: The results show a high prevalence of workplace violence in Chinese tertiary hospitals, which should not be ignored. The effects of social support on workplace behaviors suggest that it has practical implications for interventions to promote the stability of physicians' teams. TRIAL REGISTRATION: (Project Identification Code: HMUIRB2014005), Registered March 1, 2014.

Mesenchymal stem cells (MSCs) have been reported to hold promise to accelerate the wound-healing process in diabetic foot ulcer (DFU) due to the multilineage differentiation potential. Hence, this study intended to explore the wound healing role of MSC-derived exosomes containing long noncoding RNA (lncRNA) H19 in DFU. lncRNA H19 was predicated to bind to microRNA-152-3p (miR-152-3p), which targeted phosphatase and tensin homolog (PTEN) deleted on chromosome ten. Fibroblasts in DFU samples exhibited highly expressed miR-152-3p and poorly expressed lncRNA H19 and PTEN, along with an activated phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/protein kinase B (Akt1) signaling pathway. The fibroblasts were cocultured with lncRNA H19-transfected MSCs and MSC-derived exosomes to assess the effect of the lncRNA H19/miR-152-3p/PTEN axis on the biological activities and inflammation in fibroblasts. Mouse models of DFU were developed by streptozotocin, which was injected with MSC-derived exosomes overexpressing lncRNA H19. lncRNA H19 in MSCs was transferred through exosomes to fibroblasts, the mechanism of which improved wound healing in DFU, corresponded to promoted fibroblast proliferation and migration, as well as suppressed apoptosis and inflammation. Wound healing in mice with DFU was facilitated following the injection of MSC-derived exosomes overexpressing lncRNA H19. Taken together, MSC-derived exosomal lncRNA H19 prevented the apoptosis and inflammation of fibroblasts by impairing miR-152-3p-mediated PTEN inhibition, leading to the stimulated wound-healing process in DFU.

Abstract Two major treatment strategies employed in non-small cell lung cancer, NSCLC, are tyrosine kinase inhibitors, TKIs, and immune checkpoint inhibitors, ICIs. The choice of strategy is based on heterogeneous biomarkers that can dynamically change during therapy. Thus, there is a compelling need to identify comprehensive biomarkers that can be used longitudinally to help guide therapy choice. Herein, we report a 18 F-FDG-PET/CT-based deep learning model, which demonstrates high accuracy in EGFR mutation status prediction across patient cohorts from different institutions. A deep learning score (EGFR-DLS) was significantly and positively associated with longer progression free survival (PFS) in patients treated with EGFR-TKIs, while EGFR-DLS is significantly and negatively associated with higher durable clinical benefit, reduced hyperprogression, and longer PFS among patients treated with ICIs. Thus, the EGFR-DLS provides a non-invasive method for precise quantification of EGFR mutation status in NSCLC patients, which is promising to identify NSCLC patients sensitive to EGFR-TKI or ICI-treatments.

There is considerable potential for integrating transarterial chemoembolization (TACE), programmed death-(ligand)1 (PD-[L]1) inhibitors, and molecular targeted treatments (MTT) in hepatocellular carcinoma (HCC). It is necessary to investigate the therapeutic efficacy and safety of TACE combined with PD-(L)1 inhibitors and MTT in real-world situations. In this nationwide, retrospective, cohort study, 826 HCC patients receiving either TACE plus PD-(L)1 blockades and MTT (combination group, n = 376) or TACE monotherapy (monotherapy group, n = 450) were included from January 2018 to May 2021. The primary endpoint was progression-free survival (PFS) according to modified RECIST. The secondary outcomes included overall survival (OS), objective response rate (ORR), and safety. We performed propensity score matching approaches to reduce bias between two groups. After matching, 228 pairs were included with a predominantly advanced disease population. Median PFS in combination group was 9.5 months (95% confidence interval [CI], 8.4-11.0) versus 8.0 months (95% CI, 6.6-9.5) (adjusted hazard ratio [HR], 0.70, P = 0.002). OS and ORR were also significantly higher in combination group (median OS, 19.2 [16.1-27.3] vs. 15.7 months [13.0-20.2]; adjusted HR, 0.63, P = 0.001; ORR, 60.1% vs. 32.0%; P < 0.001). Grade 3/4 adverse events were observed at a rate of 15.8% and 7.5% in combination and monotherapy groups, respectively. Our results suggest that TACE plus PD-(L)1 blockades and MTT could significantly improve PFS, OS, and ORR versus TACE monotherapy for Chinese patients with predominantly advanced HCC in real-world practice, with an acceptable safety profile.

