bluuebunny/crossref_metadata_2025 huggingface dataset:
Dietary Fish Hydrolysate Improves Memory Performance Through Microglial Signature Remodeling During Aging
Authors: Chataigner Mathilde , Lucas Céline , Di Miceli Mathieu , Pallet Véronique , Laye Sophie , Mehaignerie Alexis , Bouvret Elodie , Dinel Anne-Laure , Joffre Corinne
Published: November 2021

Brain aging is characterized by a chronic low-grade inflammation, which significantly impairs cognitive function. Microglial cells, the immunocompetent cells of the brain, present a different phenotype, switching from a homeostatic signature (M0) to a more reactive phenotype called “MGnD” (microglial neurodegenerative phenotype), leading to a high production of pro-inflammatory cytokines. Furthermore, microglial cells can be activated by age-induced gut dysbiosis through the vagus nerve or the modulation of the peripheral immune system. Nutrients, in particular n-3 long chain polyunsaturated fatty acids (LC-PUFAs) and low molecular weight peptides, display powerful immunomodulatory properties, and can thus prevent age-related cognitive decline. The objective of this study was to investigate the effects of n-3 LC-PUFAs and low molecular weight peptides contained in a marine by-product-derived hydrolysate on microglial phenotypes and intestinal permeability and their consequences on cognition in mice. We demonstrated that the hydrolysate supplementation for 8 weeks prevented short- and long-term memory decline during aging. These observations were linked to the modulation of microglial signature. Indeed, the hydrolysate supplementation promoted homeostatic microglial phenotype by increasing TGF-β1 expression and stimulated phagocytosis by increasing Clec7a expression. Moreover, the hydrolysate supplementation promoted anti-inflammatory intestinal pathway and tended to prevent intestinal permeability alteration occurring during aging. Therefore, the fish hydrolysate appears as an interesting candidate to prevent cognitive decline during aging.
The Functional Role of Lactoferrin in Intestine Mucosal Immune System and Inflammatory Bowel Disease
Authors: Liu Ning , Feng Gang , Zhang Xiaoying , Hu Qingjuan , Sun Shiqiang , Sun Jiaqi , Sun Yanan , Wang Ran , Zhang Yan , Wang Pengjie , Li Yixuan
Published: November 2021

Inflammatory bowel disease (IBD), encompassing ulcerative colitis (UC) and Crohn's disease (CD), is one of the main types of intestinal inflammatory diseases with intestine mucosal immune disorder. Intestine mucosal immune system plays a remarkable and important role in the etiology and pathogenesis of IBD. Therefore, understanding the intestine mucosal immune mechanism is a key step to develop therapeutic interventions for IBD. Intestine mucosal immune system and IBD are influenced by various factors, such as inflammation, gut permeability, gut microbiota, and nutrients. Among these factors, emerging evidence show that nutrients play a key role in inflammation activation, integrity of intestinal barrier, and immune cell modulation. Lactoferrin (LF), an iron-binding glycoprotein belonging to transferrin family, is a dietary bioactive component abundantly found in mammalian milk. Notably, LF has been reported to perform diverse biological functions including antibacterial activity, anti-inflammatory activity, intestinal barrier protection, and immune cell modulation, and is involved in maintaining intestine mucosal immune homeostasis. The improved understanding of the properties of LF in intestine mucosal immune system and IBD will facilitate its application in nutrition, clinical medicine, and health. Herein, this review outlines the recent advancements on LF as a potential therapeutic intervention for IBD associated with intestine mucosal immune system dysfunction. We hope this review will provide a reference for future studies and lay a theoretical foundation for LF-based therapeutic interventions for IBD by understanding the particular effects of LF on intestine mucosal immune system.
Pre-diagnosis Cruciferous Vegetables and Isothiocyanates Intake and Ovarian Cancer Survival: A Prospective Cohort Study
Authors: Wei Yi-Fan , Hao Ying-Ying , Gao Song , Li Xiu-Qin , Liu Fang-Hua , Wen Zhao-Yan , Wang Han-Yuan , Zhang Shuang , Yan Shi , Luan Meng , Zhao Yu-Hong , Gong Ting-Ting , Wu Qi-Jun
Published: November 2021

Background: The associations of the consumption of cruciferous vegetables (CVs) and their bioactive components, isothiocyanates (ITCs), with ovarian cancer (OC) mortality have been unclear, owing to limited studies and inconsistent findings. To date, no studies have evaluated these associations among Chinese patients with OC. This study aims to provide more evidence indicating the relationships of pre-diagnosis CVs and ITC intake with OC survival.

Methods: We examined the associations of pre-diagnosis CV and ITC intake with OC mortality in a hospital-based cohort (n = 853) of Chinese patients with epithelial OC between 2015 and 2020. Pre-diagnosis dietary information was evaluated with a validated food frequency questionnaire. Deaths were ascertained until March 31, 2021 via medical records and active follow-up. The associations were examined with the Cox proportional hazards model, adjusted for potential confounders, and stratified by menopausal status, residual lesions, histological type, and body mass index (BMI).

Results: During a median follow-up of 37.2 months (interquartile: 24.7–50.2 months), we observed 130 deaths. The highest tertile of total CV intake was associated with better survival than the lowest tertile intake [hazard ratio (HR) = 0.57, 95% confidence interval (CI) = 0.33–0.98, p trend < 0.05]. In addition, higher intake of ITCs from CVs was associated with better survival (HRT3VS.T1 = 0.59, 95% CI = 0.36–0.99, p trend = 0.06). Significant inverse associations were also observed for subgroup analyses stratified by menopausal status, residual lesions, histological type, and BMI, although not all associations showed statistical significance.

