bluuebunny/crossref_metadata_2025 huggingface dataset:
IGF2BP3 promotes progression of gallbladder carcinoma by stabilizing KLK5 mRNA in N6-methyladenosine-dependent binding
Authors: Zhang Junzhe , Yang Kaini , Bu Junfeng , Yan Jiayan , Hu Xiaoqiang , Liu Ke , Gao Si , Tang Shuibin , Gao Lili , Chen Wei
Published: October 2022

Background

Recent studies have reported that IGF2BP3 is linked to the pathogenesis of various malignancies. Since IGF2BP3 is associated with poor outcomes of gallbladder carcinoma (GBC), we aimed to explore the association between its N6-methyladenosine (m6A) RNA methylation and GBC progression.

Methods

Bioinformatic analysis of GSE136982, GSE104165, and RNA-seq was performed. In vitro and in vivo gain- and loss-of-function assays were done. qPCR, Western blotting, and IHC were conducted in cells or in collected clinical tissue samples. RNA immunoprecipitation, RNA stability measurement, methylated RNA immunoprecipitation, and dual-luciferase reporter assays were performed in this study.

Results

The expression of IGF2BP3 was higher in GBC tissues than in peritumoral tissues. Functions such as cell proliferation and migration, both in vitro and in vivo, were inhibited by downregulation of IGF2BP3. The analysis of RNA-seq indicated that KLK5 was a downstream target of IGF2BP3. The expression of KLK5 was measured in GBC cells and tumor samples. It was found to be positively correlated with IGF2BP3 level. Upon IGF2BP3 depletion, ectopic expression of KLK5 could rescue cell function in part. Mechanistically, we found that IGF2BP3 directly binds to KLK5 mRNA and regulates its stability in an m6A-dependent manner. As a result, inhibition of KLK5 decreased the expression of PAR2, and deregulated phospho-Akt. Using bioinformatic prediction combined with miRNA microarray analysis, we identified that let-7g-5p is an inhibitor of IGF2BP3, and let-7g-5p expression was negatively correlated with IGF2BP3. Overexpression of let-7g-5p affected the aggressive phenotype of GBC cells by deregulating IGF2BP3, and inhibiting the KLK5/PAR2/AKT axis.

Conclusions

Our data showed that IGF2BP3 is associated with the aggressive phenotype of GBC. Mechanistically, IGF2BP3 activated the PAR2/AKT axis by stabilizing KLK5 mRNA in an m6A-dependent manner. The loss of let-7g-5p enhanced the expression of IGF2BP3 and improved GBC progression. Thus, IGF2BP3 plays a crucial role in GBC, and the let-7g-5p/IGF2BP3/KLK5/PAR2 axis may be a therapeutic target for GBC.
The antihyperlipidemic drug potassium piperonate impairs the migration and tumorigenesis of breast cancer cells via the upregulation of miR-31
Authors: Tian Xiaoxia , Lu Junping , Nanding Kathleen , Zhang Linzhe , Liu Yanrong , Mailisu Mailisu , Morigen Morigen , Fan Lifei
Published: October 2022

Background

Breast cancer is the second cause of cancer death in women, and tumor metastasis is the primary cause of mortality. Due to the involvement of many regulatory molecules and signaling pathways, the occurrence and development of metastases needs to be further studied. MicroRNAs (miRNAs) are ubiquitously expressed small non-coding RNAs that have been shown to play an important role in the diagnosis and treatment of many diseases, as well as representing an attractive candidate for metastasis control. In this study, we investigated the mechanism of potassium piperonate (GBK) in impairing breast cancer cell invasion and metastasis by targeting miR-31.

Methods

Breast cancer cells, either treated with GBK or left untreated, were assessed for migration and invasion capacities using wound healing and transwell assays. GBK-targeted miRNAs were identified and verified using RT-qPCR. Western blotting was used to validate the changes in expression levels of miR-31-targeted genes. Methylation specific PCR was performed to detect the effect of GBK on the methylation levels of the lncRNA LOC554202 host gene. The synergistic effect of GBK and the chemotherapy drug cisplatin (DDP) on breast cancer cells was verified using cell proliferation, colony formation, and RT-qPCR assays in vitro, and the tumor xenograft model in vivo.

Results

We found that miR-31 was the main target of GBK. GBK treatment affected the epigenetic modification at CpG sites by downregulating DNA methyltransferases. Thus, the CpG-associated methylation levels of lncRNA LOC554202 decreased significantly, and in turn upregulated both miR-31 and its host gene LOC554202 in breast cancer cells. We also observed the significant inhibition of miR-31-targeted genes following GBK treatment, including RHOA, WAVE3, and SATB2, with functions closely related to cancer cell invasion, migration, and proliferation. Furthermore, we revealed that the combination of GBK and DDP had a synergistic effect on inhibiting the proliferation of breast cancer cells in vitro and in vivo, especially in triple negative breast cancer (TNBC).

Conclusions

This study investigated the target of GBK in the inhibition of breast cancer migration and invasion, and the underlying mechanisms involved, providing theoretical support for the development of GBK as an auxiliary drug for clinical treatment.
Prognostic role of pre-treatment serum ALB in Patients with oropharyngeal cancer: A retrospective cohort study
Authors: Zhu Jiajia , Li Liang , Duan Yuansheng , Wu Yansheng , Wang Xudong
Published: October 2022

Background

The morbidity of oropharyngeal cancer (OPC) is continuing to rise in numerous developed countries. An accurate prognostic assessment is needed to evaluate the malignant degree or risk classification to optimize treatment. Albumin (ALB) as an independent prognostic indicator of cancer survival has been established in previous studies. This study investigated the prognostic value of pre-treatment serum ALB in OPC patients.

