bluuebunny/crossref_metadata_2025 huggingface dataset:
The Prognostic Value of Homocysteine in Acute Ischemic Stroke Patients: A Systematic Review and Meta-Analysis
Authors: Huang Shengming , Cai Jirui , Tian Yuejun
Published: February 2021

Background: This comprehensive meta-analysis aimed to assess whether an increased homocysteine (Hcy) level is an independent predictor of unfavorable outcomes in acute ischemic stroke (AIS) patients.

Methods: A comprehensive literature search was conducted up to August 1, 2020 to collect studies reporting Hcy levels in AIS patients. We analyzed all the data using Review Manager 5.3 software.

Results: Seventeen studies with 15,636 AIS patients were selected for evaluation. A higher Hcy level was associated with a poorer survival outcome (OR 1.43, 95% CI: 1.25–1.63). Compared with the AIS group, Hcy levels were significantly lower in the healthy control patients, with an SMD of 5.11 and 95% CI (1.87–8.35). Analysis of the different subgroups of AIS demonstrated significant associations between high Hcy levels and survival outcomes only in Caucasian and Asian patients. Moreover, whereas high Hcy levels were closely associated with gender, B12 deficiency, smoking, and patients who received tissue plasminogen activator treatment, no significant difference was found between increased Hcy levels and age, drinking, hypertension, diabetes mellitus, and hyperlipidemia. In addition, the cut-off value (20.0 μmol/L) might be an optimum cut-off index for AIS patients in clinical practice.

Conclusion: This meta-analysis reveals that the Hcy level may serve as an independent predictor for unfavorable survival outcomes in AIS patients, particularly in Caucasian and Asian AIS patients. Further studies can be conducted to clarify this relationship.
A Novel Insight Into Fecal Occult Blood Test for the Management of Gastric Cancer: Complication, Survival, and Chemotherapy Benefit After R0 Resection
Authors: Lu Jun , Xu Binbin , Xu Yu , Wu Yuan , Xie Jianwei , Wang Jiabin , Lin Jianxian , Chen Qiyue , Cao Longlong , Zheng Chaohui , Huang Changming , Li Ping
Published: February 2021

Background

Previous studies have shown that the all-cause mortality and non-colorectal cancer mortality of patients with fecal occult blood test (FOBT) positivity are significantly increased, implying that FOBT results may have more prognostic value.

Methods

Retrospective analysis was performed for gastric cancer (GC) patients who underwent R0 gastrectomy from July 2007 to July 2014 at our hospital. Propensity score matching (PSM) was used to reduce confounding bias and a computerized technique for the nearest available score matching without replacement was applied. The cumulative survival rate was calculated using the Kaplan-Meier method and a log-rank test. Cox proportional hazards regression and logistic regression was used to determine the independent prognostic factors associated with survival and postoperative complications, respectively. The expression level of tumor-associated macrophages (TAMs) and proinflammatory cytokines (TNF-α, IL-6) were evaluated by immunohistochemical (IHC).

Results

A total of 3,003 patients were included and 246 patients (8.2%) were in preoperative FOBT positive status. There was no significant difference in demographic data between preoperative FOBT positive and negative group after a 1:4 PSM. The overall postoperative complications, major complications, and anastomotic leakage were significantly higher in the preoperative FOBT-positive group than in the preoperative FOBT-negative group. Moreover, preoperative FOBT-positivity was an independent risk factor for 5-year overall survival (OS) (HR: 1.32, p = 0.005). For stage II/III patients, the postoperative adjuvant chemotherapy (PAC) benefit was found in preoperative FOBT-negative group (5-year OS: 49.9 vs. 36.8%, p = 0.001), whereas the PAC benefit was lost in preoperative FOBT-positive groups (5-year OS: 40.8 vs. 37.7% p = 0.896). Finally, IHC found that preoperative FOBT-positivity in patients was significantly associated with higher TAMs infiltration and higher expression of IL-6 and TNF-α in tumor tissues than in the preoperative FOBT-negative group.

Conclusion

As a simple and low-cost method, preoperative FOBT results can predict both complications and survival after R0 gastrectomy for GC. More importantly, stage II/III GC patients with FOBT-positive seem not benefit from PAC alone. Further exploration is warranted.
MicroRNA-142-3p Inhibits Tumorigenesis of Colorectal Cancer via Suppressing the Activation of Wnt Signaling by Directly Targeting to β-Catenin
Authors: Liu Peng , Cao Fuao , Sui Jinke , Hong Yonggang , Liu Qizhi , Gao XianHua , Gong Haifeng , Hao Liqiang , Lou Zheng , Zhang Wei
Published: February 2021

Background

Altered expression profile of microRNAs (miRNAs) was reported to be associated with colorectal cancer (CRC). The aims of this study are to identify the changed miRNAs in the plasma of CRC patients and explore the underlying mechanism of these miRNAs during tumorigenesis.

Methods

Plasma miRNA expression profiles were compared between healthy people and CRC patients. MiRNA expression was measured using quantitative real-time PCR. Colony formation and MTT assays were used to test cell proliferation. Luciferase assay, immunohistochemistry and Western blotting were employed to explore the molecular mechanism.

Results

MiR-142-3p level was found as the most significantly repressed miRNA in CRC patients. Overexpression of miR-142-3p dramatically repressed colony formation and cell proliferation of both HT29 and HCT116 cells while inhibition of miR-142-3p promoted those of the cells. Interestingly, overexpression of miR-142-3p reduced the level and nuclear accumulation of β-catenin. We further observed that miR-142-3p remarkably inhibited the transcriptional activity of β-catenin gene (CTNNB1). However, mutations in the predicted binding sites blocked this inhibition, suggesting that miR-142-3p may directly bind to the mRNA of β-catenin.