Conclusion: Increasing pre-diagnosis consumption of CVs and ITCs was strongly associated with better survival in patients with OC.
Caffeine and EGCG Alleviate High-Trans Fatty Acid and High-Carbohydrate Diet-Induced NASH in Mice: Commonality and Specificity
Authors: Xin Xin , Cheng Chen , Bei-yu Cai , Hong-shan Li , Hua-jie Tian , Xin Wang , Zi-ming An , Qin-mei Sun , Yi-yang Hu , Qin Feng
Published: November 2021

Caffeine and epigallocatechin-3-gallate (EGCG), which respectively, are the main functional extracts from coffee and green tea, and present protective effects against non-alcoholic fatty liver diseases (NAFLD). These two beverages and their functional extracts are highly recommended as potential treatments for obesity and NAFLD in clinics; however, their pharmacodynamic effects and pharmacological mechanisms in non-alcoholic steatohepatitis (NASH) remain unclear. Therefore, the aim of this study was to explore the commonality and specificity of the pharmacodynamic effects and pharmacological mechanisms of caffeine and EGCG on NASH mice, which were fed with a high-trans fatty acid/high-carbohydrate (HFHC) diet. C57BL/6J mice were fed a normal diet (control group) or an HFHC diet (HFHC group) for 24 weeks. HFHC group mice were additionally treated with caffeine (75 mg/kg) or EGCG (100 mg/kg) for 6 weeks, using obeticholic acid (OCA,10 mg/kg) as a positive control group. The pharmacological effects of the drugs, including effects on glucose and lipid metabolism and liver inflammation and fibrosis, were evaluated. Gene expression in liver tissue samples from the different groups were assessed. Both caffeine and EGCG significantly reduced the liver manifestations of NASH induced by HFHC. The pathological aspects of liver lipid deposition, inflammation, and liver fibrosis in both groups were strongly ameliorated. Of note, most indexes were strongly reversed in the caffeine group, although AST activity, fasting blood glucose, and the HOMA-IR index were improved in the ECGC group. There were 714 differentially expressed genes between the caffeine and HFHC groups and 268 differentially expressed genes between the EGCG and HFHC groups. Twenty and 17 NASH-related KEGG signaling pathways were enriched by caffeine and EGCG. This study confirmed that 75 mg/kg caffeine and 100 mg/kg EGCG could significantly improve liver lipid deposition, glucose metabolism, inflammation, and fibrosis in a mouse model of NASH induced by HFHC. The bioinformatics platform we built for caffeine and EGCG in NASH disease found that the two drugs may greatly overlap in improving the mechanism related to NASH inflammation. However, caffeine may have better potential in regulating glucose metabolism and EGCG may have better potential in regulating lipid metabolism.
Effects of Dietary Supplementation With Bacillus subtilis, as an Alternative to Antibiotics, on Growth Performance, Serum Immunity, and Intestinal Health in Broiler Chickens
Authors: Qiu Kai , Li Cheng-liang , Wang Jing , Qi Guang-hai , Gao Jun , Zhang Hai-jun , Wu Shu-geng
Published: December 2021

Bacillus subtilis (B. subtilis) as in-feed probiotics is a potential alternative for antibiotic growth promoters (AGP) in the poultry industry. The current study investigated the effects of B. subtilis on the performance, immunity, gut microbiota, and intestinal barrier function of broiler chickens. A 42-day feeding trial was conducted with a total of 600 1-day-old Arbor Acres broilers with similar initial body weight, which was randomly divided into one of five dietary treatments: the basal diet (Ctrl), Ctrl + virginiamycin (AGP), Ctrl + B. subtilis A (BSA), Ctrl + B. subtilis B (BSB), and Ctrl + B. subtilis A + B (1:1, BSAB). The results showed significantly increased average daily gain in a step-wise manner from the control, B. subtilis, and to the AGP groups. The mortality rate of the B. subtilis group was significantly lower than the AGP group. The concentrations of serum immunoglobulin (Ig) G (IgG), IgA, and IgM in the B. subtilis and AGP groups were higher than the control group, and the B. subtilis groups had the highest content of serum lysozyme and relative weight of thymus. Dietary B. subtilis increased the relative length of ileum and the relative weight of jejunum compared with the AGP group. The villus height (V), crypt depth (C), V/C, and intestinal wall thickness of the jejunum in the B. subtilis and AGP groups were increased relative to the control group. Dietary B. subtilis increased the messenger RNA (mRNA) expression of ZO-1, Occludin, and Claudin-1, the same as AGP. The contents of lactic acid, succinic acid, and butyric acid in the ileum and cecum were increased by dietary B. subtilis. Dietary B. subtilis significantly increased the lactobacillus and bifidobacteria in the ileum and cecum and decreased the coliforms and Clostridium perfringens in the cecum. The improved performance and decreased mortality rate observed in the feeding trial could be accrued to the positive effects of B. subtilis on the immune response capacity, gut health, and gut microflora balance, and the combination of two strains showed additional benefits on the intestinal morphology and tight junction protein expressions. Therefore, it can be concluded that dietary B. subtilis A and B could be used as alternatives to synthetic antibiotics in the promotion of gut health and productivity index in broiler production.
Solanum Fruits: Phytochemicals, Bioaccessibility and Bioavailability, and Their Relationship With Their Health-Promoting Effects
Authors: Elizalde-Romero Cristina Alicia , Montoya-Inzunza Luis Aurelio , Contreras-Angulo Laura Aracely , Heredia J. Basilio , Gutiérrez-Grijalva Erick Paul
Published: December 2021