Methods

The clinicopathological data of 246 patients diagnosed with OPC from 2010 to 2019 were analyzed retrospectively. Analyze the relationship between ALB and clinicopathological characteristics of patients. The optimal cut-off values for ALB were determined via Cutoff Finder (Method for cutoff determination: Survival: significance (log-rank test)). To determine the independent prognostic factors, the Cox proportional hazards model was used to perform univariate and multivariate analyses of the serum ALB levels related to overall survival (OS) and disease-free survival (DFS).

Results

The optimal cut-off point for ALB was 39.15 g/L determined via Cutoff Finder. Serum ALB levels were significantly associated with age (P=0.047), Presence of comorbidity (P=0.009), Charlson score index (P=0.007), Hemoglobin (P<0.001), Neutrophil to Lymphocyte Ratio (P=0.002), Albumin-To-Alkaline Phosphatase Ratio (P<0.001), Alkaline phosphatase (P=0.005), T stage (P=0.016), and HPV status (P=0.002). In the univariate and multivariate analyses, ALB was found to be an independent prognostic indicator for DFS (HR =0.39, 95% CI:0.23-0.66, P=0.000) and OS (HR =0.46, 95% CI: 0.25-0.83, P=0.01) in OPC patients.

Conclusions

Pre-treatment serum ALB could serve as a valuable prognostic biomarker for the prognostic stratification of OPC patients.
Clinical characteristics and prognostic value of renal immune complex deposition in patients with light chain amyloidosis
Authors: Yan Jipeng , Wang Di , Zhao Jin , Zhou Meilan , Huang Boyong , Xing Yan , Guo Wei-Feng , Sun Shiren
Published: October 2022

Although patients with light chain amyloidosis (AL) may present with co-deposition of amyloid and immune complexes (ICs) in renal biopsies, data on clinical characteristics and prognostic value of renal IC deposition are limited. A total of 73 patients with AL amyloidosis who were newly diagnosed by renal biopsy in Xijing Hospital (Xi’an, China) were divided into two groups (IC and non-IC groups). As a result, renal IC deposition was found in 26% of patients. Patients with IC deposition were associated with more urinary protein excretion and lower serum albumin. Notably, patients in the non-IC group achieved higher hematological overall response rate (81.5% vs. 47.4%, p = 0.007) and ≥VGPR rate (75.9% vs. 39.8%, p = 0.004) compared with those in IC group. Renal response rate was also higher in the non-IC group (63% vs. 31.6%, p = 0.031). With the median follow-up time of 19 months, a significantly worse overall survival was observed in patients with the IC group as compared with those without renal IC deposition in the Kaplan–Meier analysis (p = 0.036). Further multivariate analysis demonstrated that renal immune complex deposition was associated with worse overall survival in patients with AL amyloidosis (HR 5.927, 95% CI 2.148–16.356, p = 0.001).
Automatic volumetric diagnosis of hepatocellular carcinoma based on four-phase CT scans with minimum extra information
Authors: Ling Yating , Ying Shihong , Xu Lei , Peng Zhiyi , Mao Xiongwei , Chen Zhang , Ni Jing , Liu Qian , Gong Shaolin , Kong Dexing
Published: October 2022

We built a deep-learning based model for diagnosis of HCC with typical images from four-phase CT and MEI, demonstrating high performance and excellent efficiency.

Objectives

The aim of this study was to develop a deep-learning-based model for the diagnosis of hepatocellular carcinoma.

Materials and methods

This clinical retrospective study uses CT scans of liver tumors over four phases (non-enhanced phase, arterial phase, portal venous phase, and delayed phase). Tumors were diagnosed as hepatocellular carcinoma (HCC) and non-hepatocellular carcinoma (non-HCC) including cyst, hemangioma (HA), and intrahepatic cholangiocarcinoma (ICC). A total of 601 liver lesions from 479 patients (56 years ± 11 [standard deviation]; 350 men) are evaluated between 2014 and 2017 for a total of 315 HCCs and 286 non-HCCs including 64 cysts, 178 HAs, and 44 ICCs. A total of 481 liver lesions were randomly assigned to the training set, and the remaining 120 liver lesions constituted the validation set. A deep learning model using 3D convolutional neural network (CNN) and multilayer perceptron is trained based on CT scans and minimum extra information (MEI) including text input of patient age and gender as well as automatically extracted lesion location and size from image data. Fivefold cross-validations were performed using randomly split datasets. Diagnosis accuracy and efficiency of the trained model were compared with that of the radiologists using a validation set on which the model showed matched performance to the fivefold average. Student’s t-test (T-test) of accuracy between the model and the two radiologists was performed.

Results

The accuracy for diagnosing HCCs of the proposed model was 94.17% (113 of 120), significantly higher than those of the radiologists, being 90.83% (109 of 120, p-value = 0.018) and 83.33% (100 of 120, p-value = 0.002). The average time analyzing each lesion by our proposed model on one Graphics Processing Unit was 0.13 s, which was about 250 times faster than that of the two radiologists who needed, on average, 30 s and 37.5 s instead.