Conclusion

In conclusion, we identified miR-142-3p exerts its function as a tumor suppressor through blocking the activation of Wnt signaling by directly targeting to CTNNB1.
nab-Paclitaxel Plus Durvalumab in Patients With Previously Treated Advanced Stage Non-small Cell Lung Cancer (ABOUND.2L+)
Authors: Morgensztern Daniel , Dols Manuel Cobo , Ponce Aix Santiago , Postmus Pieter E. , Bennouna Jaafar , Fischer Jürgen R. , Juan-Vidal Oscar , Stewart David J. , Ardizzoni Andrea , Bhore Rafia , Wolfsteiner Marianne , Reck Martin , Talbot Denis , Govindan Ramaswamy , Ong Teng Jin
Published: February 2021

Background: The standard therapy for advanced stage non-small cell lung cancer (NSCLC) with no actionable gene alterations is a platinum-based chemotherapy doublet and immune checkpoint blocker (ICB), either concurrently or sequentially, followed by docetaxel at the time of tumor progression. However, more effective treatments are needed. We evaluated the nab-paclitaxel and durvalumab combination in patients with previously treated advanced stage NSCLC.

Methods: Patients with advanced stage NSCLC previously treated with one line of platinum-based doublet with or without an ICB and no activating EGFR mutations or ALK translocations received nab-paclitaxel 100 mg/m2 (days 1 and 8) plus durvalumab 1,125 mg (day 15) every 21 days. The primary endpoint was progression-free survival (PFS). Key secondary endpoints included overall survival (OS) and safety.

Results: Between February 2016 and December 2016, 79 patients were enrolled. The median age was 63 years. Most patients were males (68.4%), had non-squamous histology (69.6%), and had no prior ICB treatment (88.6%). The median PFS was 4.5 months; median OS was 10.1 months. A post hoc analysis of survival by prior ICB treatment revealed a median PFS and OS of 4.4 and 9.9 months, respectively, in ICB-naive patients and 6.9 months and not estimable, respectively, in patients previously treated with ICB. The most common treatment-emergent adverse events were asthenia (46.2%) and diarrhea (34.6%); four treatment-related deaths (5.1%) occurred.

Conclusions: The nab-paclitaxel and durvalumab combination is feasible and demonstrated antitumor activity without new safety signals. Additional studies using taxanes and ICB in patients with previously treated NSCLC are warranted.

Clinical Trial Registration:ClinicalTrials.gov registration (NCT02250326).

EudraCT number: 2014-001105-41
Reduction of Bladder Cancer Chemosensitivity Induced by the Effect of HOXA-AS3 as a ceRNA for miR-455-5p That Upregulates Notch1
Authors: Chen Dajin , Xie Shangzhi , Wu Ying , Cui Yu , Cai Ying , Lan Lan , Yang Hao , Chen Jianghua , Chen Wei
Published: February 2021

Chemoresistance is one of the main causes of recurrence in bladder cancer patients and leads to poor prognosis. Recently, long non-coding RNAs, like HOXA-AS3, have been reported to regulate chemoresistance in several types of cancer. In this study, we aimed to determine whether HOXA-AS3 can mediate cisplatin resistance in bladder cancer, and its potential mechanism of action. We determined the viability, proliferation, and apoptosis of bladder cancer cells using a CCK-8 assay, EdU staining, and flow cytometry, respectively. We used western blot analysis to assess the expression of markers of epithelial-mesenchymal transition (EMT) and Notch1. We then confirmed expression of these EMT-related markers by immunofluorescence analysis. We found that hypoxia promoted resistance to cisplatin and upregulated the level of HOXA-AS3 in BC cells. Inhibition of HOXA-AS3 enhanced hypoxia-induced cisplatin sensitivity by regulating EMT and Notch1 in BC cells. A dual-luciferase reporter assay confirmed that HOXA-AS3 directly targets miR-455-5p and that Notch1 was a potential target of miRNA-455-5p. We also found that the positive effect of HOXA-AS3 inhibition on cisplatin resistance and tumorigenesis was alleviated when BC cells were transfected with miR-455-5p. Finally, we showed combining HOXA-AS3 small interfering RNA (siRNA) with cisplatin treatment inhibited tumorigenesis in a BALB/c nu/nu mouse model. Our findings indicate that HOXA-AS3 may function as a competing endogenous RNA (ceRNA) of miR-455-5p to regulate Notch1 and play an important role in regulating chemotherapeutic drug sensitivity in BC cells. Therefore, HOXA-AS3 may be a novel therapeutic target for treating bladder cancer.
Deep CNN Model Using CT Radiomics Feature Mapping Recognizes EGFR Gene Mutation Status of Lung Adenocarcinoma
Authors: Zhang Baihua , Qi Shouliang , Pan Xiaohuan , Li Chen , Yao Yudong , Qian Wei , Guan Yubao
Published: February 2021