The Solanum genus is the largest in the Solanaceae family containing around 2,000 species. There is a great number of edibles obtained from this genus, and globally, the most common are tomato (S. lycopersicum), potato (S. tuberosum), and eggplant (S. melongena). Other fruits are common in specific regions and countries, for instance, S. nigrum, S. torvum, S. betaceum, and S. stramonifolium. Various reports have shown that flavonoids, phenolic acids, alkaloids, saponins, and other molecules can be found in these plants. These molecules are associated with various health-promoting properties against many non-communicable diseases, the main causes of death globally. Nonetheless, the transformations of the structure of antioxidants caused by cooking methods and gastrointestinal digestion impact their potential benefits and must be considered. This review provides information about antioxidant compounds, their bioaccessibility and bioavailability, and their health-promoting effects. Bioaccessibility and bioavailability studies must be considered when evaluating the bioactive properties of health-promoting molecules like those from the Solanum genus.
AI and High-Grade Glioma for Diagnosis and Outcome Prediction: Do All Machine Learning Models Perform Equally Well?
Authors: Pasquini Luca , Napolitano Antonio , Lucignani Martina , Tagliente Emanuela , Dellepiane Francesco , Rossi-Espagnet Maria Camilla , Ritrovato Matteo , Vidiri Antonello , Villani Veronica , Ranazzi Giulio , Stoppacciaro Antonella , Romano Andrea , Di Napoli Alberto , Bozzao Alessandro
Published: November 2021

Radiomic models outperform clinical data for outcome prediction in high-grade gliomas (HGG). However, lack of parameter standardization limits clinical applications. Many machine learning (ML) radiomic models employ single classifiers rather than ensemble learning, which is known to boost performance, and comparative analyses are lacking in the literature. We aimed to compare ML classifiers to predict clinically relevant tasks for HGG: overall survival (OS), isocitrate dehydrogenase (IDH) mutation, O-6-methylguanine-DNA-methyltransferase (MGMT) promoter methylation, epidermal growth factor receptor vIII (EGFR) amplification, and Ki-67 expression, based on radiomic features from conventional and advanced magnetic resonance imaging (MRI). Our objective was to identify the best algorithm for each task. One hundred fifty-six adult patients with pathologic diagnosis of HGG were included. Three tumoral regions were manually segmented: contrast-enhancing tumor, necrosis, and non-enhancing tumor. Radiomic features were extracted with a custom version of Pyradiomics and selected through Boruta algorithm. A Grid Search algorithm was applied when computing ten times K-fold cross-validation (K=10) to get the highest mean and lowest spread of accuracy. Model performance was assessed as AUC-ROC curve mean values with 95% confidence intervals (CI). Extreme Gradient Boosting (xGB) obtained highest accuracy for OS (74,5%), Adaboost (AB) for IDH mutation (87.5%), MGMT methylation (70,8%), Ki-67 expression (86%), and EGFR amplification (81%). Ensemble classifiers showed the best performance across tasks. High-scoring radiomic features shed light on possible correlations between MRI and tumor histology.
MicroRNA-1246 Mediates Drug Resistance and Metastasis in Breast Cancer by Targeting NFE2L3
Authors: Dai Yue-chu , Pan Yin , Quan Ming-ming , Chen Qi , Pan Yue , Ruan Yan-yun , Sun Jian-guo
Published: December 2021

MicroRNA (miR)-1246 is abnormally expressed and has pro-oncogenic functions in multiple types of cancer. In the present study, its functions in breast cancer and the underlying mechanisms were further elucidated. The clinical relevance of miR-1246 was analyzed and its expression in clinical specimens and cell lines was examined by reverse transcription-quantitat000000ive PCR analysis. FACS was used to detect cell apoptosis and mitochondrial transmembrane potential. A Transwell system was used to detect cell migration and invasion. Luciferase assay was used to confirm the target gene of miR-1246. Xenograft and metastasis mouse models were constructed to determine the function of miR-1246 in vivo. miR-1246 was found to be negatively associated with overall survival in breast cancer. miR-1246 inhibitor could effectively increase the cytotoxicity of docetaxel (Doc) by inducing apoptosis, and impair cell migration and invasion by suppressing epithelial-to-mesenchymal transition. Nuclear factor (erythroid 2)-like factor 3 (NFE2L3) was confirmed as a new target gene of miR-1246, and its overexpression was shown to reduce drug resistance and migration of MDA-MB-231 cells. More importantly, NFE2L3-silencing attenuated the effect of miR-1246 inhibitor. Finally, the inhibition of miR-1246 effectively enhanced the cytotoxicity of Doc in xenografts and impaired breast cancer metastasis. Therefore, miR-1246 may promote drug resistance and metastasis in breast cancer by targeting NFE2L3.
Identification of CCL4 as an Immune-Related Prognostic Biomarker Associated With Tumor Proliferation and the Tumor Microenvironment in Clear Cell Renal Cell Carcinoma
Authors: Zhang Lu , Zhang Mengzhao , Wang Lu , Li Jianlong , Yang Tao , Shao Qiuya , Liang Xiao , Ma Minghai , Zhang Nan , Jing Minxuan , Song Rundong , Fan Jinhai
Published: November 2021

