bluuebunny/crossref_metadata_2025 huggingface dataset:
Citrus Polyphenols in Brain Health and Disease: Current Perspectives
Authors: Pontifex Matthew G. , Malik Mohammad M. A. H. , Connell Emily , Müller Michael , Vauzour David
Published: February 2021

In addition to essential micronutrients such as vitamin C, citrus fruits represent a considerably rich source of non-essential bioactive compounds, in particular flavanones which form a sub-set of the flavonoid group. Preclinical studies have demonstrated the neuroprotective potential of citrus flavonoids and have highlighted both the well-established (anti-inflammatory and anti-oxidative properties), and newly emerging (influence upon blood-brain barrier function/integrity) mechanistic actions by which these neurological effects are mediated. Encouragingly, results from human studies, although limited in number, appear to support this preclinical basis, with improvements in cognitive performance and disease risk observed across healthy and disease states. Therefore, citrus fruits – both as whole fruit and 100% juices – should be encouraged within the diet for their potential neurological benefit. In addition, there should be further exploration of citrus polyphenols to establish therapeutic efficacy, particularly in the context of well-designed human interventions.
The Effects of Probiotic Supplementation on Anthropometric Growth and Gut Microbiota Composition in Patients With Prader-Willi Syndrome: A Randomized Double-Blinded Placebo-Controlled Trial
Authors: Kong Xue-Jun , Wan Guobin , Tian Ruiyi , Liu Siyu , Liu Kevin , Clairmont Cullen , Lin Xiaojing , Zhang Xiaoying , Sherman Hannah , Zhu Junli , Wang Yelan , Fong Michelle , Li Alice , Wang Bryan K. , Wang Jinghan , Liu Jun , Yu Zhehao , Shen Chen , Cui Xianghua , Cao Hanyu , Du Ting , Cao Xia
Published: February 2021

Background: Prader-Willi Syndrome (PWS) is a rare genetic disorder associated with developmental delay, obesity, and neuropsychiatric comorbidities. Bifidobacterium animalis subsp. lactis has demonstrated anti-obesity and anti-inflammatory effects in previous studies.

Aim: To evaluate the effects of Bifidobacterium animalis subsp. lactis probiotics supplementation on anthropometric growth, behavioral symptoms, and gut microbiome composition in patients with PWS.

Methods: Ethical Approval was issued by the Internal Review Board (IRB) of the Second Affiliated Hospital of Kunming Medical University (Review-YJ-2016-06). We conducted a 12-week, randomized, double-blind, placebo-controlled trial in 68 patients with Prader-Willi syndrome aged 11 months−16 years (mean = 4.2 years old) who were randomly assigned to receive daily B. lactis-11 probiotics (6 × 1010 CFUs) or a placebo sachet. Weight, height, ASQ-3, ABC, SRS-2, and CGI-I were compared between the two groups at baseline and at 6 and 12 weeks into treatment. Gut microbiome data were analyzed with the QIIME 2 software package, and functional gene analysis was conducted with PICRUSt-2.

Results: We found a significant increase in height (mean difference = 2.68 cm, P < 0.05) and improvement in CGI-I (P < 0.05) in the probiotics group compared to the placebo group. No significant change in weight or psychological measures were observed. Probiotic treatment altered the microbiome composition to favor weight loss and gut health and increased the abundance of antioxidant production-related genes.

Conclusions: The findings suggest a novel therapeutic potential for Bifidobacterium animalis subsp. lactis probiotics in Prader-Willi syndrome patients, although further investigation is warranted.
Intake of Fibre-Associated Foods and Texture Preferences in Relation to Weight Status Among 9–12 Years Old Children in 6 European Countries
Authors: Hörmann-Wallner Marlies , Krause Raphaela , Alfaro Begoña , Jilani Hannah , Laureati Monica , Almli Valérie L. , Sandell Mari , Sandvik Pernilla , Zeinstra Gertrude G. , Methven Lisa
Published: February 2021

Plant foods, rich in fibre, can offer textures that children find difficult to orally manipulate, resulting in low preferences but are important for a healthy diet and prevention of overweight in children. Our aim was to investigate preferences for food texture, intake of fibre-associated foods and the relation to BMI. Three hundred thirty European children (9–12 years, 54% female) indicated their texture preferences using the Child-Food-Texture-Preference- Questionnaire (CFTPQ), and their parents responded on fibre-associated food consumption and anthropometric information. BMI was significantly lower for children with higher intake of wholegrain alternatives of common foods; in addition to being significantly influenced by country and the wearing of a dental brace. Overall BMI-for-age-percentiles (BMI_pct) were negatively associated with the consumption of wholegrain cereals, white pasta and wholemeal products and positively associated with the intake of legumes and white biscuits. In males, BMI_pct were negatively associated with wholegrain products and dried fruits, and in females, positively with legume consumption. A few country-related associations were found for BMI_pct and wholegrain biscuits, seeds and nuts and refined products. No overall correlation was found between BMI_pct and the texture preference of soft/hard foods by CFTPQ, except in Austria. We conclude that this study revealed evidence of a connection between fibre-associated foods and children‘s BMI at a cross-cultural level and that sex is an important determinant of fibre-associated food intake and the development of overweight in childhood.
CT-Guided Pelvic Lymph Nodal Brachytherapy
Authors: Kunogi Hiroaki , Hsu I-Chow , Yamaguchi Nanae , Kusunoki Soshi , Nakagawa Keiko , Sugimori Yayoi , Fujino Kazunari , Terao Yasuhisa , Ogishima Daiki , Yoshimura Ryoichi , Sasai Keisuke
Published: February 2021

Purpose

This is a report of our initial experience using computed tomography (CT)-guided interstitial high dose rate (HDR) brachytherapy to treat bulky pelvic nodal metastases as a part of definitive radiotherapy.