To recognize the epidermal growth factor receptor (EGFR) gene mutation status in lung adenocarcinoma (LADC) has become a prerequisite of deciding whether EGFR-tyrosine kinase inhibitor (EGFR-TKI) medicine can be used. Polymerase chain reaction assay or gene sequencing is for measuring EGFR status, however, the tissue samples by surgery or biopsy are required. We propose to develop deep learning models to recognize EGFR status by using radiomics features extracted from non-invasive CT images. Preoperative CT images, EGFR mutation status and clinical data have been collected in a cohort of 709 patients (the primary cohort) and an independent cohort of 205 patients. After 1,037 CT-based radiomics features are extracted from each lesion region, 784 discriminative features are selected for analysis and construct a feature mapping. One Squeeze-and-Excitation (SE) Convolutional Neural Network (SE-CNN) has been designed and trained to recognize EGFR status from the radiomics feature mapping. SE-CNN model is trained and validated by using 638 patients from the primary cohort, tested by using the rest 71 patients (the internal test cohort), and further tested by using the independent 205 patients (the external test cohort). Furthermore, SE-CNN model is compared with machine learning (ML) models using radiomics features, clinical features, and both features. EGFR(-) patients show the smaller age, higher odds of female, larger lesion volumes, and lower odds of subtype of acinar predominant adenocarcinoma (APA), compared with EGFR(+). The most discriminative features are for texture (614, 78.3%) and the features of first order of intensity (158, 20.1%) and the shape features (12, 1.5%) follow. SE-CNN model can recognize EGFR mutation status with an AUC of 0.910 and 0.841 for the internal and external test cohorts, respectively. It outperforms the CNN model without SE, the fine-tuned VGG16 and VGG19, three ML models, and the state-of-art models. Utilizing radiomics feature mapping extracted from non-invasive CT images, SE-CNN can precisely recognize EGFR mutation status of LADC patients. The proposed method combining radiomics features and deep leaning is superior to ML methods and can be expanded to other medical applications. The proposed SE-CNN model may help make decision on usage of EGFR-TKI medicine.
P. aeruginosa Mediated Necroptosis in Mouse Tumor Cells Induces Long-Lasting Systemic Antitumor Immunity
Authors: Qi Jia-long , He Jin-rong , Jin Shu-mei , Yang Xu , Bai Hong-mei , Liu Cun-bao , Ma Yan-bing
Published: February 2021

Necroptosis is a form of programmed cell death (PCD) characterized by RIP3 mediated MLKL activation and increased membrane permeability via MLKL oligomerization. Tumor cell immunogenic cell death (ICD) has been considered to be essential for the anti-tumor response, which is associated with DC recruitment, activation, and maturation. In this study, we found that P. aeruginosa showed its potential to suppress tumor growth and enable long-lasting anti-tumor immunity in vivo. What’s more, phosphorylation- RIP3 and MLKL activation induced by P. aeruginosa infection resulted in tumor cell necrotic cell death and HMGB1 production, indicating that P. aeruginosa can cause immunogenic cell death. The necrotic cell death can further drive a robust anti-tumor response via promoting tumor cell death, inhibiting tumor cell proliferation, and modulating systemic immune responses and local immune microenvironment in tumor. Moreover, dying tumor cells killed by P. aeruginosa can catalyze DC maturation, which enhanced the antigen-presenting ability of DC cells. These findings demonstrate that P. aeruginosa can induce immunogenic cell death and trigger a robust long-lasting anti-tumor response along with reshaping tumor microenvironment.
Computer Tomography Radiomics-Based Nomogram in the Survival Prediction for Brain Metastases From Non-Small Cell Lung Cancer Underwent Whole Brain Radiotherapy
Authors: Zhang Ji , Jin Juebin , Ai Yao , Zhu Kecheng , Xiao Chengjian , Xie Congying , Jin Xiance
Published: February 2021

Prognostic parameters and models were believed to be helpful in improving the treatment outcome for patients with brain metastasis (BM). The purpose of this study was to investigate the feasibility of computer tomography (CT) radiomics based nomogram to predict the survival of patients with BM from non-small cell lung cancer (NSCLC) treated with whole brain radiotherapy (WBRT). A total of 195 patients with BM from NSCLC who underwent WBRT from January 2012 to December 2016 were retrospectively reviewed. Radiomics features were extracted and selected from pretherapeutic CT images with least absolute shrinkage and selection operator (LASSO) regression. A nomogram was developed and evaluated by integrating radiomics features and clinical factors to predict the survival of individual patient. Five radiomics features were screened out from 105 radiomics features according to the LASSO Cox regression. According to the optimal cutoff value of radiomics score (Rad-score), patients were stratified into low-risk (Rad-score <= −0.14) and high-risk (Rad-score > −0.14) groups. Multivariable analysis indicated that sex, karnofsky performance score (KPS) and Rad-score were independent predictors for overall survival (OS). The concordance index (C-index) of the nomogram in the training cohort and validation cohort was 0.726 and 0.660, respectively. An area under curve (AUC) of 0.786 and 0.788 was achieved for the short-term and long-term survival prediction, respectively. In conclusion, the nomogram based on radiomics features from CT images and clinical factors was feasible to predict the OS of BM patients from NSCLC who underwent WBRT.
Clinical Utility of 18F-PSMA-1007 Positron Emission Tomography/Magnetic Resonance Imaging in Prostate Cancer: A Single-Center Experience
Authors: Liu Ao , Zhang Miao , Huang Hai , Zhang Chuanjie , Ruan Xiaohao , Lin Wenhao , Li Biao , Chen Lu , Xu Danfeng
Published: February 2021

Purpose

This study aimed to evaluate the clinical utility of 18F-PSMA-1007 positron emission tomography (PSMA PET)/magnetic resonance imaging (MRI) imaging in patients with suspected or defined prostate cancer.

Methods

In the pilot study, we retrospectively investigated 62 patients who underwent PSMA-PET/MRI for suspected or defined PCa between June 2019 and June 2020. Patients were grouped into three subgroups: (1) suspected PCa without histological evidence, (2) primary PCa, (3) biochemical recurrent prostate cancer (BRPCa). Two nuclear physicians independently interpreted the results of PSMA-PET/MRI. Management strategies before PSMA-PET/MRI were retrospectively reported, and the management strategy was re-evaluated for each patient considering the PSMA-PET/MRI result. The changes in strategies were recorded. Besides, the correlation between prostate specific antigen (PSA) level and management changes was also accessed by Fisher exact test, and two-side p < 0.05 was assumed as statistical significance.