Conclusion

The proposed model trained on a few hundred samples with MEI demonstrates a diagnostic accuracy significantly higher than the two radiologists with a classification runtime about 250 times faster than that of the two radiologists and therefore could be easily incorporated into the clinical workflow to dramatically reduce the workload of radiologists.
Inflammatory microenvironment in classical Hodgkin’s lymphoma with special stress on mast cells
Authors: Ribatti Domenico , Tamma Roberto , Annese Tiziana , Ingravallo Giuseppe , Specchia Giorgina
Published: October 2022

Classical Hodgkin’s lymphoma (CHL) accounts for 10% of all lymphomas. Nodular sclerosis and mixed cellularity accounts for nearly 80% of all CHL cases. The number of mast cells in CHL correlates with poor prognosis, is significantly higher in nodular sclerosis than in other CHL subtypes, and an association between the degree of angiogenesis and the number of intratumoral mast cells has been demonstrated in CHL. Even with the best available treatment, a significant percentage of CHL patients progress or relapse after first-line therapy. 50% of patients with disease relapse achieve subsequent long-term disease control with salvage therapies. In this context, new potential therapeutic opportunities are required, and mast cells may be regarded as a new target for adjuvant treatment of CHL through the inhibition of angiogenesis and tissue remodeling and allowing the secretion of cytotoxic cytokines.
Case report: Success of tepotinib therapy in overcoming resistance to osimertinib in a patient with EGFR-mutant lung adenocarcinoma with a potential acquired MET exon 14 skipping mutation
Authors: Takamori Shinkichi , Seto Takashi , Yamaguchi Masafumi , Kinoshita Fumihiko , Fujishita Takatoshi , Ito Kensaku , Toyozawa Ryo , Shoji Fumihiro , Okamoto Tatsuro
Published: October 2022

Osimertinib is a standard therapy for the treatment of advanced non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor gene (EGFR) mutations, but most patients with EGFR-mutant NSCLC develop secondary resistance to osimertinib. Mesenchymal-epithelial transition gene (MET) alterations and oncogene fusions have been identified as the most common mechanisms of resistance to osimertinib. However, MET exon 14 skipping mutation (METex14del) as an acquired resistance to osimertinib has rarely been reported. A non-smoking 76-year-old woman was diagnosed with lung adenocarcinoma in the right lower lobe (cT2bN2M1c [pulmonary and bone metastases], cStage IVB). The primary tumor was submitted to cobas® EGFR Mutation Test v2 (Roche Diagnostics Ltd.), next generation sequencing (Oncomine Comprehensive Assay v3; Thermo Fisher Scientific), the AmoyDx® Essential NGS panel (Amoy Diagnostics, Xiamen, China), all of which were positive for EGFR L858R and de novo T790M. We administered daily osimertinib (80 mg/day), and achieved a partial response. However, after 14.0 months, computed tomography showed progression of the primary tumor and lung metastases. Re-biopsy of the primary tumor was conducted, and the specimen was submitted to Archer®MET companion diagnostic for detection of METex14del. Although the primary tumor was negative for METex14del, the re-biopsy specimen was positive for METex14del. We validated that the biopsy specimen of the primary tumor at diagnosis before osimertinib administration was negative for METex14del using local reverse transcription PCR. We administered daily tepotinib (500 mg/day) to the patient as a further-line treatment, and achieved a partial response (tumor shrinkage rate: 34.5%) after 2.0 months, who responded to tepotinib therapy for 8.0 months. We described a patient with lung adenocarcinoma harboring METex14del as a potential acquired resistance to osimertinib, who responded to subsequent tepotinib therapy. Re-biopsy and re-analysis of genetic profiles should be considered in NSCLC patients who develop osimertinib resistance.
Severe pneumonia caused by human adenovirus type 55 in children
Authors: Zhang Dongwei , Chen Yi , Shi Tingting , Fan Huifeng , Tian Xingui , Zhou Rong , Huang Li , Yang Diyuan , Lu Gen
Published: October 2022

Background

Emerging human adenovirus type 55 (HAdV-55) causes fatal pneumonia in adults. There is a lack of studies on severe pneumonia caused by HAdV-55 in children.

Methods

We conducted a retrospective review of pediatric patients hospitalized at Guangzhou Women and Children’s Medical Center with severe pneumonia from 2013 to 2020 who had human adenovirus (HAdV) detected in throat samples or bronchoalveolar lavage fluid using RT-PCR. The presence of HAdV-55 was determined by PCR amplification of the hypervariable regions of the hexon gene. Demographic, clinical, etiological, and outcome data were collected and analyzed.

Results

Over the eight-year period, HAdV-55 was detected in three severe and six critical pediatric pneumonia patients. None of the patients had any underlying diseases, and had a median age of 18 months (range, 6–108 months). The male to female ratio was 2:1. All patients presented with fever and cough, and three patients presented with wheezing and diarrhea. Six patients had coinfections with other respiratory pathogens, such as bacteria, Mycoplasma pneumoniae and fungi. Three critical patients developed plastic bronchitis (PB). The median lengths of invasive mechanical ventilation and hospital stay of the critical patients were 10 (8, 28.75) days and 25 (13, 32.25) days, respectively. Three critical patients died, although two of them received extracorporeal membrane oxygenation (ECMO) and blood purification. Three surviving patients developed post-infectious bronchiolitis obliterans (PIBO) at the follow-up.