Material and methods

Between February 2015 and April 2019, 14 cervical/endometrial cancer patients presenting with bulky pelvic node(s) underwent nodal interstitial brachytherapy boost in our institution. In total, 17 nodes were treated. The median maximum diameters of the positive nodes at the time of diagnosis and at the first nodal implant were 25 mm (range: 10–65 mm) and 16 mm (range: 9–51 mm), respectively. Dosimetry data of the lymph nodal target volume and small bowel were collected and compared using the paired-sample t-test. Treatment-related toxicities were classified using the Common Terminology Criteria for Adverse Events version 4.0.

Results

The median follow-up time for all patients was 26 months. Local recurrence in pelvic nodes occurred in one patient (7%) after 16 months. One patient experienced grade 3 bladder bleeding, and one patient experienced grade 2 pubic bone fracture. No patient had grade 2 or greater gastrointestinal toxicity. In the dosimetric analysis, the mean nodal brachytherapy D90% in terms of the total equivalent dose of 2 Gy (EQD2) was 65.6 Gyαβ10. The mean small bowel dose (SBD)0.1cc and SBD1cc in terms of the total EQD2 were 60.4 and 56.5 Gyαβ3, respectively. Nodal D90% was significantly higher in terms of the total EQD2 than the SBD0.1cc (p = 0.003) and SBD1cc (p < 0.001). The Kaplan-Meier 2-year pelvic control estimate was 90%.

Conclusions

CT-guided interstitial HDR pelvic nodal brachytherapy appears to be well tolerated with excellent local control in cervical or endometrial cancer patients with bulky pelvic nodes. This approach may offer a useful therapeutic option for unresected bulky pelvic nodes.
MYCT1 Inhibits the Adhesion and Migration of Laryngeal Cancer Cells Potentially Through Repressing Collagen VI
Authors: Wang Peng-Peng , Ding Si-Yu , Sun Yuan-Yuan , Li Yun-Hui , Fu Wei-Neng
Published: February 2021

MYCT1, a target of c-Myc, inhibits laryngeal cancer cell migration, but the underlying mechanism remains unclear. In the study, we detected differentially expressed genes (DEGs) from laryngeal cancer cells transfected by MYCT1 using RNA-seq (GSE123275). DEGs from head and neck squamous cell carcinoma (HNSCC) were first screened by comparison of transcription data from the Gene Expression Omnibus (GSE6631) and the Cancer Genome Atlas (TCGA) datasets using weighted gene co-expression network analysis (WGCNA). GO and KEGG pathway analysis explained the functions of the DEGs. The DEGs overlapped between GSE6631and TCGA datasets were then compared with ours to find the key DEGs downstream of MYCT1 related to the adhesion and migration of laryngeal cancer cells. qRT-PCR and Western blot were applied to validate gene expression at mRNA and protein levels, respectively. Finally, the cell adhesion, migration, and wound healing assays were to check cell adhesion and migration abilities, respectively. As results, 39 overlapping genes were enriched in the GSE6631 and TCGA datasets, and most of them revealed adhesion function. Thirteen of 39 genes including COL6 members COL6A1, COL6A2, and COL6A3 were overlapped in GSE6631, TCGA, and GSE123275 datasets. Similar to our RNA-seq results, we confirmed that COL6 is a target of MYCT1 in laryngeal cancer cells. We also found that MYCT1 inhibited the adhesion and migration of laryngeal cancer cells via COL6. These indicate that COL6 is a potential target of MYCT1 and participates the adhesion and migration of laryngeal cancer cells, which provides an important clue for further study on how MYCT1 regulating COL6 in laryngeal cancer progression.
A Ten-N6-Methyladenosine (m6A)-Modified Gene Signature Based on a Risk Score System Predicts Patient Prognosis in Rectum Adenocarcinoma
Authors: Huang Wei , Li Gen , Wang Zihang , Zhou Lin , Yin Xin , Yang Tianshu , Wang Pei , Teng Xu , Feng Yajuan , Yu Hefen
Published: February 2021

Objectives

The study aims to analyze the expression of N6-methyladenosine (m6A)-modified genes in rectum adenocarcinoma (READ) and identify reliable prognostic biomarkers to predict the prognosis of READ.

Materials and Methods

RNA sequence data of READ and corresponding clinical survival data were obtained from The Cancer Genome Atlas (TCGA) database. N6-methyladenosine (m6A)-modified genes in READ were downloaded from the “m6Avar” database. Differentially expressed m6A-modified genes in READ stratified by different clinicopathological characteristics were identified using the “limma” package in R. Protein-protein interaction (PPI) network and co-expression analysis of differentially expressed genes (DEGs) were performed using “STRING” and Cytoscape, respectively. Principal component analysis (PCA) was done using R. In addition, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were used to functionally annotate the differentially expressed genes in different subgroups. Univariate Cox regression analyses were conducted to identify the powerful independent prognostic factors in READ associated with overall survival (OS). A robust likelihood-based survival model was built using the “rbsurv” package to screen for survival-associated signature genes. The Support Vector Machine (SVM) was used to predict the prognosis of READ through the risk score of survival-associated signature genes. Correlation analysis were carried out using GraphPad prism 8.