Results

There were 28 patients in the suspected PCa group (group 1), 12 in the primary PCa group (group 2), and 22 in the BRPCa group (group 3). Overall, the intended decisions were changed in 26 (41.9%) of 62 patients after PSMA-PET/MRI, including 11/28 (39.3%) in suspected PCa group, 1/12 (8.4%) in primary PCa group, and 14/24 (63.6%) in BCR group. In group 1, the main impact on subsequent management included decreased active surveillance (from 20 to 9) and increased prostate biopsy (from 8 to 19). PSA levels were not significantly associated with management changes in suspected PCa patients (p = 0.865). In group 2, the main impact on subsequent management included decreased radical surgery (from 8 to 7), and multimodal therapy appearance (n = 1). Only in the category of PSA levels of ≥20 ng/ml, the management of primary PCa was changed. In group 3, the main impact on subsequent management included decreased salvage radiotherapy (from 5 to 2), increased systemic therapy (from 6 to 7), and increased multimodal therapy (from 11 to 13). The highest proportion of management changes occurred in BCR patients with 0.5≤PSA<1 ng/ml.

Conclusion

From our preliminary experience, PSMA-PET/MRI may be a valued tool for defining PCa lesions and changing management. The biggest impact of management intent was in patients with BRPCa, especially in patients with 0.5≤PSA<1 ng/ml. However, further studies are needed to confirm our pilot findings.
Globally Rare BRCA2 Variants With Founder Haplotypes in the South African Population: Implications for Point-of-Care Testing Based on a Single-Institution BRCA1/2 Next-Generation Sequencing Study
Authors: Oosthuizen Jaco , Kotze Maritha J. , Van Der Merwe Nicole , Myburgh Ettienne J. , Bester Phillip , van der Merwe Nerina C.
Published: February 2021

Breast cancer patients historically benefitted from population-based genetic research performed in South Africa, which led to the development of founder-based BRCA1/2 diagnostic tests. With the advent of next-generation sequencing (NGS) technologies, the clinical utility of limited, targeted genetic assays were questioned. The study focused on mining NGS data obtained from an extensive single-institution NGS series (n=763). The aims were to determine (i) the prevalence of the most common recurrent/founder variants in patients referred for NGS directly; and (ii) to explore the data for inferred haplotypes associated with previous and potential new recurrent/founder variants. The identification of additional founder variants was essential for promoting and potentially advancing to rapid founder-based BRCA1/2 point-of-care (POC) technology as a time- and cost-effective alternative. NGS revealed actionable BRCA1/2 variants in 11.1% of patients tested (BRCA1 – 4.7%; BRCA2 – 6.4%), of which 22.4% represented variants currently screened for using first-tier targeted genetic testing. A retrospective investigation into the overall mutation-positive rate for an extended cohort (n=1906), which included first-tier test results, revealed that targeted genetic testing identified 74% of all pathogenic variants. This percentage justified the use of targeted genetic testing as a first-tier assay. Inferred haplotype analysis confirmed the founder status of BRCA2 c.5771_5774del (rs80359535) and c.7934del (rs80359688) and revealed an additional African founder variant (BRCA2 c.582G>A – rs80358810). A risk-benefit analysis using a questionnaire-based survey was performed in parallel to determine genetic professionals’ views regarding POC testing. This was done to bridge the clinical implementation gap between haplotype analysis and POC testing as a first-tier screen during risk stratification of breast and ovarian cancer patients. The results reflected high acceptance (94%) of BRCA1/2 POC testing when accompanied by genetic counselling. Establishing the founder status for several recurrent BRCA2 variants across ethnic groups supports unselected use of the BRCA POC assay in all SA breast/ovarian cancer patients by recent local and international public health recommendations. Incorporating POC genotyping into the planned NGS screening algorithm of the Department of Health will ensure optimal use of the country’s recourses to adhere to the set standards for optimal care and management for all breast cancer patients.
Ubiquitination of Nonhistone Proteins in Cancer Development and Treatment
Authors: Zhang Xiuzhen , Meng Tong , Cui Shuaishuai , Feng Ling , Liu Dongwu , Pang Qiuxiang , Wang Ping
Published: February 2021

Ubiquitination, a crucial post-translation modification, regulates the localization and stability of the substrate proteins including nonhistone proteins. The ubiquitin-proteasome system (UPS) on nonhistone proteins plays a critical role in many cellular processes such as DNA repair, transcription, signal transduction, and apoptosis. Its dysregulation induces various diseases including cancer, and the identification of this process may provide potential therapeutic targets for cancer treatment. In this review, we summarize the regulatory roles of key UPS members on major nonhistone substrates in cancer-related processes, such as cell cycle, cell proliferation, apoptosis, DNA damage repair, inflammation, and T cell dysfunction in cancer. In addition, we also highlight novel therapeutic interventions targeting the UPS members (E1s, E2s, E3s, proteasomes, and deubiquitinating enzymes). Furthermore, we discuss the application of proteolysis-targeting chimeras (PROTACs) technology as a novel anticancer therapeutic strategy in modulating protein target levels with the aid of UPS.
Which Definition of Upper Rectal Cancer Is Optimal in Selecting Stage II or III Rectal Cancer Patients to Avoid Postoperative Adjuvant Radiation?
Authors: Gao Xian Hua , Zhai Bai Zhi , Li Juan , Kabemba Jean Luc Tshibangu , Gong Hai Feng , Bai Chen Guang , Liu Ming Lu , Zhang Shao Ting , Shen Fu , Liu Lian Jie , Zhang Wei
Published: February 2021

Background

In most guidelines, upper rectal cancers (URC) are not recommended to take neoadjuvant or adjuvant radiation. However, the definitions of URC vary greatly. Five definitions had been commonly used to define URC: 1) >10 cm from the anal verge by MRI; 2) >12 cm from the anal verge by MRI; 3) >10 cm from the anal verge by colonoscopy; 4) >12 cm from the anal verge by colonoscopy; 5) above the anterior peritoneal reflection (APR). We hypothesized that the fifth definition is optimal to identify patients with rectal cancer to avoid adjuvant radiation.