The last decade has witnessed revolutionary advances taken in immunotherapy for various malignant tumors. However, immune-related molecules and their characteristics in the prediction of clinical outcomes and immunotherapy response in clear cell renal cell carcinoma (ccRCC) remain largely unclear. C-C Motif Chemokine Ligand 4 (CCL4) was extracted from the intersection analysis of common differentially expressed genes (DEGs) of four microarray datasets from the Gene Expression Omnibus database and immune-related gene lists in the ImmPort database using Cytoscape plug-ins and univariate Cox regression analysis. Subsequential analysis revealed that CCL4 was highly expressed in ccRCC patients, and positively correlated with multiple clinicopathological characteristics, such as grade, stage and metastasis, while negatively with overall survival (OS). We performed gene set enrichment analysis (GSEA) and gene set variant analysis (GSVA) with gene sets coexpressed with CCL4, and observed that gene sets positively related to CCL4 were enriched in tumor proliferation and immune-related pathways while metabolic activities in the negatively one. To further explore the correlation between CCL4 and immune-related biological process, the CIBERSORT algorithm, ESTIMATE method, and tumor mutational burden (TMB) score were employed to evaluate the tumor microenvironment (TME) characteristics of each sample and confirmed that high CCL4 expression might give rise to high immune cell infiltration. Moreover, correlation analysis revealed that CCL4 was positively correlated with common immune checkpoint genes, such as programmed cell death protein 1 (PD-1), cytotoxic T-lymphocyte-associated protein 4 (CTLA4), and lymphocyte activating 3 (LAG3). Overall, this study demonstrated that CCL4 might serve as a potential immune-related prognostic biomarker to predict clinical outcomes and immunotherapy response in ccRCC. Moreover, CCL4 might contribute to TME modulation, indicating the mechanism CCL4 involved in tumor proliferation and metastasis, which could provide novel therapeutic perceptions for ccRCC patients.
Development and Validation of Prognostic Nomogram in Patients With WHO Grade III Meningioma: A Retrospective Cohort Study Based on SEER Database
Authors: Jia Zetian , Yan Yaqi , Wang Jiuxin , Yang He , Zhan Haihua , Chen Qian , He Yawei , Hu Yuhua
Published: December 2021

Introduction

World Health Organization (WHO) Grade III meningioma is a central nervous system tumor with a poor prognosis. In this retrospective cohort study, the authors constructed a nomogram for predicting the prognosis of WHO Grade III meningioma.

Methods

The patients of this nomogram were based on the Surveillance, Epidemiology, and End Results (SEER) database between 2000 and 2018. All patients were randomly divided into a development cohort (964 patients) and a validation cohort (410 patients) in a 7:3 ratio. The least absolute shrinkage and selection operator (LASSO) regression was used to screen the predictors. The Cox hazards regression model was constructed and the prognosis was visualized by nomogram. The performance of the prognostic nomogram was determined by consistency index (C-index), clinical net benefit, and calibration.

Results

Eight variables were included in the nomogram: gender, race, age at diagnosis, histology, tumor site, tumor size, laterality, and surgical method. The C-index of the training set and verification set were 0.654 and 0.628. The calibration plots showed that the nomogram was in good agreement with the actual observation. The clinical decision curve indicates that the nomogram has a good clinical net benefit in WHO Grade III meningioma.

Conclusions

A prognostic nomogram of a large cohort of WHO Grade III meningioma was established and verified based on the SEER database. The nomogram we established may help clinicians provide personalized treatment services and clinical decisions for patients.
Clinical Utility of Circulating Tumor DNA in Advanced Rare Cancers
Authors: Okuma Hitomi Sumiyoshi , Yonemori Kan , Kojima Yuki , Tanioka Maki , Sudo Kazuki , Noguchi Emi , Hijioka Susumu , Wakakuwa Keiko , Kato Ken , Hirakawa Akihiro , Kuchiba Aya , Kubo Takashi , Ichikawa Hitoshi , Yoshida Akihiko , Yatabe Yasushi , Nakamura Kenichi , Mano Hiroyuki , Yamamoto Noboru , Fujiwara Yasuhiro
Published: November 2021

Purpose

Patients with advanced/relapsed rare cancers have few treatment options. Analysis of circulating tumor DNA in plasma may identify actionable genomic biomarkers using a non-invasive approach.

Patients and Methods

Rare cancer patients underwent prospective plasma-based NGS testing. Tissue NGS to test concordance was also conducted. Plasma DNA alterations were assessed for incidence, functional impact, therapeutic implications, correlation to survival, and comparison with tissue NGS.

Results

Ninety-eight patients were analyzed. Diseases included soft-tissue sarcoma, ovarian carcinoma, and others. Mean turn-around-time for results was 9.5 days. Seventy-six patients had detectable gene alterations in plasma, with a median of 2.8 alterations/patient. Sixty patients had a likely pathogenic alteration. Five received matched-therapy based on plasma NGS results. Two developed known resistance mutations while on targeted therapy. Patients with an alteration having VAF ≥5% had a significantly shorter survival compared to those of lower VAF. Tissue NGS results from eleven of 22 patients showed complete or partial concordance with plasma NGS.

Conclusion

Plasma NGS testing is less invasive and capable of identifying alterations in advanced rare cancers in a clinically meaningful timeframe. It should be further studied as a prospective enrollment assay in interventional studies for patients with rare advanced stage cancers.

Clinical Registration

[https://www.umin.ac.jp/ctr/index-j.htm], identifier UMIN000034394.
Pseudomonas aeruginosa PcrV Enhances the Nitric Oxide-Mediated Tumoricidal Activity of Tumor-Associated Macrophages via a TLR4/PI3K/AKT/mTOR-Glycolysis-Nitric Oxide Circuit
Authors: Yu Hua , Bai Ying , Qiu Jing , He Xiaomei , Xiong Junzhi , Dai Qian , Wang Xingmin , Li Yuanyuan , Sheng Halei , Xin Rong , Jiang Lu , Li Qiaoqiao , Li Defeng , Zhang Hong , Zhang Le , Chen Qian , Peng Jin , Hu Xiaomei , Zhang Kebin
Published: November 2021