Conclusions

HAdV-55 can cause fatal pneumonia in children, and shows a high rate of co-infection with other respiratory pathogens and a poorer prognosis combined with PB. Thus, HAdV-55 may be an important subtype in patients with HAdV-induced pneumonia who develop PIBO.
Case report: Local bleomycin injection: A possible treatment option for primitive myxoid mesenchymal tumor of infancy
Authors: Yang Binbin , Chen Qingjiang , Zhu Yueling , Wang Jianbing , Dong Ao , Chen Yi , He Xue , Gu Weizhong , Gao Zhigang , Qian Yunzhong
Published: October 2022

In recent years, it has been determined that primitive myxoid mesenchymal tumors of infancy (PMMTI) are solid tumors. To date, very few cases of PMMTI have been reported, and there is no consensus regarding treatment. To provide additional references, it is necessary to collect and report the diagnoses and treatment outcomes of related cases. We report the case of a 38-day-old girl who presented with a 5-cm purple tumor in the right shoulder. Upon hospital admission, the patient received an intratumoral injection of bleomycin after diagnosis of a possible lymphangioma. 10 days after the treatment, the tumor began to develop inflammation and necrosis, resulting in a clear demarcation between the tumor and surrounding tissue. Hence, during the second hospitalization, we performed a successful tumor resection. Postoperatively, the tumor was pathologically diagnosed as PMMTI. 3 months after excision, the patient showed no local recurrence on re-examination. To the best of our knowledge, this is the first report of a PMMTI in which bleomycin, or other similar chemotherapeutic drugs, have been injected into tumors. This result offers novel insights into the treatment of PMMTI. Injection therapy with bleomycin and similar chemotherapeutics may result in specific responses to PMMTI, which may help in developing better surgical conditions or improving outcomes in non-surgical patients.
Investigating the effects and mechanisms of Erchen Decoction in the treatment of colorectal cancer by network pharmacology and experimental validation
Authors: Shao Yanfei , Chen Jingxian , Hu Yujie , Wu Yuan , Zeng Hualin , Lin Shuying , Lai Qiying , Fan Xiaodong , Zhou Xueliang , Zheng Minhua , Gao Bizhen , Sun Jing
Published: October 2022

Objective: Erchen Decoction (ECD), a well-known traditional Chinese medicine, exerts metabolism-regulatory, immunoregulation, and anti-tumor effects. However, the action and pharmacological mechanism of ECD remain largely unclear. In the present study, we explored the effects and mechanisms of ECD in the treatment of CRC using network pharmacology, molecular docking, and systematic experimental validation.

Methods: The active components of ECD were obtained from the TCMSP database and the potential targets of them were annotated by the STRING database. The CRC-related targets were identified from different databases (OMIM, DisGeNet, GeneCards, and DrugBank). The interactive targets of ECD and CRC were screened and the protein-protein interaction (PPI) networks were constructed. Then, the hub interactive targets were calculated and visualized from the PPI network using the Cytoscape software. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed. In addition, the molecular docking was performed. Finally, systematic in vitro, in vivo and molecular biology experiments were performed to further explore the anti-tumor effects and underlying mechanisms of ECD in CRC.

Results: A total of 116 active components and 246 targets of ECD were predicted based on the component-target network analysis. 2406 CRC-related targets were obtained from different databases and 140 intersective targets were identified between ECD and CRC. 12 hub molecules (STAT3, JUN, MAPK3, TP53, MAPK1, RELA, FOS, ESR1, IL6, MAPK14, MYC, and CDKN1A) were finally screened from PPI network. GO and KEGG pathway enrichment analyses demonstrated that the biological discrepancy was mainly focused on the tumorigenesis-, immune-, and mechanism-related pathways. Based on the experimental validation, ECD could suppress the proliferation of CRC cells by inhibiting cell cycle and promoting cell apoptosis. In addition, ECD could inhibit tumor growth in mice. Finally, the results of molecular biology experiments suggested ECD could regulate the transcriptional levels of several hub molecules during the development of CRC, including MAPKs, PPARs, TP53, and STATs.

Conclusion: This study revealed the potential pharmacodynamic material basis and underlying molecular mechanisms of ECD in the treatment of CRC, providing a novel insight for us to find more effective anti-CRC drugs.
A monoamine oxidase B inhibitor ethyl ferulate suppresses microglia-mediated neuroinflammation and alleviates ischemic brain injury
Authors: Zou Xinxin , Gao Shenghan , Li Jiangnan , Li Chenggang , Wu Chuyu , Cao Xiang , Xia Shengnan , Shao Pengfei , Bao Xinyu , Yang Haiyan , Liu Pinyi , Xu Yun
Published: October 2022

Microglia are the resident macrophages in the brain, which play a critical role in post-stroke neuroinflammation. Accordingly, targeting neuroinflammation could be a promising strategy to improve ischemic stroke outcomes. Ethyl ferulate (EF) has been confirmed to possess anti-inflammatory properties in several disease models, including acute lung injury, retinal damage and diabetes-associated renal injury. However, the effects of EF on microglial activation and the resolution of post-stroke neuroinflammation remains unknown. Here, we found that EF suppressed pro-inflammatory response triggered by lipopolysaccharide (LPS) stimulation in primary microglia and BV2 cell lines, as well as post-stroke neuroinflammation in an in vivo transient middle cerebral artery occlusion (tMCAO) stroke model in C57BL/6 mice, consequently ameliorating ischemic brain injury. Furthermore, EF could directly bind and inhibit the activity of monoamine oxidase B (MAO-B) to reduce pro-inflammatory response. Taken together, our study identified a MAO-B inhibitor, Ethyl ferulate, as an active compound with promising potentials for suppressing post-stroke neuroinflammation.
Propolis induces cardiac metabolism changes in 6-hydroxydopamine animal model: A dietary intervention as a potential cardioprotective approach in Parkinson’s disease
Authors: Goncalves Valeria C. , Silva da Fonsêca Victor , de Paula Faria Daniele , Izidoro Mario Augusto , Berretta Andresa Aparecida , de Almeida Antônio-Carlos G. , Affonso Fonseca Fernando Luiz , Scorza Fulvio Alexandre , Scorza Carla Alessandra
Published: October 2022

