bluuebunny/crossref_metadata_2025 huggingface dataset:
Generalizing Longitudinal Age Effects on Brain Structure – A Two-Study Comparison Approach
Authors: Jockwitz Christiane , Mérillat Susan , Liem Franziskus , Oschwald Jessica , Amunts Katrin , Jäncke Lutz , Caspers Svenja
Published: April 2021

Cross-sectional studies indicate that normal aging is accompanied by decreases in brain structure. Longitudinal studies, however, are relatively rare and inconsistent regarding their outcomes. Particularly the heterogeneity of methods, sample characteristics and the high inter-individual variability in older adults prevent the deduction of general trends. Therefore, the current study aimed to compare longitudinal age-related changes in brain structure (measured through cortical thickness) in two large independent samples of healthy older adults (n = 161 each); the Longitudinal Healthy Aging Brain (LHAB) database project at the University of Zurich, Switzerland, and 1000BRAINS at the Research Center Juelich, Germany. Annual percentage changes in the two samples revealed stable to slight decreases in cortical thickness over time. After correction for major covariates, i.e., baseline age, sex, education, and image quality, sample differences were only marginally present. Results suggest that general trends across time might be generalizable over independent samples, assuming the same methodology is used, and similar sample characteristics are present.
Effects of Perturbation Velocity, Direction, Background Muscle Activation, and Task Instruction on Long-Latency Responses Measured From Forearm Muscles
Authors: Weinman Jacob , Arfa-Fatollahkhani Paria , Zonnino Andrea , Nikonowicz Rebecca C. , Sergi Fabrizio
Published: April 2021

The central nervous system uses feedback processes that occur at multiple time scales to control interactions with the environment. The long-latency response (LLR) is the fastest process that directly involves cortical areas, with a motoneuron response measurable 50 ms following an imposed limb displacement. Several behavioral factors concerning perturbation mechanics and the active role of muscles prior or during the perturbation can modulate the long-latency response amplitude (LLRa) in the upper limbs, but the interactions among many of these factors had not been systematically studied before. We conducted a behavioral study on thirteen healthy individuals to determine the effect and interaction of four behavioral factors – background muscle torque, perturbation direction, perturbation velocity, and task instruction – on the LLRa evoked from the flexor carpi radialis (FCR) and extensor carpi ulnaris (ECU) muscles after velocity-controlled wrist displacements. The effects of the four factors were quantified using both a 0D statistical analysis on the average perturbation-evoked EMG signal in the period corresponding to an LLR, and using a timeseries analysis of EMG signals. All factors significantly modulated LLRa, and their combination nonlinearly contributed to modulating the LLRa. Specifically, all the three-way interaction terms that could be computed without including the interaction between instruction and velocity significantly modulated the LLR. Analysis of the three-way interaction terms of the 0D model indicated that for the ECU muscle, the LLRa evoked when subjects are asked to maintain their muscle activation in response to the perturbations was greater than the one observed when subjects yielded to the perturbations (p < 0.001), but this effect was not measured for muscles undergoing shortening or in absence of background muscle activation. Moreover, higher perturbation velocity increased the LLRa evoked from the stretched muscle in presence of a background torque (p < 0.001), but no effects of velocity were measured in absence of background torque. Also, our analysis identified significant modulations of LLRa in muscles shortened by the perturbation, including an interaction between torque and velocity, and an effect of both torque and velocity. The time-series analysis indicated the significance of additional transient effects in the LLR region for muscles undergoing shortening.
Automated Quantitative Analysis of ex vivo Blood-Brain Barrier Permeability Using Intellesis Machine-Learning
Authors: Nesbit Michael , Mamo John C. , Majimbi Maimuna , Lam Virginie , Takechi Ryusuke
Published: April 2021

Background

An increase in blood brain barrier permeability commonly precedes neuro-inflammation and cognitive impairment in models of dementia. Common methods to estimate capillary permeability have potential confounders, or require laborious and subjective semi-manual analysis.