Tumor-associated macrophages (TAMs), which display a tumor-supportive M2 phenotype, are closely related to tumor growth and metastasis. The reprogramming of TAMs toward a tumoricidal M1 profile has emerged as an attractive strategy for cancer immunotherapy. In this study, we found that the intratumoral injection of PcrV protein, a component of the Pseudomonas aeruginosa type 3 secretion system, suppressed tumor growth and increased apoptosis, inducible nitric oxide synthase (iNOS) expression, and the percentage of M1-polarized TAMs in tumor tissues. Furthermore, the intratumoral injection of PcrV-primed macrophages exerted a similar tumoricidal effect. In vitro analyses revealed that PcrV reeducated TAMs toward an antitumoral M1 phenotype and augmented their nitric oxide (NO)-mediated cytotoxicity against cancer cells. Mechanistically, we found that these effects were dependent on the activation of Toll-like receptor 4 (TLR4)/myeloid differentiation factor 88 (MyD88)-mediated regulation of a PI3K/AKT/mTOR-glycolysis-NO feedback loop via direct interaction with TLR4. Collectively, these results revealed a potential role for PcrV in cancer immunotherapy through the targeting of TAM plasticity.
N6-Methyladenosine Methyltransferase METTL14-Mediated Autophagy in Malignant Development of Oral Squamous Cell Carcinoma
Authors: Wang Fang , Zhu Yue , Cai Hongshi , Liang Jianfeng , Wang Wenjin , Liao Yan , Zhang Yadong , Wang Cheng , Hou Jinsong
Published: November 2021

N6-methyladenosine (m6A) is the most abundant internal mRNA modification in eukaryotes and is related to stability, localization, or translation efficiency in tumorigenesis. Autophagy plays an important role in the occurrence and development of tumours. However, the relationship between m6A and autophagy remains unclear. In this study, we used a rapamycin-induced autophagy model of oral squamous cell carcinoma (OSCC) cells, and observed increased m6A RNA methylation. When autophagy was activated, the methyltransferase-like 14 (METTL14) expression was upregulated and influenced the proliferation, migration, and invasiveness of OSCC cells. Through meRIP-seq and RNA-seq analysis, we found that METTL14 directly combined with eukaryotic translation initiation factor gamma 1 (eIF4G1) mRNA and decreased its RNA stability. According to the dual-luciferase reporter and mutagenesis assay, the mutated site 1 of exon 11 of eIF4G1 is the key target of METTL14. Knockdown of the main m6A binding protein YTHDF2 may rescue the shortened half-life of eIF4G1 mRNA induced by METTL14 overexpression. Furthermore, an in vivo tumour xenograft model confirmed that a high METTL14 expression can effectively reduce OSCC growth. Additionally, using clinical samples, we found that patients with advanced or moderately/poorly differentiated tumours exhibited lower METTL14 levels. Taken together, our results revealed that METTL14 mediated eIF4G1 expression via m6A modification and regulated autophagy levels and biological functions in OSCC. Our findings not only expand our understanding of the correlation between autophagy and RNA methylation in tumorigenesis but also present an opportunity to develop new therapeutic options.
Prostate Cancer Gleason Score From Biopsy to Radical Surgery: Can Ultrasound Shear Wave Elastography and Multiparametric Magnetic Resonance Imaging Narrow the Gap?
Authors: Wei Cheng , Zhang Yilong , Zhang Xinyu , Ageeli Wael , Szewczyk-Bieda Magdalena , Serhan Jonathan , Wilson Jennifer , Li Chunhui , Nabi Ghulam
Published: November 2021

Objectives

To investigate the impact of ultrasound shear wave elastography (USWE) and multiparametric magnetic resonance imaging (mpMRI) in predicting a change in biopsy-assigned Gleason Score (GS) after radical surgery for localised prostate cancer (PCa).

Method

A total of 212 men opting for laparoscopic radical prostatectomy (LRP) between September 2013 and June 2017 were recruited into this study. All the participants had 12-core transrectal ultrasound (TRUS) biopsies and imaging using USWE and mpMRI before radical surgery. The predictive accuracy for imaging modalities was assessed in relation to upgrading and downgrading of PCa GS between the biopsies and radical prostatectomy using Student’s t-test and multivariable logistic regression analyses. A decision analysis curve was constructed assessing the impact of nomogram on clinical situations using different thresholds of upgrading probabilities.

Results

Most GS 6 diseases on biopsies were upgraded on radical surgery (37/42, 88.1%). Major downgrading was seen in GS 8 category of disease (14/35; 37.1%), whereas no alteration was observed in GS 7 on biopsies in most men (55/75; 73.3%). In univariate analysis, higher preoperative prostate-specific antigen (PSA) (p = 0.001), higher prostate-specific antigen density (PSAD) (p = 0.002), stiffer USWE lesions (p = 0.009), and higher prostate imaging–reporting and data system (PIRADS) (p = 0.002) on mpMRI were significant predictors of upgrading. In multivariate logistic regression analyses, only PSA (p = 0.016) and USWE-measured tissue stiffness (p = 0.029) showed statistical significance in predicting upgrading.

Conclusions

Measurement of tissue stiffness using USWE in clinically localised PCa can predict upgrading of GS and has the potential to improve patient management options.
Glioma Imaging by O-(2-18F-Fluoroethyl)-L-Tyrosine PET and Diffusion-Weighted MRI and Correlation With Molecular Phenotypes, Validated by PET/MR-Guided Biopsies
Authors: Cheng Ye , Song Shuangshuang , Wei Yukui , Xu Geng , An Yang , Ma Jie , Yang Hongwei , Qi Zhigang , Xiao Xinru , Bai Jie , Xu Lixin , Hu Zeliang , Sun Tingting , Wang Leiming , Lu Jie , Lin Qingtang
Published: December 2021