While there is sustained growth of the older population worldwide, ageing is a consistent risk factor for neurodegenerative diseases, such as Parkinson’s-disease (PD). Considered an emblematic movement disorder, PD comprises a miscellany of non-motor symptoms, for which effective management remains an unfulfilled need in clinical practice. Highlighted are the cardiovascular abnormalities, that cause significant burden in PD patients. Evidence suggests that key biological processes underlying PD pathophysiology can be modulated by diet-derived bioactive compounds, such as green propolis, a natural functional food with biological and pharmacological properties. The effects of propolis on cardiac affection associated to PD have received little coverage. In this study, a metabolomics approach and Positron Emission Tomography (PET) imaging were used to assess the metabolic response to diet supplementation with green propolis on heart outcomes of rats with Parkinsonism induced by 6-hydroxydopamine (6-OHDA rats). Untargeted metabolomics approach revealed four cardiac metabolites (2-hydroxybutyric acid, 3-hydroxybutyric acid, monoacylglycerol and alanine) that were significantly modified between animal groups (6-OHDA, 6-OHDA + Propolis and sham). Propolis-induced changes in the level of these cardiac metabolites suggest beneficial effects of diet intervention. From the metabolites affected, functional analysis identified changes in propanoate metabolism (a key carbohydrate metabolism related metabolic pathway), glucose-alanine cycle, protein and fatty acid biosynthesis, energy metabolism, glutathione metabolism and urea cycle. PET imaging detected higher glucose metabolism in the 17 areas of the left ventricle of all rats treated with propolis, substantially contrasting from those rats that did not consume propolis. Our results bring new insights into cardiac metabolic substrates and pathways involved in the mechanisms of the effects of propolis in experimental PD and provide potential novel targets for research in the quest for future therapeutic strategies.
NEUROD1 predicts better prognosis in pancreatic cancer revealed by a TILs-based prognostic signature
Authors: Jiang Zhiyang , Pan Jiadong , Lu Jiahui , Mei Jie , Xu Rui , Xia Dandan , Yang Xuejing , Wang Huiyu , Liu Chaoying , Xu Junying , Ding Junli
Published: October 2022

It has been well-defined that tumor-infiltrating lymphocytes (TILs) play critical roles in pancreatic cancer (PaCa) progression. This research aimed to comprehensively explore the composition of TILs in PaCa and their potential clinical significance. A total of 178 samples from the TCGA and 63 samples from the GSE57495 dataset were enrolled in our study. ImmuCellAI was applied to calculate the infiltrating abundance of 24 immune cell types in PaCa and further survival analysis revealed the prognostic values of TILs in PaCa. Moreover, the Hallmark enticement analysis of differentially expressed genes (DEGs) between low- and high-risk groups was performed as well. Immunohistochemistry staining was used to evaluate NEUROD1 expression. As result, different kinds of TILs had distinct infiltrating features. In addition, Specific TILs subsets had notable prognostic values in PaCa. We further established a 6-TILs signature to assess the prognosis of PaCa patients. Kaplan-Meier and Cox regression analyses both suggested the significant prognostic value of the signature in PaCa. Based on the prognostic signature, we screened a great deal of potential prognostic biomarkers and successfully validated NEUROD1 as a novel prognostic biomarker in PaCa. Overall, the current study illuminated the immune cells infiltrating the landscape in PaCa and identified a TILs-dependent signature and NEUROD1 for prognostic prediction in PaCa patients.
Application of advanced technology in traditional Chinese medicine for cancer therapy
Authors: Ke Gaofeng , Zhang Jia , Gao Wufeng , Chen Jiayi , Liu Luotong , Wang Simiao , Zhang Huan , Yan Guojun
Published: October 2022

Although cancer has seriously threatened people’s health, it is also identified by the World Health Organization as a controllable, treatable and even curable chronic disease. Traditional Chinese medicine (TCM) has been extensively used to treat cancer due to its multiple targets, minimum side effects and potent therapeutic effects, and thus plays an important role in all stages of tumor therapy. With the continuous progress in cancer treatment, the overall efficacy of cancer therapy has been significantly improved, and the survival time of patients has been dramatically prolonged. In recent years, a series of advanced technologies, including nanotechnology, gene editing technology, real-time cell-based assay (RTCA) technology, and flow cytometry analysis technology, have been developed and applied to study TCM for cancer therapy, which efficiently improve the medicinal value of TCM and accelerate the research progress of TCM in cancer therapy. Therefore, the applications of these advanced technologies in TCM for cancer therapy are summarized in this review. We hope this review will provide a good guidance for TCM in cancer therapy.
Regulation of transient receptor potential channels by traditional Chinese medicines and their active ingredients
Authors: Yan Shidu , Huang Yuchan , Xiao Qian , Su Zixia , Xia Lei , Xie Jinling , Zhang Fan , Du Zhengcai , Hou Xiaotao , Deng Jiagang , Hao Erwei
Published: October 2022