Methods

The data of stage II/III rectal cancer patients who underwent radical surgery without preoperative chemoradiotherapy were retrospectively reviewed. The height of the APR was measured, and compared with the tumor height measured by digital rectal examination (DRE), MRI and colonoscopy. The five definitions were compared in terms of prediction of local recurrence, survival, and percentages of patients requiring radiation.

Results

A total of 576 patients were included, with the intraoperative location of 222 and 354 tumors being above and straddle/below the APR, respectively. The median distance of the APR from anal verge (height of APR) as measured by MRI was 8.7 (range: 4.5–14.3) cm. The height of APR positively correlated with body height (r=0.862, P<0.001). The accuracy of the MRI in determining the tumor location with respect to the APR was 92.1%. Rectal cancer above the APR had a significantly lower incidence of local recurrence than those straddle/below the APR (P=0.042). For those above the APR, there was no significant difference in local recurrence between the radiation and no-radiation group. Multivariate analyses showed that tumor location regarding APR was an independent risk factor for LRFS. Tumor height as measured by DRE, MRI and colonoscopy were not related with survival outcomes. Fewer rectal cancer patients required adjuvant radiation using the definition by the APR, compared with other four definitions based on a numerical tumor height measured by MRI and colonoscopy.

Conclusions

The definition of URC as rectal tumor above the APR, might be the optimal definition to select patients with stage II/III rectal cancer to avoid postoperative adjuvant radiation.
A-to-I RNA Editing in Cancer: From Evaluating the Editing Level to Exploring the Editing Effects
Authors: Wang Heming , Chen Sinuo , Wei Jiayi , Song Guangqi , Zhao Yicheng
Published: February 2021

As an important regulatory mechanism at the posttranscriptional level in metazoans, adenosine deaminase acting on RNA (ADAR)-induced A-to-I RNA editing modification of double-stranded RNA has been widely detected and reported. Editing may lead to non-synonymous amino acid mutations, RNA secondary structure alterations, pre-mRNA processing changes, and microRNA-mRNA redirection, thereby affecting multiple cellular processes and functions. In recent years, researchers have successfully developed several bioinformatics software tools and pipelines to identify RNA editing sites. However, there are still no widely accepted editing site standards due to the variety of parallel optimization and RNA high-seq protocols and programs. It is also challenging to identify RNA editing by normal protocols in tumor samples due to the high DNA mutation rate. Numerous RNA editing sites have been reported to be located in non-coding regions and can affect the biosynthesis of ncRNAs, including miRNAs and circular RNAs. Predicting the function of RNA editing sites located in non-coding regions and ncRNAs is significantly difficult. In this review, we aim to provide a better understanding of bioinformatics strategies for human cancer A-to-I RNA editing identification and briefly discuss recent advances in related areas, such as the oncogenic and tumor suppressive effects of RNA editing.
iNOS Associates With Poor Survival in Melanoma: A Role for Nitric Oxide in the PI3K-AKT Pathway Stimulation and PTEN S-Nitrosylation
Authors: Ding Zhen , Ogata Dai , Roszik Jason , Qin Yong , Kim Sun-Hee , Tetzlaff Michael T. , Lazar Alexander J. , Davies Michael A. , Ekmekcioglu Suhendan , Grimm Elizabeth A.
Published: February 2021

We previously showed that inducible nitric oxide synthase (iNOS) protein expression in melanoma tumor cells is associated with poor patient prognosis. Here, we analyzed the association between iNOS and the oncogenic PI3K-AKT pathway. TCGA data show that iNOS and phospho-Akt Ser473 expression were associated significantly only in the subset of tumors with genetically intact PTEN. Employing a stage III melanoma TMA, we showed that iNOS protein presence is significantly associated with shorter survival only in tumors with PTEN protein expression. These findings led to our hypothesis that the iNOS product, nitric oxide (NO), suppresses the function of PTEN and stimulates PI3K-Akt activation. Melanoma cells in response to NO exposure in vitro exhibited enhanced AKT kinase activity and substrate phosphorylation, as well as attenuated PTEN phosphatase activity. Biochemical analysis showed that NO exposure resulted in a post-translationally modified S-Nitrosylation (SNO) PTEN, which was also found in cells expressing iNOS. Our findings provide evidence that NO-rich cancers may exhibit AKT activation due to post-translational inactivation of PTEN. This unique activation of oncogenic pathway under nitrosative stress may contribute to the pathogenesis of iNOS in melanoma. Significance: Our study shows that iNOS expression is associated with increased PI3K-AKT signaling and worse clinical outcomes in melanoma patients with wt (intact) PTEN. Mutated PTEN is already inactivated. We also demonstrate that NO activates the PI3K-AKT pathway by suppressing PTEN suppressor function concurrent with the formation of PTEN-SNO. This discovery provides insight into the consequences of inflammatory NO produced in human melanoma and microenvironmental cells. It suggests that NO–driven modification provides a marker of PTEN inactivation, and represents a plausible mechanism of tumor suppressor inactivation in iNOS expressing subset of cancers.
Linc00963 Promote Cell Proliferation and Tumor Growth in Castration-Resistant Prostate Cancer by Modulating miR-655/TRIM24 Axis
Authors: Bai Minghua , He Chenchen , Shi Shengjia , Wang Mincong , Ma Jinlu , Yang Pengtao , Dong Yiping , Mou Xingyi , Han Suxia
Published: February 2021