New method

Here we used snap frozen mouse and rat brain sections that were double-immunofluorescent labeled for immunoglobulin G (IgG; plasma protein) and laminin-α4 (capillary basement membrane). A Machine Learning Image Analysis program (Zeiss ZEN Intellisis) was trained to recognize and segment laminin-α4 to equivocally identify blood vessels in large sets of images. An IgG subclass based on a threshold intensity was segmented and quantitated only in extravascular regions. The residual parenchymal IgG fluorescence is indicative of blood-to-brain extravasation of IgG and was accurately quantitated.

Results

Automated machine-learning and threshold based segmentation of only parenchymal IgG extravasation accentuates otherwise indistinct capillary permeability, particularly frequent in minor BBB leakage. Comparison with Existing Methods: Large datasets can be processed and analyzed quickly and robustly to provide an overview of vascular permeability throughout the brain. All human bias or ambiguity involved in classifying and measuring leakage is removed.

Conclusion

Here we describe a fast and precise method of visualizing and quantitating BBB permeability in mouse and rat brain tissue, while avoiding the confounding influence of unphysiological conditions such as perfusion and eliminating any human related bias from analysis.
Study of the Compositional, Microbiological, Biochemical, and Volatile Profile of Red-Veined Cheese, an Internal Monascus-Ripened Variety
Authors: Jiao Jingkai , Zheng Zhiqiang , Liu Zhenmin , You Chunping
Published: April 2021

Red-Veined Cheese is an experimental internal mold-ripened cheese using red koji powder as the red starter. The objective of this study was to characterize the physicochemical parameters, microorganisms, proteolysis, lipolysis, and volatile profile of the cheese during 33 days of ripening. The gross composition was 56.7% (w/w) for total solids, 45.8% (w/w) for fat-in-dry matter, 2.58% (w/w) for salt content and 37.8% (w/w) for protein. The pH increased from 4.88 to 5.23 during ripening. The Monascus density first rose and then fell, while total mesophilic bacteria count declined steadily throughout the maturation. Proteolysis degree in experimental group was significantly higher than in control group without inoculation of red koji powder. Analysis of the fatty acid profile showed that the internal Monascus-fermentation also promoted lipolysis. A total of 63 volatile compounds, including 12 ketones, 14 alcohols, 15 acids, 13 esters, 5 aldehydes, 3 lactones and 1 phenol, were identified by gas chromatography-mass spectrometry (GC–MS) coupled with headspace solid-phase microextraction (HS-SPME). The main chemical groups of volatile compounds were ketones, alcohols, acids and esters whereas aldehydes, lactones, and phenols represented only minor components. At the end of ripening, the levels of ketones, alcohols, esters were significantly higher in the experimental cheese compared with the control. Our results therefore show that the internal Monascus-fermentation is not only a suitable technology to form red veins in the paste but also an effective method to impact the composition of volatile compounds in cheese, which can thus distinguish it from other internal mold-ripened cheeses and surface-ripened Monascus-fermented cheese.
Bovine Lactoferrin Protects Dextran Sulfate Sodium Salt Mice Against Inflammation and Impairment of Colonic Epithelial Barrier by Regulating Gut Microbial Structure and Metabolites
Authors: Wang Shalong , Zhou Jingyu , Xiao Da , Shu Guoshun , Gu Li
Published: April 2021

Background: Ulcerative colitis is characterized by relapsing and remitting mucosal inflammation. Bovine lactoferrin (BL) is a multifunctional protein that could regulate the intestinal flora and has anti-inflammatory effects. The aim of this study was to investigate the therapeutic effect of BL on colitis.