In recent years, activation of thermal transient receptor potential (TRP) ion channels at a range of temperatures has received widespread attention as a target for traditional Chinese medicine (TCM) to regulate body temperature and relieve pain. Discovery of transient receptor potential vanilloid 1 (TRPV1) was awarded a Nobel Prize, reflecting the importance of these channels. Here, the regulatory effects of TCMs and their active ingredients on TRP ion channels are reviewed, and future directions for research on the cold, hot, warm, cool, and neutral natures of TCMs are considered. In herbs with cold, hot, warm, cool, and neutral natures, we found 29 TCMs with regulatory effects on TRP ion channels, including Cinnamomi Cortex, Capsici Fructus, Rhei Radix et Rhizoma, Macleayae cordatae Herba, Menthae Haplocalycis Herba, and Rhodiolae Crenulatae Radix et Rhizoma. Although some progress has been made in understanding the regulation of TRP ion channels by TCMs and their ingredients, the molecular mechanism by which TCMs have this effect remains to be further studied. We hope this review will provide a reference for further research on the cold, hot, warm, cool, and neutral natures of TCMs.
Advanced targeted nanomedicines for vulnerable atherosclerosis plaque imaging and their potential clinical implications
Authors: Li Xue , Wu Menglin , Li Jiang , Guo Qi , Zhao Yang , Zhang Xuening
Published: October 2022

Atherosclerosis plaques caused by cerebrovascular and coronary artery disease have been the leading cause of death and morbidity worldwide. Precise assessment of the degree of atherosclerotic plaque is critical for predicting the risk of atherosclerosis plaques and monitoring postinterventional outcomes. However, traditional imaging techniques to predict cardiocerebrovascular events mainly depend on quantifying the percentage reduction in luminal diameter, which would immensely underestimate non-stenotic high-risk plaque. Identifying the degree of atherosclerosis plaques still remains highly limited. vNanomedicine-based imaging techniques present unique advantages over conventional techniques due to the superior properties intrinsic to nanoscope, which possess enormous potential for characterization and detection of the features of atherosclerosis plaque vulnerability. Here, we review recent advancements in the development of targeted nanomedicine-based approaches and their applications to atherosclerosis plaque imaging and risk stratification. Finally, the challenges and opportunities regarding the future development and clinical translation of the targeted nanomedicine in related fields are discussed.
Phospholipid-mimicking block, graft, and block-graft copolymers for phase-transition microbubbles as ultrasound contrast agents
Authors: Huang Jianbo , Wang Hong , Huang Lei , Zhou Yuqing
Published: October 2022

Background: Lipid and polymer microbubbles (MBs) are widely used as ultrasound contrast agents in clinical diagnosis, and possess great potential in ultrasound-mediated therapy due to their drug loading function. However, overcoming the limitations of stability and echo enhancement of MBs are still a considerable challenge.

Methods: A series novel block, graft and block-graft copolymers was proposed and prepared in this work, and these copolymers were used as shells to encapsulate perfluoropentane as ultrasound contrast agents. First, block, graft and block-graft copolymers with different topological structures were prepared. Then, these copolymers were prepared into block copolymer phase-transition MBs, graft copolymer phase-transition MBs, and block-graft copolymer phase-transition MBs, respectively. Finally, the dexamethasone was used for drug-loaded phase-transition microbubbles model to explore the potential of theranostic microbubbles.

Results: Finally, these three resulting copolymer MBs with average size of 4–5 μm exhibited well enhancement of ultrasound imaging under the influence of different frequencies and mechanical index, and they exhibited a longer contrast-enhanced ultrasound imaging time and higher resistance to mechanical index compared with SonoVue in vitro and in vivo. In vitro drug release results also showed that these copolymer MBs could encapsulate dexamethasone drugs, and the drug release could be enhanced by ultrasonic triggering. These copolymer MBs were therapeutic MBs for targeted triggering drug release.

Conclusion: Therefore, the feasibility of block, graft, and block-graft copolymers as ultrasonic contrast agents was verified, and their ultrasonic enhancement performance in vitro and in vivo was compared. The ultrasound contrast agents developed in this work have excellent development potential in comprehensive diagnosis and treatment.
Comparison of different methods to assess tacrolimus concentration intra-patient variability as potential marker of medication non-adherence
Authors: Kostalova Barbora , Mala-Ladova Katerina , Sulkova Sylvie Dusilova , Denhaerynck Kris , De Geest Sabina , Maly Josef
Published: October 2022

Background and objective: Non-adherence to tacrolimus commonly manifests as low drug concentrations and/or high intra-patient variability (IPV) of concentrations across multiple measurements. We aimed to compare several methods of tacrolimus IPV calculation and evaluate how well each reflects blood concentration variation due to medication non-adherence in kidney transplant recipients.

Methods: This Czech single-center retrospective longitudinal study was conducted in 2019. All outpatients ≥18 years of age, ≥3 months post-transplant, and on tacrolimus-based regimens were approached. After collecting seven consecutive tacrolimus concentrations we asked participating patients to self-report adherence to immunosuppressants (BAASIS© scale). The IPV of tacrolimus was calculated as the medication level variability index (MLVI), the coefficient of variation (CV), the time-weighted CV, and via nonlinearly modeled dose-corrected trough levels. These patient-level variables were analyzed using regression analysis. Detected nonlinearities in the dose-response curve were controlled for by adding tacrolimus dosing and its higher-order terms as covariates, along with self-reported medication adherence levels.

Results: Of 243 patients using tacrolimus, 42% (n = 102) reported medication non-adherence. Non-adherence was associated with higher CVs, higher time-weighted CVs, and lower dose-corrected nonlinearly modeled trough levels; however, it was not associated with MLVIs. All of the significant operationalizations suggested a weak association that was similar across the applied methods.