// Hongli Zhao 1,* , Liyuan Guo 2,* , Hong Zhao 1,* , Jiaxin Zhao 3 , Hao Weng 4 and Bin Zhao 5 1 Department of Medical Oncology, The Third Affiliated Hospital of Harbin Medical University, Harbin, China 2 Department of Gynecological Oncology, The Third Affiliated Hospital of Harbin Medical University, Harbin, China 3 Department of Neurosurgery, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, China 4 Shanghai Jiaotong University Affiliated Sixth People&rsquo;s Hospital South Campus, Shanghai, China 5 Harbin Medical University, Daqing Campus, China * Authors contributed equally to this work and were co-first authors Correspondence: Bin Zhao, email: // Keywords : CXCR4, cancer, survival, prognostic biomarker, meta-analysis Received : November 23, 2014 Accepted : December 28, 2014 Published : December 31, 2014 Abstract C-X-C chemokine receptor 4 (CXCR4) is frequently over-expressed in various types of cancer; many agents against CXCR4 are in clinical development currently despite variable data for the prognostic impact of CXCR4 expression. Here eighty-five studies with a total of 11,032 subjects were included to explore the association between CXCR4 and progression-free survival (PFS) or overall survival (OS) in subjects with cancer. Pooled analysis shows that CXCR4 over-expression is significantly associated with poorer PFS (HR 2.04; 95% CI, 1.72-2.42) and OS (HR=1.94; 95% CI, 1.71-2.20) irrespective of cancer types. Subgroup analysis indicates significant association between CXCR4 and shorter PFS in hematological malignancy, breast cancer, colorectal cancer, esophageal cancer, renal cancer, gynecologic cancer, pancreatic cancer and liver cancer; the prognostic effects remained consistent across age, risk of bias, levels of adjustment, median follow-up period, geographical area, detection methods, publication year and size of studies. CXCR4 over-expression predicts unfavorable OS in hematological malignancy, breast cancer, colorectal cancer, esophageal cancer, head and neck cancer, renal cancer, lung cancer, gynecologic cancer, liver cancer, prostate cancer and gallbladder cancer; these effects were independence of age, levels of adjustment, publication year, detection methods and follow-up period. In conclusion, CXCR4 over-expression is associated with poor prognosis in cancer.

Abstract Immunotherapy has only limited efficacy against pancreatic ductal adenocarcinoma (PDAC) due to the presence of an immunosuppressive tumor-associated stroma. Here, we demonstrate an effective modulation of that stroma by irreversible electroporation (IRE), a local ablation technique that has received regulatory approval in the United States. IRE induces immunogenic cell death, activates dendritic cells, and alleviates stroma-induced immunosuppression without depleting tumor-restraining collagen. The combination of IRE and anti-programmed cell death protein 1 (anti-PD1) immune checkpoint blockade promotes selective tumor infiltration by CD8 + T cells and significantly prolongs survival in a murine orthotopic PDAC model with a long-term memory immune response. Our results suggest that IRE is a promising approach to potentiate the efficacy of immune checkpoint blockade in PDAC.

Here, we sought to explore the underlying role of interleukin (IL)-8 in neutrophil extracellular traps (NETs) formation during atherosclerosis (AS).The concentration of pro-inflammatory cytokines IL-8, IL-6 and IL-1β was determined by enzyme-linked immunosorbent assay (ELISA). NETs formation was evaluated by immunofluorescence and myeloperoxidase (MPO)-DNA complex ELISA. The mRNA levels of IL-8 and Toll-like receptor 9 (TLR9) were measured by quantitative real-time PCR (qRT-PCR). The phosphorylation levels of NF-κB p65 were detected by western blotting. The hematoxylin and eosin (H&E) staining of atherosclerotic lesion areas was performed in ApoE-deficiency mice.Results showed that patients with AS showed higher serum levels of IL-8, a pro-inflammatory cytokine and NETs. IL-8 interacted with its receptor CXC chemokine receptor 2 (CXCR2) on neutrophils, leading to the formation of NETs via Src and extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinases (MAPK) signaling to aggravate AS progression in vivo. PMA-induced NETosis directly upregulated the TLR9/NF-κB pathway in macrophages and subsequently initiated the release of IL-8.Our data reveal a neutrophil-macrophage interaction in AS progression, and indicate that NETs represent as a novel therapeutic target in treatment of AS and other cardiovascular diseases (CVD).

BACKGROUND: MicroRNAs (miRNAs) are important post-transcriptional regulators that have been demonstrated to play an important role in human diseases. Elucidating the associations between miRNAs and diseases at the systematic level will deepen our understanding of the molecular mechanisms of diseases. However, miRNA-disease associations identified by previous computational methods are far from completeness and more effort is needed. RESULTS: We developed a computational framework to identify miRNA-disease associations by performing random walk analysis, and focused on the functional link between miRNA targets and disease genes in protein-protein interaction (PPI) networks. Furthermore, a bipartite miRNA-disease network was constructed, from which several miRNA-disease co-regulated modules were identified by hierarchical clustering analysis. Our approach achieved satisfactory performance in identifying known cancer-related miRNAs for nine human cancers with an area under the ROC curve (AUC) ranging from 71.3% to 91.3%. By systematically analyzing the global properties of the miRNA-disease network, we found that only a small number of miRNAs regulated genes involved in various diseases, genes associated with neurological diseases were preferentially regulated by miRNAs and some immunological diseases were associated with several specific miRNAs. We also observed that most diseases in the same co-regulated module tended to belong to the same disease category, indicating that these diseases might share similar miRNA regulatory mechanisms. CONCLUSIONS: In this study, we present a computational framework to identify miRNA-disease associations, and further construct a bipartite miRNA-disease network for systematically analyzing the global properties of miRNA regulation of disease genes. Our findings provide a broad perspective on the relationships between miRNAs and diseases and could potentially aid future research efforts concerning miRNA involvement in disease pathogenesis.