Methods: Dextran sulfate sodium salt (DSS) was utilized to establish a mouse model of colitis. BL was administered to treat DSS mice. The weight, the activity, and fecal status of the mice were recorded every day. Disease activity index was calculated. After the mice were euthanized, the colon length was measured. Hematoxylin and eosin staining was used to observe the pathological changes of the colon, and histological activity index was calculated. The myeloperoxidase (MPO) activity of colon tissue was measured. Western blot and immunohistochemistry were used to detect the expressions of Claudin-1, Occludin, and ZO-1. The expressions of IL-1β, IL-6, IL-10, TNF-α, and TGF-β in colon tissue were detected by ELISA. The protein expressions of MUC2, Reg3γ, β-defensin (HBD-2), and cAMP were detected by immunofluorescence (IF). 16S rDNA sequencing determined the type and structure of intestinal flora. Liquid chromatography–tandem mass spectrometry (LC-MS/MS) measured the metabolites of the intestinal flora.

Results: Compared with the DSS group, the mice's weight in the BL group was higher and the length of the colon was longer. At the 14th day, MPO activity was higher in the BL group. The expressions of Claudin-1, Occludin, and ZO-1 in the colon were up-regulated in the BL group compared with the DSS group. The expressions of IL-1β, IL-6, and TNF-α were lower. The expressions of IL-10 and TGF-β were higher. IF showed that the expressions of MUC2 and β-defensin (HBD-2) were down-regulated, and the expressions of Reg3γ and cAMP were up-regulated. The 16S rDNA sequencing results showed that the alpha diversity and beta diversity were notably changed in the DSS mice treated with BL. Metabolomics results showed that BL changed purine metabolism in the DSS mice.

Conclusion: BL alleviated colitis in mice by improving the inflammatory response and the structure of the colon barrier in the colon. BL changed the composition and metabolites of the intestinal flora. Thus, BL might be an effective nutritional supplement for colitis treatment.
Non-Genomic Control of Dynamic MYCN Gene Expression in Liver Cancer
Authors: Qin Xian-Yang , Gailhouste Luc
Published: April 2021

UpregulatedMYCNgene expression is restricted to specialized cell populations such as EpCAM+cancer stem cells in liver cancer, regardless of DNA amplification and mutation. Here, we reviewed the role ofMYCNgene expression in liver homeostasis, regeneration, and tumorigenesis, and discussed the potential non-genomic mechanisms involved in controllingMYCNgene expression in liver cancer, with a focus on inflammation-mediated signal transduction and microRNA-associated post-transcriptional regulation. We concluded that dynamicMYCNgene expression is an integrated consequence of multiple signals in the tumor microenvironment, including tumor growth-promoting signals, lipid desaturation-mediated endoplasmic reticulum stress adaptation signals, and tumor suppressive miRNAs, making it a potential predictive biomarker of tumor stemness and plasticity. Therefore, understanding and tracing the dynamic changes and functions ofMYCNgene expression will shed light on the origin of liver tumorigenesis at the cellular level and the development of novel therapeutic and diagnostic strategies for liver cancer treatment.
Comprehensive and Computable Molecular Diagnostic Panel (C2Dx) From Small Volume Specimens for Precision Oncology: Molecular Subtyping of Non-Small Cell Lung Cancer From Fine Needle Aspirates
Authors: Su Jing , Huang Lynn S. , Barnard Ryan , Parks Graham , Cappellari James , Bellinger Christina , Dotson Travis , Craddock Lou , Prakash Bharat , Hovda Jonathan , Clark Hollins , Petty William Jeffrey , Pasche Boris , Chan Michael D. , Miller Lance D. , Ruiz Jimmy
Published: April 2021

The Comprehensive, Computable NanoString Diagnostic gene panel (C2Dx) is a promising solution to address the need for a molecular pathological research and diagnostic tool for precision oncology utilizing small volume tumor specimens. We translate subtyping-related gene expression patterns of Non-Small Cell Lung Cancer (NSCLC) derived from public transcriptomic data which establish a highly robust and accurate subtyping system. The C2Dx demonstrates supreme performance on the NanoString platform using microgram-level FNA samples and has excellent portability to frozen tissues and RNA-Seq transcriptomic data. This workflow shows great potential for research and the clinical practice of cancer molecular diagnosis.
An Immune Cell-Based Signature Associating With EMT Phenotype Predicts Postoperative Overall Survival of ESCC
Authors: Yu Hongliang , Gu Dayong , Yue Chao , Xu Jianhua , Yan Feng , He Xia
Published: April 2021