Discussion and conclusion: Implementation non-adherence was reflected by higher CV or time-weighted CV and by lower blood concentrations of tacrolimus. As an additional tool for identifying patients at risk for non-adherence, simple IPV calculations incorporated into medical records should be considered in everyday clinical practice.
Current status of immunotherapy for non-small cell lung cancer
Authors: Yang Tao , Xiong Yilin , Zeng Yufei , Wang Yan , Zeng Jing , Liu Jie , Xu Shangfu , Li Li-Sheng
Published: October 2022

Nowadays, lung cancer is still the deadliest oncological disease in the world. Among them, non-small cell lung cancer (NSCLC) accounts for 80%∼85% of all lung cancers, and its 5-year survival rate is less than 15%, making the situation critical. In the past decades, despite some clinical advances in conventional treatments, the overall survival rate of NSCLC is still not optimistic due to its unique physiological conditions and the frequent occurrence of tumor escape. In recent years, immunotherapy has become a new hot spot in lung cancer research, including antibody therapy and cell therapy, which have been developed and utilized one after another, especially immune checkpoint inhibitor (ICI). These approaches have effectively improved the overall survival rate and objective response rate of NSCLC patients by enhancing the immune capacity of the body and targeting tumor cells more effectively, which is more specific and less toxic compared with conventional chemotherapy, and providing more strategies for NSCLC treatment. In this paper, we reviewed the relevant targets, clinical progress and adverse reaction in monoclonal antibodies, antibody-drug conjugates, ICI, bispecific antibodies, T-cell receptor engineered T cell therapy (TCR-T), Chimeric antigen receptor T-cell immunotherapy (CAR-T), and also report on their combination therapy from the immune-related background to provide better NSCLC treatment and prospective.
Tandem mass tag-based proteomics analysis reveals the multitarget mechanisms of Phyllanthus emblica against liver fibrosis
Authors: Gong Puyang , Yin Kehuan , Luo Xiaomin , Gu Jian , Tan Rui , Wu Yan , Li Dapeng
Published: October 2022

Phyllanthus emblica (PE), a traditional multiethnic herbal medicine, is commonly applied to treat liver diseases. Our previous study demonstrated that aqueous extract of PE (AEPE) could alleviate carbon tetrachloride (CCl4)-induced liver fibrosis in vivo, but the underlying molecular mechanisms are still unclear. The present study was undertaken to clarify the multitarget mechanisms of PE in treating liver fibrosis by proteomics clues. A CCl4-induced liver fibrosis rat model was established. The anti-liver fibrosis effects of chemical fractions from AEPE were evaluated by serum biochemical indicators and pathological staining. Additionally, tandem mass tag (TMT) - based quantitative proteomics technology was used to detect the hepatic differentially expressed proteins (DEPs). The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment, gene ontology (GO) enrichment and protein-protein interaction (PPI) network were used to perform bioinformatics analysis of DEPs. Western blot analysis was used to verify the key potential targets regulated by the effective fraction of AEPE. The low-molecular-weight fraction of AEPE (LWPE) was determined to be the optimal anti-liver fibrosis active fraction, that could significantly improve ALT, AST, HA, Col IV, PCIII, LN, Hyp levels and reduce the pathological fibrotic lesion of liver tissue in model rats. A total of 195 DEPs were screened after LWPE intervention. GO analysis showed that the DEPs were related mostly to extracellular matrix organization, actin binding, and extracellular exosomes. KEGG pathway analysis showed that DEPs are mainly related to ECM-receptor interactions, focal adhesion and PI3K-Akt signaling pathway. Combined with the GO, KEGG and Western blot results, COL1A2, ITGAV, TLR2, ACE, and PDGFRB may be potential targets for PE treatment of liver fibrosis. In conclusion, LWPE exerts therapeutic effects through multiple pathways and multiple targets regulation in the treatment of liver fibrosis. This study may provide proteomics clues for the continuation of research on liver fibrosis treatment with PE.
International cooperation analysis of Asian political distance network constructed using event data
Authors: Sada Sotaro , Oikawa Keita , Iwasaki Fusanori , Ikeda Yuichi
Published: October 2022

Economic integration is underway in East Asia and the Asia-Pacific region, including the Association of Southeast Asian Nations (ASEAN) community-building process, with the Comprehensive and Progressive Agreement for Trans-Pacific Partnership (CPTPP) coming into effect in 2018 and the Regional Comprehensive Economic Partnership (RCEP) in 2022. While these Regional Trade Agreements (RTAs) have deepened multilateral relations, there is an insufficient mechanism to quantify multilateral diplomacy within the region. Therefore, this study analyzed the region from three perspectives: countries that have contributed to diplomacy for intra-regional cooperation (diplomatic ranking), the cohesiveness of countries in diplomatic stances (diplomatic clusters), and the synchronization period of cooperative events (diplomatic synchronization); and we quantified them by the ranking of diplomatic centrality, blockmodeling of the signed network, and analytic signal, respectively. For analysis, we used bilateral event data to create a political distance network consisting of the original East Asia Summit (EAS) member countries (ASEAN+6) and the United States for the period 1985–2020 and to define diplomatic centrality. Diplomatic ranking indicated three major trends: 1985–1992, 1993–2011, and 2012–2020. Until 1992, Japan, the ASEAN member states (AMS), and Australia ranked at the top, and from 1993 to 2011, Japan and China almost dominated the top. Since 2012, AMS have joined Japan and China in the top ranks. Diplomatic clusters showed the stances of Australia and New Zealand were closest. Throughout the 36 years, the stances of Japan and Republic of Korea were also closer, followed by China, AMS, and the United States. Diplomatic synchronization quantified the progress of regionalism in East Asia. Furthermore, diplomatic rankings in synchronous periods revealed the difference between the diplomatic positions of Japan and China in East Asia and illustrated that AMS were at the center of multilateral diplomacy in the region in 2018–2019.
Acoustic wavefront manipulation via transmission-type labyrinth structure
Authors: Wang Rui , Yang Fengbao
Published: October 2022