Results

We screened 974 differentially expressed m6A-modified genes among four types of READ samples. Two READ subgroups (group 1 and group 2) were identified by K means clustering according to the expression of DEGs. The two subgroups were significantly different in overall survival and pathological stages. Next, 118 differentially expressed genes between the two subgroups were screened and the expression of 112 genes was found to be related to the prognosis of READ. Next, a panel of 10 survival-associated signature genes including adamtsl1, csmd2, fam13c, fam184a, klhl4, olfml2b, pdzd4, sec14l5, setbp1, tmem132b was constructed. The signature performed very well for prognosis prediction, time-dependent receiver-operating characteristic (ROC) analysis displaying an area under the curve (AUC) of 0.863, 0.8721, and 0.8752 for 3-year survival rate, prognostic status, and pathological stage prediction, respectively. Correlation analysis showed that the expression levels of the 10 m6A-modified genes were positively correlated with that of m6A demethylase FTO and ALKBH5.

Conclusion

This study identified potential m6A-modified genes that may be involved in the pathophysiology of READ and constructed a novel gene expression panel for READ risk stratification and prognosis prediction.
Vacuolar Membrane ATPase Activity 21 Predicts a Favorable Outcome and Acts as a Suppressor in Colorectal Cancer
Authors: Zhang Fan , Shen Hao , Fu Yating , Yu Guanyu , Cao Fuao , Chang Wenjun , Xie Zhongdong
Published: February 2021

Extracellular and/or intracellular manipulation of pH in tumor may have noticeable potential in cancer treatment. Although the assembly factor genes of V0 domain of the V-ATPase complex are required for intracellular pH homeostasis, their significance in colorectal cancer (CRC) remains largely unknown. Here, we used bioinformatics to identify the candidates from known assembly factor genes of the V0 domain, which were further evaluated by immunohistochemistry (IHC) in CRC and adjacent normal specimens from 661 patients. Univariate and multivariate Cox analyses were used to evaluate factors contributing to prognosis. The effects of variations in the expression of VMA21 on tumor growth were assessed in vitro and in vivo. Of five known assembly factors, only VMA21 showed differential expression between CRC and adjacent normal tissues at both mRNA and protein levels. Patients with high VMA21 expression had higher differentiation grade and longer disease-specific survival (DSS) at stages I–III disease. High VMA21 expression in tumors was also an independent predictor of DSS (hazard ratio, 0.345; 95% confidence interval, 0.123–0.976), with covariates included TNM stage and differentiation grade. VMA21 overexpression decreased CRC growth, whereas VMA21 knockdown increased CRC growth in vitro and in vivo. VMA21 expression suppresses CRC growth and predicts a favorable DSS in patients with stage I-III disease.
Human Papillomavirus-Negative Cervical Cancer: A Comprehensive Review
Authors: Xing Biyuan , Guo Jianfeng , Sheng Yuhan , Wu Gang , Zhao Yingchao
Published: February 2021

Human papillomavirus (HPV) has been the leading cause of cervical cancer for over 25 years. Approximately 5.5–11% of all cervical cancers are reported to be HPV-negative, which can be attributed to truly negative and false-negative results. The truly HPV-negative cervical cancers are almost all cervical adenocarcinomas with unclear etiology. False HPV negativity can arise from histological misclassification, latent HPV infection, disruption of the targeting fragment, non-high risk HPV infection, and HPV testing methods. HPV-negative cervical cancers are often diagnosed at an advanced FIGO stage and have a poor prognosis; thus, the management of these cases requires greater attention.
An Unconventional View of T Cell Reconstitution After Allogeneic Hematopoietic Cell Transplantation
Authors: Andrlová Hana , van den Brink Marcel R. M. , Markey Kate A.
Published: February 2021

Allogeneic hematopoietic cell transplantation (allo-HCT) is performed as curative-intent therapy for hematologic malignancies and non-malignant hematologic, immunological and metabolic disorders, however, its broader implementation is limited by high rates of transplantation-related complications and a 2-year mortality that approaches 50%. Robust reconstitution of a functioning innate and adaptive immune system is a critical contributor to good long-term patient outcomes, primarily to prevent and overcome post-transplantation infectious complications and ensure adequate graft-versus-leukemia effects. There is increasing evidence that unconventional T cells may have an important immunomodulatory role after allo-HCT, which may be at least partially dependent on the post-transplantation intestinal microbiome. Here we discuss the role of immune reconstitution in allo-HCT outcome, focusing on unconventional T cells, specifically mucosal-associated invariant T (MAIT) cells, γδ (gd) T cells, and invariant NK T (iNKT) cells. We provide an overview of the mechanistic preclinical and associative clinical studies that have been performed. We also discuss the emerging role of the intestinal microbiome with regard to hematopoietic function and overall immune reconstitution.
Radiomics Signature Facilitates Organ-Saving Strategy in Patients With Esophageal Squamous Cell Cancer Receiving Neoadjuvant Chemoradiotherapy
Authors: Li Yue , Liu Jun , Li Hong-xuan , Cai Xu-wei , Li Zhi-gang , Ye Xiao-dan , Teng Hao-hua , Fu Xiao-long , Yu Wen
Published: February 2021

After neoadjuvant chemoradiotherapy (NCRT) in locally advanced esophageal squamous cell cancer (ESCC), roughly 40% of the patients may achieve pathologic complete response (pCR). Those patients may benefit from organ-saving strategy if the probability of pCR could be correctly identified before esophagectomy. A reliable approach to predict pathological response allows future studies to investigate individualized treatment plans.

Method

All eligible patients treated in our center from June 2012 to June 2019 were retrospectively collected. Radiomics features extracted from pre-/post-NCRT CT images were selected by univariate logistic and LASSO regression. A radiomics signature (RS) developed with selected features was combined with clinical variables to construct RS+clinical model with multivariate logistic regression, which was internally validated by bootstrapping. Performance and clinical usefulness of RS+clinical model were assessed by receiver operating characteristic (ROC) curves and decision curve analysis, respectively.