Gliomas exhibit high intra-tumoral histological and molecular heterogeneity. Introducing stereotactic biopsy, we achieved a superior molecular analysis of glioma using O-(2-18F-fluoroethyl)-L-tyrosine (FET)-positron emission tomography (PET) and diffusion-weighted magnetic resonance imaging (DWI). Patients underwent simultaneous DWI and FET-PET scans. Correlations between biopsy-derived tumor tissue values, such as the tumor-to-background ratio (TBR) and apparent diffusion coefficient (ADC)/exponential ADC (eADC) and histopathological diagnoses and those between relevant genes and TBR and ADC values were determined. Tumor regions with human telomerase reverse transcriptase (hTERT) mutation had higher TBR and lower ADC values. Tumor protein P53 mutation correlated with lower TBR and higher ADC values. α-thalassemia/mental-retardation-syndrome-X-linked gene (ATRX) correlated with higher ADC values. 1p/19q codeletion and epidermal growth factor receptor (EGFR) mutations correlated with lower ADC values. Isocitrate dehydrogenase 1 (IDH1) mutations correlated with higher TBRmean values. No correlation existed between TBRmax/TBRmean/ADC/eADC values and phosphatase and tensin homolog mutations (PTEN) or O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation. Furthermore, TBR/ADC combination had a higher diagnostic accuracy than each single imaging method for high-grade and IDH1-, hTERT-, and EGFR-mutated gliomas. This is the first study establishing the accurate diagnostic criteria for glioma based on FET-PET and DWI.
Profile of Basal Cell Carcinoma Mutations and Copy Number Alterations - Focus on Gene-Associated Noncoding Variants
Authors: Nawrocka Paulina Maria , Galka-Marciniak Paulina , Urbanek-Trzeciak Martyna Olga , M-Thirusenthilarasan Ilamathi , Szostak Natalia , Philips Anna , Susok Laura , Sand Michael , Kozlowski Piotr
Published: December 2021

Basal cell carcinoma (BCC) of the skin is the most common cancer in humans, characterized by the highest mutation rate among cancers, and is mostly driven by mutations in genes involved in the hedgehog pathway. To date, almost all BCC genetic studies have focused exclusively on protein-coding sequences; therefore, the impact of noncoding variants on the BCC genome is unrecognized. In this study, with the use of whole-exome sequencing of 27 tumor/normal pairs of BCC samples, we performed an analysis of somatic mutations in both protein-coding sequences and gene-associated noncoding regions, including 5’UTRs, 3’UTRs, and exon-adjacent intron sequences. Separately, in each region, we performed hotspot identification, mutation enrichment analysis, and cancer driver identification with OncodriveFML. Additionally, we performed a whole-genome copy number alteration analysis with GISTIC2. Of the >80,000 identified mutations, ~50% were localized in noncoding regions. The results of the analysis generally corroborated the previous findings regarding genes mutated in coding sequences, including PTCH1, TP53, and MYCN, but more importantly showed that mutations were also clustered in specific noncoding regions, including hotspots. Some of the genes specifically mutated in noncoding regions were identified as highly potent cancer drivers, of which BAD had a mutation hotspot in the 3’UTR, DHODH had a mutation hotspot in the Kozak sequence in the 5’UTR, and CHCHD2 frequently showed mutations in the 5’UTR. All of these genes are functionally implicated in cancer-related processes (e.g., apoptosis, mitochondrial metabolism, and de novo pyrimidine synthesis) or the pathogenesis of UV radiation-induced cancers. We also found that the identified BAD and CHCHD2 mutations frequently occur in melanoma but not in other cancers via The Cancer Genome Atlas analysis. Finally, we identified a frequent deletion of chr9q, encompassing PTCH1, and unreported frequent copy number gain of chr9p, encompassing the genes encoding the immune checkpoint ligands PD-L1 and PD-L2. In conclusion, this study is the first systematic analysis of coding and noncoding mutations in BCC and provides a strong basis for further analyses of the variants in BCC and cancer in general.
Cohort Profile: The Socioeconomic Consequences in Adult Life After Childhood Cancer in Scandinavia (SALiCCS) Research Programme
Authors: Erdmann Friederike , Frederiksen Line Elmerdahl , Mogensen Hanna , Pedersen Camilla , Mader Luzius , Talbäck Mats , Bautz Andrea , Hirvonen Elli , Kyrönlahti Anniina , Korhonen Liisa Maria , Hasle Henrik , Malila Nea , Madanat-Harjuoja Laura-Maria , Feychting Maria , Winther Jeanette Falck
Published: December 2021

Introduction

The growing number of survivors of childhood cancer, with many years of life ahead, demonstrates the increasing clinical and public health relevance of investigating the risks of social and socioeconomic impairment after a childhood cancer diagnosis and the life-saving treatment. To enrich understanding of the mental, social and socioeconomic difficulties that childhood cancer survivors may face during their life-course, identify particularly vulnerable survivors and overcome the limitations of previous research, we initiated the Socioeconomic Consequences in Adult Life after Childhood Cancer in Scandinavia (SALiCCS) research programme.

Methods

This Nordic cross-border research programme is a collaboration between the Danish Cancer Society, the Finnish Cancer Registry and Karolinska Institutet to investigate a broad range of mental, social and socioeconomic conditions in long-term childhood cancer survivors in Denmark, Finland and Sweden. SALiCCS is based on a registry-based matched cohort design, comprising five-year survivors of cancer diagnosed at ages 0–19 years (1971–2008 in Denmark, 1971–2009 in Finland, 1971–2011 in Sweden), age-, sex- and country-matched population comparisons and sibling comparisons who were followed over time. Outcomes of interest included mental disorders, educational achievements, employment and profession, family life and the need of social security benefits. Individual-level data linkage among various national registries provided the data for the research programme.

Results

The SALiCCS core population comprises 21,292 five-year survivors, 103,303 population comparisons and 29,644 siblings as a second comparison group. The most common diagnoses in survivors were central nervous system tumours, leukaemias and lymphomas.