Previous studies have shown that both long intergenic non-coding RNA 00963 (Linc00963) and tripartite motif containing 24 (TRIM24) are activators of the PI3K/AKT pathway, and both are involved in the carcinogenesis and progression of prostate cancer. However, the regulatory mechanisms between Linc00963 and TRIM24 are still unclear. In this study, we aimed to elucidate the underlying relationship between Linc00963 and TRIM24 in castration-resistant prostate cancer (CRPC). We found that TRIM24, an established oncogene in CRPC, was positively correlated with Linc00963 in prostate cancer tissues. In addition, TRIM24 was positively regulated by Lin00963 in CRPC cells. Mechanistically, TRIM24 was the direct target of microRNA-655 (miR-655) in CRPC cells, and Linc00963 could competitively bind miR-655 and upregulate TRIM24 expression. Using gain- and loss-of- function assays and rescue assays, we identified that miR-655 inhibits TRIM24 expression and cell proliferation and colony forming ability in CRPC, and that Linc00963 promotes TRIM24 expression, cell proliferation, and colony forming ability of CRPC cells by directly suppressing miR-655 expression. We further identified that Linc00963 could promote tumor growth of CRPC cells by inhibiting miR-655 and upregulating TRIM24 axis in vivo. Taken together, our study reveals a new mechanism for the Linc00963/miR-655/TRIM24 competing endogenous RNA (ceRNA) network in accelerating cell proliferation in CRPC in vitro and in vivo, and suggests that Linc00963 could be considered a novel therapeutic target for CRPC.
Endothelin-1 Exhibiting Pro-Nociceptive and Pro-Peristaltic Activities Is Increased in Peritoneal Carcinomatosis
Authors: Greco Céline , Basso Lilian , Désormeaux Cléo , Fournel Audren , Demuynck Benedicte , Lafendi Leila , Chapiro Sylvie , Lemoine Antoinette , Zhu Ying-Ying , Knauf Claude , Cenac Nicolas , Boucheix Claude , Dietrich Gilles
Published: February 2021

Background: Peritoneal carcinomatosis often results in alterations in intestinal peristalsis and recurrent abdominal pain. Pain management in these patients is often unsatisfactory. This study aimed to investigate whether endothelin-1 (EDN1) was involved in pain mediation in peritoneal carcinomatosis, and thus whether the EDN1 pathway could be a new therapeutic target for peritoneal carcinomatosis-associated pain.

Methods: EDN1 plasma levels and abdominal pain severity were assessed in patients with abdominal tumors, with or without peritoneal carcinomatosis, and in healthy donors. The effects of EDN1 on the visceromotor response to colorectal distension, and on colonic contractions were then examined in mice, and the mechanism of action of EDN1 was then investigated by measuring the impact of EDN1 exposure on calcium mobilization in cultured neurons. Inhibition studies were also performed to determine if the effects of EDN1 exposure could be reversed by EDN1-specific receptor antagonists.

Results: A positive correlation between EDN1 plasma levels and abdominal pain was identified in patients with peritoneal carcinomatosis. EDN1 exposure increased visceral sensitivity and the amplitude of colonic contractions in mice and induced calcium mobilization by direct binding to its receptors on sensory neurons. The effects of EDN1 were inhibited by antagonists of the EDN1 receptors.

Conclusions: This preliminary study, using data from patients with peritoneal carcinomatosis combined with data from experiments performed in mice, suggests that EDN1 may play a key role mediating pain in peritoneal carcinomatosis. Our findings suggest that antagonists of the EDN1 receptors might be beneficial in the management of pain in patients with peritoneal carcinomatosis.
Identification of FPR3 as a Unique Biomarker for Targeted Therapy in the Immune Microenvironment of Breast Cancer
Authors: Qi Jian , Liu Yu , Hu Jiliang , Lu Li , Dou Zhen , Dai Haiming , Wang Hongzhi , Yang Wulin
Published: February 2021

Although research into immunotherapy is growing, its use in the treatment of breast cancer remains limited. Thus, identification and evaluation of prognostic biomarkers of tissue microenvironments will reveal new immune-based therapeutic strategies for breast cancer. Using an in silico bioinformatic approach, we investigated the tumor microenvironmental and genetic factors related to breast cancer. We calculated the Immune score, Stromal score, Estimate score, Tumor purity, TMB (Tumor mutation burden), and MATH (Mutant-allele tumor heterogeneity) of Breast cancer patients from the Cancer Genome Atlas (TCGA) using the ESTIMATE algorithm and Maftools. Significant correlations between Immune/Stromal scores with breast cancer subtypes and tumor stages were established. Importantly, we found that the Immune score, but not the Stromal score, was significantly related to the patient's prognosis. Weighted correlation network analysis (WGCNA) identified a pattern of gene function associated with Immune score, and that almost all of these genes (388 genes) are significantly upregulated in the higher Immune score group. Protein-protein interaction (PPI) network analysis revealed the enrichment of immune checkpoint genes, predicting a good prognosis for breast cancer. Among all the upregulated genes, FPR3, a G protein-coupled receptor essential for neutrophil activation, is the sole factor that predicts poor prognosis. Gene set enrichment analysis analysis showed FRP3 upregulation synergizes with the activation of many pathways involved in carcinogenesis. In summary, this study identified FPR3 as a key immune-related biomarker predicting a poor prognosis for breast cancer, revealing it as a promising intervention target for immunotherapy.
Gallic Acid Ameliorated Impaired Lipid Homeostasis in a Mouse Model of High-Fat Diet—and Streptozotocin-Induced NAFLD and Diabetes through Improvement of β-oxidation and Ketogenesis
Authors: Chao Jung , Cheng Hao-Yuan , Chang Ming-Ling , Huang Shyh-Shyun , Liao Jiunn-Wang , Cheng Yung-Chi , Peng Wen-Huang , Pao Li-Heng
Published: February 2021