Results

Among the 121 eligible patients, 51 achieved pCR (42.1%) after NCRT. Eighteen radiomics features were selected and incorporated into RS. The RS+clinical model has improved prediction performance for pCR compared with the clinical model (corrected area under the ROC curve, 0.84 vs. 0.70). At the 60% probability threshold cutoff (i.e., the patient would opt for observation if his probability of pCR was >60%), net 13% surgeries could be avoided by RS+clinical model, equivalent to implementing organ-saving strategy in 31.37% of the 51 true-pCR cases.

Conclusion

The model built with CT radiomics features and clinical variables shows the potential of predicting pCR after NCRT; it provides significant clinical benefit in identifying qualified patients to receive individualized organ-saving treatment plans.
Clinical and Dermoscopic Factors for the Identification of Aggressive Histologic Subtypes of Basal Cell Carcinoma
Authors: Pampena Riccardo , Parisi Gabriele , Benati Mattia , Borsari Stefania , Lai Michela , Paolino Giovanni , Cesinaro Anna Maria , Ciardo Silvana , Farnetani Francesca , Bassoli Sara , Argenziano Giuseppe , Pellacani Giovanni , Longo Caterina
Published: February 2021

Background

Infiltrative basal cell carcinoma (BCC) has a higher risk for post-surgical recurrence as compared to the most common low-aggressive superficial and nodular BCC. Independent diagnostic criteria for infiltrative BCC diagnosis have not been still defined. Improving the pre-surgical recognition of infiltrative BCC might significantly reduce the risk of incomplete excision and recurrence.

Objective

The aim of this study is to define clinical and dermoscopic criteria that can differentiate infiltrative BCC from the most common low-aggressive superficial and nodular BCC.

Methods

Clinical and dermoscopic images of infiltrative, superficial, and nodular BCC were retrospectively retrieved from our database and jointly evaluated by two experienced dermoscopists, blinded for the histologic subtype. Pairwise comparisons between the three histologic subtypes were performed and multivariable logistic regression models were constructed in order to define clinical and dermoscopic factors independently associated with each subtype. To validate our findings, two experienced dermoscopists not previously involved in the study were asked to evaluate clinical and dermoscopic images from an external dataset, guessing the proper BCC subtype between infiltrative, nodular and superficial, before and after being provided with the study results.

Result

A total of 481 histopathologically proven BCCs (51.4% nodular, 33.9% superficial, and 14.8% infiltrative) were included. We found that infiltrative BCC mostly appeared on the head and neck as an amelanotic hypopigmented plaque or papule, displaying ulceration on dermoscopic examination, along with arborizing and fine superficial telangiectasia. Shiny white structures were also frequently observed. Multivariate regression analysis allowed us to define a clinical-dermoscopic profile of infiltrative BCC.

Conclusions

We defined the clinical-dermoscopic profile of infiltrative BCC, allowing to differentiate this variant from superficial and nodular BCC. This will improve pre-surgical recognition of infiltrative forms, reducing the risk for post-surgical recurrence.
Use of Radiomics to Improve Diagnostic Performance of PI-RADS v2.1 in Prostate Cancer
Authors: Li Mou , Yang Ling , Yue Yufeng , Xu Jingxu , Huang Chencui , Song Bin
Published: February 2021

Objective

To investigate whether a radiomics model can help to improve the performance of PI-RADS v2.1 in prostate cancer (PCa).

Methods

This was a retrospective analysis of 203 patients with pathologically confirmed PCa or non-PCa between March 2015 and December 2016. Patients were divided into a training set (n = 141) and a validation set (n = 62). The radiomics model (Rad-score) was developed based on multi-parametric MRI including T2 weighted imaging (T2WI), diffusion weighted imaging (DWI), apparent diffusion coefficient (ADC) imaging, and dynamic contrast enhanced (DCE) imaging. The combined model involving Rad-score and PI-RADS was compared with PI-RADS for the diagnosis of PCa by using the receiver operating characteristic curve (ROC) analysis.

Results

A total of 112 (55.2%) patients had PCa, and 91 (44.8%) patients had benign lesions. For PCa versus non-PCa, the Rad-score had a significantly higher area under the ROC curve (AUC) [0.979 (95% CI, 0.940–0.996)] than PI-RADS [0.905 (0.844–0.948), P = 0.002] in the training set. However, the AUC between them was insignificant in the validation set [0.861 (0.749–0.936) vs. 0.845 (0.731–0.924), P = 0.825]. When Rad-score was added to PI-RADS, the performance of the PI-RADS was significantly improved for the PCa diagnosis (AUC = 0.989, P < 0.001 for the training set and AUC = 0.931, P = 0.038 for the validation set).

Conclusions

The radiomics based on multi-parametric MRI can help to improve the diagnostic performance of PI-RADS v2.1 in PCa.
Potential Roles of Acute Phase Proteins in Cancer: Why Do Cancer Cells Produce or Take Up Exogenous Acute Phase Protein Alpha1-Antitrypsin?
Authors: Janciauskiene Sabina , Wrenger Sabine , Günzel Steffen , Gründing Anna Ricarda , Golpon Heiko , Welte Tobias
Published: February 2021