Esophageal squamous cell carcinoma (ESCC) is one of the deadliest solid malignancies and has a poor survival rate worldwide. In this study, we aimed to establish a tumor-infiltrating immune cell-based prognosis signature (IPS) to predict patients’ survival times and aid in the development of targeted therapies or immunotherapies. The abundances of 22 types of immune cells were determined by the CIBERSORT algorithm from ESCC patient gene expression data in the Gene Expression Omnibus (GEO) training set (n = 179) and The Cancer Genome Atlas (TCGA) validation set (n = 95). Then, the IPS was established by using the least absolute shrinkage and selection operator (LASSO) regression method. Kaplan-Meier analysis showed that patients with high IPS scores had significantly worse overall survival times than patients with low IPS scores in both the training set and the validation set (log-rank p = 0.001, and p = 0.050, respectively). Univariate and multivariate Cox regression analyses proved that the IPS was a robust prognostic factor for ESCC, independent of age, sex, tumor node metastasis (TNM) stage, pathology grade, and tumor location. In the mechanistic study, the epithelial-mesenchymal transition (EMT) process was identified by both gene set enrichment analysis (GSEA) and weighted correlation network analysis (WGCNA) as the underlying mechanism by which the IPS affects the prognosis of ESCC. After systematic correlation analyses, we found that M2 macrophages were the only cell type in the IPS significantly correlated with the EMT process. This relationship between M2 macrophage infiltration and the EMT phenotype was also confirmed by our preliminary immunochemistry (IHC) and multiplexed immunofluorescence study. In conclusion, we constructed an IPS that predicts the postoperative prognosis of ESCC patients and uncovered the critical role of M2 macrophages in the interplay between immune status and the EMT phenotype in ESCC.
Pembrolizumab Plus Chemotherapy or Anlotinib vs. Pembrolizumab Alone in Patients With Previously Treated EGFR-Mutant NSCLC
Authors: Chen Ya , Yang Zhengyu , Wang Yanan , Hu Minjuan , Zhang Bo , Zhang Yanwei , Qian Fangfei , Zhang Wei , Han Baohui
Published: April 2021

Objectives

More and more encouraging evidence revealed that immunotherapy could improve clinical outcomes in patients with previously treated non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) variations. However, immunotherapy is still a controversy for NSCLC patients with EGFR mutation.

Method

In this retrospective analysis, we compared the clinical efficacy of pembrolizumab monotherapy (PM), pembrolizumab combined with chemotherapy (P+C) and pembrolizumab combined with anlotinib (P+A) in NSCLC patients with EGFR mutation who had failed on EGFR-TKI and platinum-based chemotherapy.

Result

Eighty-six patients were included in this study. The overall median progression free survival (PFS) was 3.24 months. Multivariate analysis suggested that EGFRL858R and combined therapy were positive prognostic factors of PFS. The overall median OS was 12.28 months. Multivariate analysis found that high PD-L1 expression (≥50%) and combined therapy seemed to be positive prognostic factors of OS. Among the population, 32 patients received PM, 26 patients received P+C and 28 patients received P+A. Up to Jan 30, 2021, the median progression-free survival was 1.5 months in the PM group, 4.30 months in the P+C group and 3.24 months in the P+A group. The median OS were 7.41, 14.92 and 15.97 months, respectively. The ORR were 3.1%, 23.1% and 21.4%.