Gallic acid (GA) is a simple polyphenol found in food and traditional Chinese medicine. Here, we determined the effects of GA administration in a combined mouse model of high-fat diet (HFD)-induced obesity and low-dose streptozotocin (STZ)-induced hyperglycemia, which mimics the concurrent non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes pathological condition. By combining the results of physiological assessments, pathological examinations, metabolomic studies of blood, urine, liver, and muscle, and measurements of gene expression, we attempted to elucidate the efficacy of GA and the underlying mechanism of action of GA in hyperglycemic and dyslipidemic mice. HFD and STZ induced severe diabetes, NAFLD, and other metabolic disorders in mice. However, the results of liver histopathology and serum biochemical examinations indicated that daily GA treatment alleviated the high blood glucose levels in the mice and decelerated the progression of NAFLD. In addition, our results show that the hepatoprotective effect of GA in diabetic mice occurs in part through a partially preventing disordered metabolic pathway related to glucose, lipids, amino acids, purines, and pyrimidines. Specifically, the mechanism responsible for alleviation of lipid accumulation is related to the upregulation of β-oxidation and ketogenesis. These findings indicate that GA alleviates metabolic diseases through novel mechanisms.
Chemical Characteristics of Platycodon grandiflorum and its Mechanism in Lung Cancer Treatment
Authors: Deng Yaling , Ye Xianwen , Chen Yufan , Ren Hongmin , Xia Lanting , Liu Ying , Liu Minmin , Liu Haiping , Zhang Huangang , Wang Kairui , Zhang Jinlian , Zhang Zhongwei
Published: February 2021

Objective: The technology, network pharmacology and molecular docking technology of the ultra performance liquid chromatography-quadrupole time-of-flight tandem mass spectrometry (UPLC-Q-TOF-MS/MS) were used to explore the potential molecular mechanism of Platycodon grandiflorum (PG) in the treatment of lung cancer (LC).

Methods: UPLC-Q-TOF-MS/MS technology was used to analyze the ingredients of PG and the potential LC targets were obtained from the Traditional Chinese Medicine Systems Pharmacology database, and the Analysis Platform (TCMSP), GeneCards and other databases. The interaction network of the drug-disease targets was constructed with the additional use of STRING 11.0. The pathway enrichment analysis was carried out using Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) in Metascape, and then the “Drug-Ingredients-Targets-Pathways-Disease” (D-I-T-P-D) network was constructed using Cytoscape v3.7.1. Finally, the Discovery Studio 2016 (DS) software was used to evaluate the molecular docking.

Results: Forty-seven compounds in PG, including triterpenoid saponins, steroidal saponins and flavonoids, were identified and nine main bioactive components including platycodin D were screened. According to the method of data mining, 545 potential drug targets and 2,664 disease-related targets were collected. The results of topological analysis revealed 20 core targets including caspase 3 (CASP3) and prostaglandin-endoperoxide synthase 2 (PTGS2) suggesting that the potential signaling pathway potentially involved in the treatment of LC included MAPK signaling pathway and P13K-AKT signaling pathway. The results of molecular docking proved that the bound of the ingredients with potential key targets was excellent.

Conclusion: The results in this study provided a novel insight in the exploration of the mechanism of action of PG against LC.
Pirfenidone Is a Vasodilator: Involvement of KV7 Channels in the Effect on Endothelium-Dependent Vasodilatation in Type-2 Diabetic Mice
Authors: Beck Lilliana , Pinilla Estéfano , Arcanjo Daniel Dias Rufino , Hernanz Raquel , Prat-Duran Judit , Petersen Asbjørn Graver , Köhler Ralf , Sheykhzade Majid , Comerma-Steffensen Simon , Simonsen Ulf
Published: February 2021

Endothelial cell dysfunction and fibrosis are associated with worsening of the prognosis in patients with cardiovascular disease. Pirfenidone has a direct antifibrotic effect, but vasodilatation may also contribute to the effects of pirfenidone. Therefore, in a first study we investigated the mechanisms involved in the relaxant effect of pirfenidone in rat intrapulmonary arteries and coronary arteries from normal mice. Then in a second study, we investigated whether pirfenidone restores endothelial function in the aorta and mesenteric arteries from diabetic animals. From 16–18-week old normal male C57BL/6 mice and normoglycemic (db/db+), and type 2 diabetic (db/db) male and female mice, arteries were mounted in microvascular isometric myographs for functional studies, and immunoblotting was performed. In rat pulmonary arteries and mouse coronary arteries, pirfenidone induced relaxations, which were inhibited in preparations without endothelium. In mouse coronary arteries, pirfenidone relaxation was inhibited in the presence of a nitric oxide (NO) synthase inhibitor, NG-nitro-l-arginine (L-NOARG), a blocker of large-conductance calcium-activated potassium channels (BKCa), iberiotoxin, and a blocker of KV7 channels, XE991. Patch clamp studies in vascular smooth muscle revealed pirfenidone increased iberiotoxin-sensitive current. In the aorta and mesenteric small arteries from diabetic db/db mice relaxations induced by the endothelium-dependent vasodilator, acetylcholine, were markedly reduced compared to db/db + mice. Pirfenidone enhanced the relaxations induced by acetylcholine in the aorta from diabetic male and female db/db mice. An opener of KV7 channels, flupirtine, had the same effect as pirfenidone. XE991 reduced the effect of pirfenidone and flupirtine and further reduced acetylcholine relaxations in the aorta. In the presence of iberiotoxin, pirfenidone still increased acetylcholine relaxation in aorta from db/db mice. Immunoblotting for KV7.4, KV7.5, and BKCa channel subunits were unaltered in aorta from db/db mice. Pirfenidone failed to improve acetylcholine relaxation in mesenteric arteries, and neither changed acetylcholine-induced transient decreases in blood pressure in db/db+ and db/db mice. In conclusion, pirfenidone vasodilates pulmonary and coronary arteries. In coronary arteries from normal mice, pirfenidone induces NO-dependent vasodilatation involving BKCa and KV7 channels. Pirfenidone improves endothelium-dependent vasodilatation in aorta from diabetic animals by a mechanism involving voltage-gated KV7 channels, a mechanism that may contribute to the antifibrotic effect of pirfenidone.
Identification and Enzymatic Activity Evaluation of a Novel CYP2C9 Allelic Variant Discovered in a Patient
Authors: Zhou Xiao-Yang , Lu Xiang-Ran , Li Ying-Hui , Ma Ya-Qing , Zhao Shi-Wen , Wang Fang , Xu Ren-Ai , Hu Guo-Xin , Cai Jian-Ping
Published: February 2021