An association between acute-phase proteins (APPs) and cancer has long been established and there are numerous reports correlating altered levels and/or molecular forms of APPs with different types of cancers. Many authors have shown a positive correlation between high levels of APPs, like alpha1-antitrypsin (AAT), and unfavorable clinical outcome in cancers. Conversely, others proposed that high levels of APPs are probably just a part of nonspecific inflammatory response to cancer development. However, this might not be always true, because many cancerous cells produce or take up exogenous APPs. What is the biological significance of this and what benefit do cancer cells have from these proteins remains largely unknown. Recent data revealed that some APPs, including AAT, are able to enhance cancer cell resistance against anticancer drug-induced apoptosis and autophagy. In this review, we specifically discuss our own findings and controversies in the literature regarding the role of AAT in cancer.
Individualized Surgical Reconstruction of the Right Ventricle Outflow Tract in Double Outlet Right Ventricle With Mirror Image-Dextrocardia
Authors: Chen Wangping , Iroegbu Chukwuemeka Daniel , Xie Xia , Zhou Wenwu , Wu Ming , Wu Xun , Fan Chengming , Borovjagin Anton V. , Yang Jinfu
Published: February 2021

Introduction: The purpose of this study was to report our experience in the surgical reconstruction of the right ventricular outflow tract in double outlet right ventricle with a major coronary artery crossing the right ventricular outflow tract in the presence of mirror image-dextrocardia.

Methods: From January 2005 to December 2019, 19 double outlet right ventricle patients (median age 4 years) with mirror image-dextrocardia and a major coronary artery crossing the right ventricular outflow tract received surgical repair. An autologous pericardial patch was used to enlarge the right ventricular outflow tract in four patients without pulmonary stenosis and three patients with mild pulmonary stenosis. A valved bovine jugular venous conduit was added to a hypoplastic native pathway in nine patients, among which six patients with moderate pulmonary stenosis received small-sized bovine jugular venous conduit implantation (diameter ≤ 16 mm). In comparison, a large-sized bovine jugular venous conduit (diameter >16 mm) was adopted in a total of three patients with severe pulmonary stenosis. Finally, three patients with preoperative pulmonary hypertension (mean pulmonary artery pressure ≥40 mmHg) did not undergo further intervention of right ventricular outflow tract due to the adequate outflow tract blood flow.

Results: There was no hospital mortality. One patient with sub-pulmonary ventricular septal defect and concomitant severe pulmonary hypertension died from respiratory failure 11 months after the operation. Kaplan-Meier survival was 94% at 5, 10 years. Within a mean echocardiographic follow-up of 6.9 ± 3.6 years, a total of two patients received reintervention due to valvular stenosis of the bovine jugular venous conduit (pressure gradient > 50 mmHg at 4 and 9 years) after surgical operation. Actuarial freedom from reoperation was 90 and 72% at 5 and 10 years, respectively. During the last echocardiographic follow-up phase, all the survivors were in NYHA class I.

Conclusions: Double outlet right ventricle with mirror image-dextrocardia is a rare and complicated congenital cardiac malformation. Surgical reconstruction of the right ventricular outflow tract should be individualized based on the degree of pulmonary stenosis and the specific anatomical features of each patient. Reconstructing the pulmonary artery using the various sizes of valved bovine jugular venous conduit is a safe and effective surgical method.
Body Mass Index Trajectories in the First 5 Years and Associated Antenatal Factors
Authors: Mattsson Molly , Murray Deirdre M. , Hawkes Colin P. , Kiely Mairead , Ní Chaoimh Carol , McCarthy Fergus P. , Biesma Regien , Boland Fiona
Published: February 2021

Background: The increasing prevalence of childhood obesity is an important public health issue and the development of obesity in early life and associated risk factors need to be better understood. The aim of this study was to identify distinct body mass index trajectories in the first 5 years of life and to examine their associations with factors identified in pregnancy, including metabolic parameters.

Methods: BMI measurements from 2,172 children in Ireland enrolled in the BASELINE cohort study with BMI assessments at birth, 2, 6, and 12 months, and 2 and 5 years were analyzed. Growth mixture modeling was used to identify distinct BMI trajectories, and multivariate multinomial logistic regression was used to assess the association between these trajectories and antenatal factors.

Results: Three distinct BMI trajectories were identified: normal (89.6%); rapid gain in the first 6 months (7.8%); and rapid BMI after 12 months (2.6%). Male sex and higher maternal age increased the likelihood of belonging to the rapid gain in the first 6 months trajectory. Raised maternal BMI at 15 weeks of pregnancy and lower cord blood IGF-2 were associated with rapid gain after 1 year.

Conclusion: Sex, maternal age and BMI, and IGF-2 levels were found to be associated with BMI trajectories in early childhood departing from normal growth. Further research and extended follow-up to examine the effects of childhood growth patterns are required to understand their relationship with health outcomes.
Characterization of the T Cell Response to Lactobacillus casei Cell Wall Extract in Children With Kawasaki Disease and Its Potential Role in Vascular Inflammation
Authors: Hsieh Li-En , Tremoulet Adriana H. , Burns Jane C. , Noval Rivas Magali , Arditi Moshe , Franco Alessandra
Published: February 2021