Discussion

SALiCCS is the largest, most comprehensive population-based research initiative in this field, based on high-quality registry data with minimal risk of bias. The findings will be informative for evidence-based survivorship care targeting not only somatic late effects but also psychosocial impairments.
High Serpin Family A Member 10 Expression Confers Platinum Sensitivity and Is Associated With Survival Benefit in High-Grade Serous Ovarian Cancer: Based on Quantitative Proteomic Analysis
Authors: Guo Wenwen , He Xue , Ni Jing , Ma Liya , Cheng Xianzhong , Wang Congyang , Chen Xiaoxiang , Wang Yan
Published: November 2021

This study aims to identify differentially expressed proteins related with platinum sensitivity and to find biomarkers for predicting platinum response and survival outcomes in patients with high-grade serous ovarian cancer (HGSOC). Eligible HGSOC patients were divided into platinum-sensitive and platinum-resistant groups according to platinum-free interval (PFI). Tissue protein lysates from tumor tissues were subjected to an in-solution tryptic digest followed by tandem mass tag (TMT) labeling of the resulting peptides and mass spectrometric analysis. Candidate proteins were identified using differentially expressed protein and gene set enrichment analysis (GSEA) and confirmed by immunohistochemistry (IHC), and their survival relevance was evaluated in The Cancer Genome Atlas (TCGA) ovarian cancer cohort. The results showed that there was a significant difference in the protein expression profiling between the two patient groups. In the GSEA model, a gene set of 239 extracellular matrix (ECM)-related proteins was significantly enriched in the platinum-sensitive group [normalized enrichment score (NES) = 3.82, q < 10−5], and this finding was confirmed in TCGA ovarian cancer cohort. Interestingly, an ECM-related gene expression, serpin family A member 10 (SERPINA10), was identified to be significantly positively correlated with overall survival (OS) and progression-free survival (PFS) in TCGA ovarian cancer cohort (all p < 0.05). IHC results demonstrated that HGSOC patients with high SERPINA10 expression had longer PFI than the patients with low SERPINA10 expression (9 vs. 5 months, p = 0.038), and the SERPINA10 expression had an area under the receiver operating characteristic curve (AUC) value of 0.758 (95% CI = 0.612–0.905; p = 0.005) to discriminate the platinum-sensitive group from the platinum-resistant group. In conclusion, the results suggested that SERPINA10 could be a promising biomarker for predicting the response and survival in platinum-based chemotherapy of HGSOC.
Recent Advances in Brachytherapy Using Radioactive Nanoparticles: An Alternative to Seed-Based Brachytherapy
Authors: Seniwal Baljeet , Thipe Velaphi C. , Singh Sukhvir , Fonseca Telma C. F. , Freitas de Freitas Lucas
Published: November 2021

Interstitial brachytherapy (BT) is generally used for the treatment of well-confined solid tumors. One example of this is in the treatment of prostate tumors by permanent placement of radioactive seeds within the prostate gland, where low doses of radiation are delivered for several months. However, successful implementation of this technique is hampered due to several posttreatment adverse effects or symptoms and operational and logistical complications associated with it. Recently, with the advancements in nanotechnology, radioactive nanoparticles (radio-NPs) functionalized with tumor-specific biomolecules, injected intratumorally, have been reported as an alternative to seed-based BT. Successful treatment of solid tumors using radio-NPs has been reported in several preclinical studies, on both mice and canine models. In this article, we review the recent advancements in the synthesis and use of radio-NPs as a substitute to seed-based BT. Here, we discuss the limitations of current seed-based BT and advantages of radio-NPs for BT applications. Recent progress on the types of radio-NPs, their features, synthesis methods, and delivery techniques are discussed. The last part of the review focuses on the currently used dosimetry protocols and studies on the dosimetry of nanobrachytherapy applications using radio-NPs. The current challenges and future research directions on the role of radio-NPs in BT treatments are also discussed.
Worst Pattern of Perineural Invasion Redefines the Spatial Localization of Nerves in Oral Squamous Cell Carcinoma
Authors: Fu Yong , Zhang Xinwen , Ding Zhuang , Zhu Nisha , Song Yuxian , Zhang Xiaoxin , Jing Yue , Yu Yijun , Huang Xiaofeng , Zhang Lei , Hu Qingang , Ni Yanhong , Ding Liang
Published: December 2021

As a key histopathological characteristic of tumor invasion, perineural invasion (PNI) assists tumor dissemination, whereas the current definition of PNI by dichotomy is not accurate and the prognostic value of PNI has not reached consensus. To define PNI status in each patient when mixed types of PNI occurred simultaneously, we here further subclassified the traditional PNI in 183 patients with oral squamous cell carcinoma (OSCC). The spatial localization of nerves in OSCC microenvironment was thoroughly evaluated and successfully concluded into four types of PNI: 0, tumor cells away from nerves; 1, tumor cells encircling nerves less than 33%; 2, tumor cells encircling nerves at least 33%; and 3, tumor cells infiltrating into nerve sheathes. Sequentially, patients were stratified by single and mixed types of PNI. Traditionally, types 0 and 1 were defined as PNI−, while types 2 and 3 were PNI+, which predicted shorter survival time. When multiple types of PNI existed within one tumor, patients with higher score of PNI types tended to have a relatively worse prognosis. Therefore, to define the status of PNI more precisely, the new variable worst pattern of PNI (WPNI) was proposed, which was taken as the highest score of PNI types present in each patient no matter how focal. Results showed that patients with WPNI 1 had longest survival time, and WPNI 2 correlated with better overall survival (p= 0.02), local-regional recurrence-free survival (p= 0.03), and distant metastasis-free survival (p= 0.046) than WPNI 3. Multivariate Cox analysis confirmed that only WPNI 3 could independently predict patients’ prognosis, which could be explained by a more damaged immune response in WPNI 3 patients with less CD3+CD8+T cells and CD19+B cells. Conclusively, WPNI by trichotomy provide more meticulous and precise pathological information for tumor-nerve interactions in OSCC patients.
Chromothripsis in Chronic Lymphocytic Leukemia: A Driving Force of Genome Instability
Authors: Zavacka Kristyna , Plevova Karla
Published: December 2021