In this work, a transmission-type labyrinth structure (LS) is proposed to construct subwavelength acoustic functional metasurfaces, through which various desirable acoustic wavefront manipulation can be achieved in a broadband from 2,700 Hz to 3,900 Hz. By utilizing the excellent guiding property of LS, an invisibility cloak is designed to shield the target scattering body in the transmitted field. In addition, gradient metasurfaces composed of several LSs with different phase responses are constructed to obtain broadband beam deflection and focusing. Moreover, binary coding approach is adopted to further simplify the design philosophy of the metasurfaces by taking advantage of only two kinds of LS with opposite phase responses. Numerous wavefront manipulations including acoustic splitting beam and self-bending beam can be realized by using corresponding coding sequences. Our work provides a solution for multifunctional acoustic wavefront manipulation in a broadband, which may have potential applications in acoustic communication, detection and holography.
High-repetition rate picosecond laser-induced damage properties of Ta2O5:SiO2 coatings
Authors: Zhang Mingxiao , Qiu Fumin , Qiao Zhao , Zhou Qiang , Pu Yunti , Xiong Bingcheng , Die Junhui , Lv Liang , Ma Ping
Published: October 2022

High-repetition rate laser-induced damage of Ta2O5:SiO2 coatings was investigated at 355 nm wavelength and a repetition rate of 30 kHz. Laser-induced damage thresholds of coatings with different mixture ratios were measured. The relationships between laser-induced damage threshold and the material band gap and defect absorption were analyzed. Laser-induced damage threshold decreased with increase in number of laser pulses owing to enhancement of the absorption. Enhancement of absorption is attributed to the increase in density of mid-state defects induced by the picosecond laser pulses. The relationship between mid-state defects and the material mixture ratio was also analyzed.
Circulating concentrations of glycocalyx degradation products in preeclampsia
Authors: Carlberg Niclas , Cluver Catherine , Hesse Camilla , Thörn Sven-Egron , Gandley Robin , Damén Tor , Bergman Lina
Published: October 2022

Background and Objectives: Preeclampsia is a multisystem disorder that affects maternal endothelium. The glycocalyx lines and protects the endothelial surface. In severe systemic diseases, like sepsis, it is shed and glycocalyx degradation products can be detected in increased concentrations in plasma. The aim of this study was to compare circulating concentrations of glycocalyx degradation products in degrees of preeclampsia severity.

Study design: In this observational study, we included women from the South African PROVE biobank. Women were divided into normotensive controls, women with preeclampsia without end-organ complications, women with a single end-organ complication and women with multiple end-organ complications. Plasma samples taken at inclusion after diagnosis (preeclampsia cases) or at admission for delivery (normotensive controls) were analyzed with ELISA for syndecan-1, hyaluronic acid and thrombomodulin and compared between groups.

Results: Women with preeclampsia (n = 47) had increased plasma concentrations of hyaluronic acid (100.3 ng/ml IQR 54.2–204 vs. 27.0 ng/ml IQR (13.5–66.6), p < 0,001) and thrombomodulin (4.22 ng/ml IQR 3.55–5.17 vs. 3.49 ng/ml IQR 3.01–3.68, p = 0.007) but not syndecan-1 compared with normotensive women (n = 10). There were no differences in plasma concentration in any of these biomarkers in women with preeclampsia with no end-organ complications (n = 10) compared with women with preeclampsia and one end-organ complication (n = 24). Women with preeclampsia with two or more end-organ complications (n = 13) had increased plasma concentrations of thrombomodulin (5.46 ng/ml, IQR 4.85–7.83 vs. 4.66 ng/ml, IQR 3.45–4.88, p = 0.042) compared with women with preeclampsia and no end-organ complications.

Conclusion: Thrombomodulin was associated with disease severity and may be valuable for risk-stratifying women with preeclampsia.
Kidney transcriptome response to salinity adaptation in Labeo rohita
Authors: Harshini Vemula , Shukla Nitin , Raval Ishan , Kumar Sujit , Shrivastava Vivek , Patel Amrutlal K. , Joshi Chaitanya G.
Published: October 2022

The increasing salinization of freshwater resources, owing to global warming, has caused concern to freshwater aquaculturists. In this regard, the present study is aimed at economically important freshwater fish, L. rohita (rohu) adapting to varying degrees of salinity concentrations. The RNA-seq analysis of kidney tissue samples of L. rohita maintained at 2, 4, 6, and 8 ppt salinity was performed, and differentially expressed genes involved in various pathways were studied. A total of 755, 834, 738, and 716 transcripts were downregulated and 660, 926, 576, and 908 transcripts were up-regulated in 2, 4, 6, and 8 ppt salinity treatment groups, respectively, with reference to the control. Gene ontology enrichment analysis categorized the differentially expressed genes into 69, 154, 92, and 157 numbers of biological processes with the p value < 0.05 for 2, 4, 6, and 8 ppt salinity groups, respectively, based on gene functions. The present study found 26 differentially expressed solute carrier family genes involved in ion transportation and glucose transportation which play a significant role in osmoregulation. In addition, the upregulation of inositol-3-phosphate synthase 1A (INO1) enzyme indicated the role of osmolytes in salinity acclimatization of L. rohita. Apart from this, the study has also found a significant number of genes involved in the pathways related to salinity adaptation including energy metabolism, calcium ion regulation, immune response, structural reorganization, and apoptosis. The kidney transcriptome analysis elucidates a step forward in understanding the osmoregulatory process in L. rohita and their adaptation to salinity changes.