KD is an acute febrile illness and systemic vasculitis of unknown etiology among young children, which can cause coronary artery abnormalities and aneurysms (CAA) and is the leading cause of acquired heart disease among children in the US. Lactobacillus casei cell wall extract (LCWE) induces in mice a vasculitis following intraperitoneal injection defined by the activation of macrophages, dendritic cells and CD8+ cytotoxic T cells leading to aortitis, coronary arteritis, aneurysms and myocarditis that strongly mimic the immunopathology and the cardiac lesions observed in children with Kawasaki disease (KD). To address a potential pathogenic role of LCWE-specific T cells in human vascular inflammation, we studied the activation of circulating CD4+ and CD8+ T cells ex vivo in response to LCWE in 3 cohorts: (1) KD children 2–3 weeks after fever onset, (2) age-similar healthy children controls, (3) healthy adult controls. In all subjects studied, pro-inflammatory CD4+ and CD8+T cells responded to LCWE with no significant differences. Peripherally-induced regulatory T cells (iTreg) also responded to LCWE and potentially reverted to Th17, as suggested by the detection of IL-17 in culture supernatants. Central memory T cells were also detectable and were more abundant in adults. The potential homing to the vessels of LCWE-specific T cells was suggested by the expression of CCR6 and CD31. In conclusion, a non-pathogenic, LCWE-specific T cell repertoire could lead to KD depending upon priming conditions, genetic factors and immune activation by other antigens.
Icariin Treatment Protects Against Gentamicin-Induced Ototoxicity via Activation of the AMPK-SIRT3 Pathway
Authors: Hu Yue , Ma Xiulan
Published: February 2021

Ototoxicity is a serious health problem that greatly affects millions of people worldwide. This condition is caused by the entry of aminoglycosides into auditory hair cells, subsequently inducing reactive oxygen species (ROS) production and accumulation. Several strategies have been adopted to overcome irreversible ROS-induced hair cell loss in mammals. In recent years, icariin, a major active component of the traditional herb Epimedium, has been widely studied and revealed to have antioxidant, anti-inflammatory, and anti-apoptotic properties. In this study, we found that icariin pretreatment improved the survival rate of gentamicin-treated House Ear Institute-Organ of Corti 1 (HEI-OC1) cells and cochlear explants. Icariin remarkably suppressed HEI-OC1 cell apoptosis and inhibited ROS production in cells. Notably, icariin upregulated PGC-1α (SIRT3 promoter) and SIRT3 expression in HEI-OC1 cells. In addition, SIRT3 inhibition significantly attenuated the anti-apoptotic effect of icariin. We also found that icariin can increase AMPK phosphorylation. Further studies showed that inhibition of SIRT3 activity had no significant effect on AMPK phosphorylation. Furthermore, the AMPK inhibitor compound C significantly suppressed SIRT3 expression, meaning that AMPK, as an upstream molecule, regulates SIRT3 expression. Meanwhile, inhibition of AMPK activity significantly reduced the protective effect of icariin on gentamicin ototoxicity. Based on these results, icariin exerts its protective effect on gentamicin-induced ototoxicity via activation of the AMPK-SIRT3 signaling pathway, thus providing a new strategy for treating ototoxicity caused by aminoglycoside antibiotics.
Long-Term Outcomes of Patients With Cocaine Use Disorder: A 18-years Addiction Cohort Study
Authors: Sanvisens Arantza , Hernández-Rubio Anna , Zuluaga Paola , Fuster Daniel , Papaseit Esther , Galan Sara , Farré Magí , Muga Robert
Published: February 2021

Objective: Cocaine Use Disorder (CUD) has been associated with multiple complications and premature death. The purpose of the present study was to analyze the relationship between baseline medical comorbidity and long-term medical outcomes (i.e., hospitalization, death) in a cohort of patients primarily admitted for detoxification. In addition, we aimed to analyze cause-specific mortality.

Methods: longitudinal study in CUD patients admitted for detoxification between 2001 and 2018. Substance use characteristics, laboratory parameters and medical comorbidity by VACS Index were assessed at admission. Follow-up and health-related outcomes were ascertained through visits and e-health records. Kaplan-Meier and Cox regression models were used to analyze survival and predictors of hospitalization and death.

Results: 175 patients (77.7% men) were included. Age at admission was 35 years [IQR: 30–41 years], 59.4% of the patients being intranasal users, 33.5% injectors, and 7.1% smokers. Almost 23% of patients had concomitant alcohol use disorder, 39% were cannabis users and 9% opiate users. The median VACS Index score on admission was 10 points [IQR: 0–22]. After 12 years [IQR: 8.6–15 years] of follow-up there were 1,292 (80.7%) ED admissions and 308 (19.3%) hospitalizations. The incidence rate of ED admission and hospitalization was 18.6 × 100 p-y (95% CI: 15.8–21.8 × 100 p-y). Mortality rate was 1.4 × 100 p-y (95% CI: 0.9–2.0 × 100 p-y) and, baseline comorbidity predicted hospitalization and mortality: those with VACS Index >40 were 3.5 times (HR:3.52, 95% CI: 1.19–10.4) more likely to dye with respect to patients with VACS < 20.

Conclusion: addiction care warrants optimal stratification of medical comorbidity to improve health outcomes and survival of CUD patients seeking treatment of the disorder.
The Structural Understanding of Transthyretin Misfolding and the Inspired Drug Approaches for the Treatment of Heart Failure Associated With Transthyretin Amyloidosis
Authors: He Shan , He Xinyue , Liu Lei , Zhang Wenbo , Yu Lanlan , Deng Zhun , Feiyi Zhang , Mo Shanshan , Fan Yue , Zhao Xinyue , Wang Lun , Wang Chenxuan , Zhang Shuyang
Published: February 2021

Substantial controversies exist in the exploration of the molecular mechanism of heart failure (HF) and pose challenges to the diagnosis of HF and the discovery of specific drugs for the treatment. Recently, cardiac transthyretin (TTR) amyloidosis is becoming recognized as one of major causes of underdiagnosed HF. The investigation and modulation of TTR misfolding and amyloidal aggregation open up a new revenue to reveal the molecular mechanisms of HF and provide new possibilities for the treatment of HF. The aim of this review is to briefly introduce the recent advances in the study of TTR native and misfolding structures, discuss the correlation between the genotype and phenotype of cardiac TTR amyloidosis, and summarize the therapeutic applications of TTR structural stabilizers in the treatment of TTR amyloidosis-associated HF.
Inhibition of 5-Lipoxygenase in Hepatic Stellate Cells Alleviates Liver Fibrosis
Authors: Pu Shiyun , Li Yanping , Liu Qinhui , Zhang Xu , Chen Lei , Li Rui , Zhang Jinhang , Wu Tong , Tang Qin , Yang Xuping , Zhang Zijing , Huang Ya , Kuang Jiangying , Li Hong , Zou Min , Jiang Wei , He Jinhan
Published: February 2021