Warfarin is a widely prescribed anticoagulant but the doses required to attain the optimum therapeutic effect exhibit dramatic inter-individual variability. Pharmacogenomics-guided warfarin dosing has been recommended to improve safety and effectiveness. We analyzed the cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase complex subunit 1 (VKORC1) genes among 120 patients taking warfarin. A new coding variant was identified by sequencing CYP2C9. The novel A > G mutation at nucleotide position 14,277 led to an amino acid substitution of isoleucine with valine at position 213 (I213V). The functional consequence of the variant was subsequently evaluated in vitro. cDNA of the novel variant was constructed by site-directed mutagenesis and the recombinant protein was expressed in vitro using a baculovirus–insect cell expression system. The recombinant protein expression was quantified at apoprotein and holoprotein levels. Its enzymatic activities toward tolbutamide, warfarin and losartan were then assessed. It exhibited changed apparent Km values and increases of 148%, 84% and 67% in the intrinsic clearance of tolbutamide, warfarin and losartan, respectively, compared to wild-type CYP2C9*1, indicating dramatically enhanced in vitro enzymatic activity. Our study suggests that the amino acid at position 213 in wild-type CYP2C9*1 may be important for the enzymatic activity of CYP2C9 toward tolbutamide, warfarin and losartan. In summary, a patient taking high-dose warfarin (6.0 mg/day) in order to achieve the target international normalized ratio was found to have a mutation in the CYP2C9 gene.
Ginsenosides Improve Nonalcoholic Fatty Liver Disease via Integrated Regulation of Gut Microbiota, Inflammation and Energy Homeostasis
Authors: Liang Wenyi , Zhou Kun , Jian Ping , Chang Zihao , Zhang Qiunan , Liu Yuqi , Xiao Shuiming , Zhang Lanzhen
Published: February 2021

Ginseng, the root and rhizome of Panax ginseng C. A. Mey., is a famous herbal medicine, and its major ginsenosides exert beneficial effects on nonalcoholic fatty liver disease (NAFLD). Due to the multicomponent and multitarget features of ginsenosides, their detailed mechanisms remain unclear. This study aimed to explore the role of ginsenosides on NAFLD and the potential mechanisms mediated by the gut microbiota and related molecular processes. C57BL/6J mice were fed a high-fat diet (HFD) supplemented or not supplemented with ginsenoside extract (GE) for 12 weeks. A strategy that integrates bacterial gene sequencing, serum pharmacochemistry and network pharmacology was applied. The results showed that GE significantly alleviated HFD-induced NAFLD symptoms in a dose-dependent manner. Furthermore, GE treatment modulated the HFD-induced imbalance in the gut microbiota and alleviated dysbiosis-mediated gut leakage and metabolic endotoxemia. Additionally, 20 components were identified in the mouse plasma after the oral administration of GE, and they interacted with 82 NAFLD-related targets. A network analysis revealed that anti-inflammatory effects and regulation of the metabolic balance might be responsible for the effects of GE on NAFLD. A validation experiment was then conducted, and the results suggested that GE suppressed NF-κB/IκB signaling activation and decreased the release and mRNA levels of proinflammatory factors (TNF-α, IL-1β and IL-6). Additionally, GE promoted hepatic lipolytic genes (CPT-1a), inhibited lipogenic genes (SREBP-1c, FAS, ACC-1) and improved leptin resistance. These findings imply that the benefits of GE are involved in modulating the gut microbiota, enhancing the gut barrier function, restoring the energy balance, and alleviating metabolic inflammation. Moreover, GE might serve as a potential agent for the prevention of NAFLD through the integration of prebiotic, anti-inflammatory and energy-regulatory effects.
Network-centric Indicators for Fragility in Global Financial Indices
Authors: Samal Areejit , Kumar Sunil , Yadav Yasharth , Chakraborti Anirban
Published: February 2021

Over the last 2 decades, financial systems have been studied and analyzed from the perspective of complex networks, where the nodes and edges in the network represent the various financial components and the strengths of correlations between them. Here, we adopt a similar network-based approach to analyze the daily closing prices of 69 global financial market indices across 65 countries over a period of 2000–2014. We study the correlations among the indices by constructing threshold networks superimposed over minimum spanning trees at different time frames. We investigate the effect of critical events in financial markets (crashes and bubbles) on the interactions among the indices by performing both static and dynamic analyses of the correlations. We compare and contrast the structures of these networks during periods of crashes and bubbles, with respect to the normal periods in the market. In addition, we study the temporal evolution of traditional market indicators, various global network measures, and the recently developed edge-based curvature measures. We show that network-centric measures can be extremely useful in monitoring the fragility in the global financial market indices.