Chromothripsis represents a mechanism of massive chromosome shattering and reassembly leading to the formation of derivative chromosomes with abnormal functions and expression. It has been observed in many cancer types, importantly, including chronic lymphocytic leukemia (CLL). Due to the associated chromosomal rearrangements, it has a significant impact on the pathophysiology of the disease. Recent studies have suggested that chromothripsis may be more common than initially inferred, especially in CLL cases with adverse clinical outcome. Here, we review the main features of chromothripsis, the challenges of its assessment, and the potential benefit of its detection. We summarize recent findings of chromothripsis occurrence across hematological malignancies and address its causes and consequences in the context of CLL clinical features, as well as chromothripsis-related molecular abnormalities described in published CLL studies. Furthermore, we discuss the use of the current knowledge about genome functions associated with chromothripsis in the optimization of treatment strategies in CLL.
Effect of Chemotherapy on Overall Survival in Contemporary Metastatic Prostate Cancer Patients
Authors: Hoeh Benedikt , Würnschimmel Christoph , Flammia Rocco S. , Horlemann Benedikt , Sorce Gabriele , Chierigo Francesco , Tian Zhe , Saad Fred , Graefen Markus , Gallucci Michele , Briganti Alberto , Terrone Carlo , Shariat Shahrokh F. , Tilki Derya , Kluth Luis A. , Mandel Philipp , Chun Felix K. H. , Karakiewicz Pierre I.
Published: November 2021

Introduction

Randomized clinical trials demonstrated improved overall survival in chemotherapy exposed metastatic prostate cancer patients. However, real-world data validating this effect with large scale epidemiological data sets are scarce and might not agree with trials. We tested this hypothesis.

Materials and Methods

We identified de novo metastatic prostate cancer patients within the Surveillance, Epidemiology, and End Results (SEER) database (2014-2015). Kaplan-Meier plots and Cox regression models tested for overall survival differences between chemotherapy-exposed patients vs chemotherapy-naïve patients. All analyses were repeated in propensity-score matched cohorts. Additionally, landmark analyses were applied to account for potential immortal time bias.

Results

Overall, 4295 de novo metastatic prostate cancer patients were identified. Of those, 905 (21.1%) patients received chemotherapy vs 3390 (78.9%) did not. Median overall survival was not reached at 30 months follow-up. Chemotherapy-exposed patients exhibited significantly better overall survival (61.6 vs 54.3%, multivariable HR:0.82, CI: 0.72-0.96, p=0.01) at 30 months compared to their chemotherapy-naïve counterparts. These findings were confirmed in propensity score matched analyses (multivariable HR: 0.77, CI:0.66-0.90, p<0.001). Results remained unchanged after landmark analyses were applied in propensity score matched population.

Conclusions

In this contemporary real-world population-based cohort, chemotherapy for metastatic prostate cancer patients was associated with better overall survival. However, the magnitude of overall survival benefit was not comparable to phase 3 trials.
Impact of Preoperative vs Postoperative Radiotherapy on Overall Survival of Locally Advanced Breast Cancer Patients
Authors: Deng Yujiao , Li Hongtao , Zheng Yi , Zhai Zhen , Wang Meng , Lin Shuai , Li Yizhen , Wei Bajin , Xu Peng , Wu Ying , Deng Xinyue , Yang Si , Lyu Jun , Hu Jingjing , Dong Huaying , Dai Zhijun
Published: November 2021

Background

The treatment for locally advanced breast cancer (LABC) is a severe clinical problem. The postoperative radiotherapy is a conventional treatment method for patients with LABC, whereas the effect of preoperative radiotherapy on outcome of LABC remains controversial. This study aimed to examine and compare the overall survival (OS) in patients with LABC who underwent preoperative radiotherapy or postoperative radiotherapy.

Methods

This retrospective cohort study included 41,618 patients with LABC from the National Cancer Database (NCDB) between 2010 and 2014. We collected patients’ demographic, clinicopathologic, treatment and survival information. Propensity score was used to match patients underwent pre-operative radiotherapy with those who underwent post-operative radiotherapy. Cox proportional hazard regression model was performed to access the association between variables and OS. Log-rank test was conducted to evaluate the difference in OS between groups.

Results

The estimated median follow-up of all included participants was 69.6 months (IQR: 42.84-60.22); 70.1 months (IQR: 46.85-79.97) for postoperative radiotherapy, 68.5 (IQR: 41.13-78.23) for preoperative radiotherapy, and 67.5 (IQR: 25.92-70.99) for no radiotherapy. The 5-year survival rate was 80.01% (79.56-80.47) for LABC patients who received postoperative radiotherapy, 64.08% (57.55-71.34) for preoperative radiotherapy, and 59.67% (58.60-60.77) for no radiotherapy. Compared with no radiation, patients receiving postoperative radiotherapy had a 38% lower risk of mortality (HR=0.62, 95%CI: 0.60-0.65, p<0.001), whereas those who received preoperative radiotherapy had no significant survival benefit (HR=0.88, 95%CI: 0.70-1.11, p=0.282). Propensity score matched analysis indicated that patients treated with preoperative radiotherapy had similar outcomes as those treated with postoperative radiotherapy (AHR=1.23, 95%CI: 0.88-1.72, p=0.218). Further analysis showed that in C0 (HR=1.45, 95%CI: 1.01-2.07, p=0.044) and G1-2 (AHR=1.74, 95%CI: 1.59-5.96, p=0.001) subgroup, patients receiving preoperative radiotherapy showed a worse OS than those who received postoperative radiotherapy.

Conclusions

Patients with LABC underwent postoperative radiotherapy had improved overall survival, whereas no significant survival benefit was observed in patients receiving preoperative radiotherapy. Preoperative radiotherapy did not present a better survival than postoperative radiotherapy for LABC patients.