Background and Purpose: Activation of hepatic stellate cells (HSC) is a central driver of liver fibrosis. 5-lipoxygenase (5-LO) is the key enzyme that catalyzes arachidonic acid into leukotrienes. In this study, we examined the role of 5-LO in HSC activation and liver fibrosis.

Main Methods: Culture medium was collected from quiescent and activated HSC for target metabolomics analysis. Exogenous leukotrienes were added to culture medium to explore their effect in activating HSC. Genetic ablation of 5-LO in mice was used to study its role in liver fibrosis induced by CCl4 and a methionine-choline-deficient (MCD) diet. Pharmacological inhibition of 5-LO in HSC was used to explore the effect of this enzyme in HSC activation and liver fibrosis.

Key Results: The secretion of LTB4 and LTC4 was increased in activated vs. quiescent HSC. LTB4 and LTC4 contributed to HSC activation by activating the extracellular signal-regulated protein kinase pathway. The expression of 5-LO was increased in activated HSC and fibrotic livers of mice. Ablation of 5-LO in primary HSC inhibited both mRNA and protein expression of fibrotic genes. In vivo, ablation of 5-LO markedly ameliorated the CCl4- and MCD diet-induced liver fibrosis and liver injury. Pharmacological inhibition of 5-LO in HSC by targeted delivery of the 5-LO inhibitor zileuton suppressed HSC activation and improved CCl4- and MCD diet-induced hepatic fibrosis and liver injury. Finally, we found increased 5-LO expression in patients with non-alcoholic steatohepatitis and liver fibrosis.

Conclusion: 5-LO may play a critical role in activating HSC; genetic ablation or pharmacological inhibition of 5-LO improved CCl4-and MCD diet-induced liver fibrosis.
Isorhamnetin Inhibits Human Gallbladder Cancer Cell Proliferation and Metastasis via PI3K/AKT Signaling Pathway Inactivation
Authors: Zhai Tianyu , Zhang Xiaoyu , Hei Zhenyu , Jin Longyang , Han Chao , Ko Audrey Tsznam , Yu Xiaofeng , Wang Jiandong
Published: February 2021

Gallbladder cancer (GBC) is the most common biliary tract tumor with a poor prognosis. Isorhamnetin is a flavonoid compound extracted from Hippophae rhamnoides L. and has several pharmacological effects including anti-inflammatory and anti-cancer properties. We treated GBC-SD and NOZ of GBC cell lines with different isorhamnetin concentrations in vitro. A cell counting kit-8 (CCK-8) assay, transwell assay, Hoechst 33342 stain assay, flow cytometric analysis, and a colony-forming assay were performed to investigate the effect of isorhamnetin on the proliferation, apoptosis, metastasis, and cycle arrest of GBC cells. A western blotting assay was conducted to explore the related protein expression level of GBC cells. A mice xenograft model and immunohistochemistry staining were employed to assess the effect of isorhamnetin in vivo. Isorhamnetin was found to suppress cell proliferation and metastasis, and trigger apoptosis and arrest the G2/M phase in GBC cells via the inactivation of the PI3K/AKT signaling cascade. Our findings are of clinical significance in providing a novel treatment approach for GBC.
The Comparative Methylome and Transcriptome After Change of Direction Compared to Straight Line Running Exercise in Human Skeletal Muscle
Authors: Maasar Mohd-Firdaus , Turner Daniel C. , Gorski Piotr P. , Seaborne Robert A. , Strauss Juliette A. , Shepherd Sam O. , Cocks Matt , Pillon Nicolas J. , Zierath Juleen R. , Hulton Andrew T. , Drust Barry , Sharples Adam P.
Published: February 2021

The methylome and transcriptome signatures following exercise that are physiologically and metabolically relevant to sporting contexts such as team sports or health prescription scenarios (e.g., high intensity interval training/HIIT) has not been investigated. To explore this, we performed two different sport/exercise relevant high-intensity running protocols in five male sport team members using a repeated measures design of: (1) change of direction (COD) versus; (2) straight line (ST) running exercise with a wash-out period of at least 2 weeks between trials. Skeletal muscle biopsies collected from the vastus lateralis 30 min and 24 h post exercise, were assayed using 850K methylation arrays and a comparative analysis with recent (subject-unmatched) sprint and acute aerobic exercise meta-analysis transcriptomes was performed. Despite COD and ST exercise being matched for classically defined intensity measures (speed × distance and number of accelerations/decelerations), COD exercise elicited greater movement (GPS-Playerload), physiological (HR), metabolic (lactate) as well as central and peripheral (differential RPE) exertion measures compared with ST exercise, suggesting COD exercise evoked a higher exercise intensity. The exercise response alone across both conditions evoked extensive alterations in the methylome 30 min and 24 h post exercise, particularly in MAPK, AMPK and axon guidance pathways. COD evoked a considerably greater hypomethylated signature across the genome compared with ST exercise, particularly at 30 min post exercise, enriched in: Protein binding, MAPK, AMPK, insulin, and axon guidance pathways. Comparative methylome analysis with sprint running transcriptomes identified considerable overlap, with 49% of genes that were altered at the expression level also differentially methylated after COD exercise. After differential methylated region analysis, we observed that VEGFA and its downstream nuclear transcription factor, NR4A1 had enriched hypomethylation within their promoter regions. VEGFA and NR4A1 were also significantly upregulated in the sprint transcriptome and meta-analysis of exercise transcriptomes. We also confirmed increased gene expression of VEGFA, and considerably larger increases in the expression of canonical metabolic genes PPARGC1A (that encodes PGC1-α) and NR4A3 in COD vs. ST exercise. Overall, we demonstrate that increased physiological/metabolic load via COD exercise in human skeletal muscle evokes considerable epigenetic modifications that are associated with changes in expression of genes responsible for adaptation to exercise.
Human Red Blood Cells Modulate Cytokine Expression in Monocytes/Macrophages Under Anoxic Conditions
Authors: Antonelli Antonella , Scarpa Emanuele Salvatore , Magnani Mauro
Published: February 2021

In the bone marrow (BM) hematopoietic niche, the oxygen tension is usually very low. Such condition affects stem and progenitor cell proliferation and differentiation and, at cellular level regulates hematopoietic growth factors, chemokines and adhesion molecules expression. In turn, these molecules affect the proliferation and maturation of other cellular components of the niche. Due to the complexity of the system we started thein vitroinvestigations of the IL-6, IL-8, TNFα cytokines expression and the vascular endothelial growth factor (VEGF), considered key mediators of the hematopoietic niche, in human macrophages and macrophage cell line. Since in the niche the oxygen availability is mediated by red blood cells (RBCs), we have influenced the anoxic cell cultures by the administration of oxygenated or deoxygenated RBCs (deoxy RBCs). The results reported in this brief paper show that the presence of RBCs up-regulates IL-8 mRNA while IL-6 and VEGF mRNA expression appears down-regulated. This does not occur when deoxy RBCs are used. Moreover, it appears that the administration of RBCs leads to an increase of TNFα expression levels in MonoMac 6 (MM6). Interestingly, the modulation of these factors likely occurs in a hypoxia-inducible factor-1α (HIF-1α) independent manner. Considering the role of oxygen in the hematopoietic niche further studies should explore these preliminary observations in more details.
Cardiovascular and Metabolic Crosstalk in the Brain: Leptin and Resistin
Authors: Badoer Emilio
Published: February 2021

Leptin and resistin are cytokines whose plasma levels correlate with adiposity. Leptin is a hormone synthesised and released from adipocytes and can be transported into the brain. Resistin is produced in adipocytes in rodents and in macrophages in humans, particularly macrophages that have infiltrated adipose tissue. Both hormones can act within the brain to influence sympathetic nerve activity. Leptin appears to have a generalised sympatho-excitatory actions whilst resistin appears to increase sympathetic nerve activity affecting the cardiovascular system but inhibits sympathetic nerve activity to brown adipose tissue, which contrasts with leptin. Since both hormones can be elevated in conditions of metabolic dysfunction, interactions/crosstalk between these two hormones in the brain is a real possibility. This review describes the current knowledge regarding such crosstalk within the central nervous system. The evidence suggests that with respect to sympathetic nerve activity, crosstalk between leptin and resistin can elicit enhanced sympatho-excitatory responses to the kidneys. In contrast, with respect to food intake, resistin has weaker effects, but in regard to insulin secretion and thermogenesis, leptin and resistin have opposing actions. Thus, in conditions in which there is increased resistin and leptin levels, the result of crosstalk in the central nervous system could contribute to worse cardiovascular and metabolic complications.
A Simple Score to Identify Super-Responders to Sacubitril/Valsartan in Ambulatory Patients With Heart Failure
Authors: Moliner-Abós Carles , Mojón Álvarez Diana , Rivas-Lasarte Mercedes , Belarte Laia Carla , Pamies Besora Julia , Solé-González Eduard , Fluvià-Brugues Paula , Zegrí-Reiriz Isabel , López López Laura , Brossa Vicens , Pirla Maria José , Mesado Nuria , Mirabet Sonia , Roig Eulàlia , Álvarez-García Jesús
Published: February 2021

Introduction

Sacubitril/valsartan (SV) promotes cardiac remodeling and improves prognosis in patients with heart failure (HF). However, the response to the drug may vary between patients and its implementation in daily clinical practice has been slower than expected. Our objective was to develop a score predicting the super-response to SV in HF outpatients.

Methods

This is a retrospective analysis of 185 consecutive patients prescribed SV from two tertiary hospitals between September 2016 and February 2018. Super-responder was defined as a patient taking the drug and (i) without HF admissions, death, or heart transplant, and (ii) with a ≥50% reduction in NT-proBNP levels and/or an increase of ≥10 points in LVEF in a 12-month follow-up period after starting SV. Clinical, echocardiographic, ECG, and biochemical variables were used in a logistic regression analysis to construct a score for super-response to SV which was internally validated using bootstrap method.

Results

Out of 185 patients, 65 (35%) fulfilled the super-responder criteria. Predictors for super-response to SV were absence of both previous aldosterone antagonist and diuretic treatment, NYHA I-II class, female gender, previous 1-year HF admission, and sinus rhythm. An integrating score distinguished a low- (<25%), intermediate- (∼46%), and high-probability (>80%) for 1-year super-response to SV. The AUC for the model was 0.72 (95%CI: 0.64–0.80), remaining consistent after internal validation.

Conclusion

One-third of our patients presented a super-response to SV. We propose an easy-to-calculate score to predict super-response to SV after 1-year initiation based on variables that are currently assessed in clinical practice.