Conclusion

The addition of chemotherapy or antiangiogenic therapy to pembrolizumab resulted in significantly longer PFS, OS and ORR than pembrolizumab alone in our study. EGFRL858R might be a positive prognostic factor of PFS and high PD-L1 expression might be a positive prognostic factor of OS.
CD21lo/−CD27−IgM− Double-Negative B Cells Accumulate in the Joints of Patients With Antinuclear Antibody-Positive Juvenile Idiopathic Arthritis
Authors: Dirks Johannes , Fischer Jonas , Haase Gabriele , Holl-Wieden Annette , Hofmann Christine , Girschick Hermann , Morbach Henner
Published: April 2021

Juvenile idiopathic arthritis (JIA) encompasses a heterogeneous group of diseases. The appearance of antinuclear antibodies (ANAs) in almost half of the patients suggests B cell dysregulation as a distinct pathomechanism in these patients. Additionally, ANAs were considered potential biomarkers encompassing a clinically homogenous subgroup of JIA patients. However, in ANA+ JIA patients, the site of dysregulated B cell activation as well as the B cell subsets involved in this process is still unknown. Hence, in this cross-sectional study, we aimed in an explorative approach at characterizing potential divergences in B cell differentiation in ANA+ JIA patients by assessing the distribution of peripheral blood (PB) and synovial fluid (SF) B cell subpopulations using flow cytometry. The frequency of transitional as well as switched-memory B cells was higher in PB of JIA patients than in healthy controls. There were no differences in the distribution of B cell subsets between ANA- and ANA+ patients in PB. However, the composition of SF B cells was different between ANA- and ANA+ patients with increased frequencies of CD21lo/−CD27−IgM− “double negative” (DN) B cells in the latter. DN B cells might be a characteristic subset expanding in the joints of ANA+ JIA patients and are potentially involved in the antinuclear immune response in these patients. The results of our explorative study might foster further research dissecting the pathogenesis of ANA+ JIA patients.
Hypoglycemia Associated With Drug–Drug Interactions in Patients With Type 2 Diabetes Mellitus Using Dipeptidylpeptidase-4 Inhibitors
Authors: Ray Chin-Ying , Wu Victor Chien-Chia , Wang Chun-Li , Tu Hui-Tzu , Huang Yu-Tung , Kuo Chang-Fu , Chang Shang-Hung
Published: April 2021

Background: Dipeptidylpeptidase-4 inhibitors (DPP-4i′s) are considered to be safe for patients with type 2 diabetes mellitus (T2DM). However, little is known about drug–drug interactions between DPP-4i′s and concurrent medications.

Methods: Data on patients using DPP-4i′s for T2DM during 2011–2017 were retrieved from Chang Gung Research database provided by Chang Gung Memorial Hospital. Patients were excluded if they were aged <30 years or >90 years; had incomplete demographic data; had insulinoma; or had records of concomitant insulin use. A generalized estimating equation–based Poisson model was employed for statistical analysis. The primary outcome was hypoglycemia events.

Results: We retrieved data on a total of 97,227 patients using DPP-4i′s. After patients were excluded according to the mentioned criteria, the remaining 77,047 DPP-4i users were studied (mean age 64 ± 12 years, men 54.4%). The most common medications coprescribed with DPP4is over all person-quarters were acetaminophen, simvastatin, fluvastatin, and colchicine (all >20,000 person-quarters). The combinations of a DPP-4i with bumetanide, captopril, colchicine, acetaminophen, cotrimoxazole, and pantoprazole were associated with an increased risk of hypoglycemia. Compared with the ratios observed for person-quarters of DPP-4i use alone (reference category), the adjusted prevalence ratios per 100 person-years of hypoglycemia for person-quarters of DPP-4i use in combination with bumetanide, captopril, colchicine, acetaminophen, cotrimoxazole, and pantoprazole were 2.44 (95% confidence interval [CI], 1.78–3.36), 2.97 (95% CI, 2.26–3.90), 1.87 (95% CI, 1.44–2.42), 2.83 (95% CI, 2.44–3.29), 2.27 (95% CI, 1.27–4.04), and 3.03 (95% CI, 1.96–4.68), respectively.

Conclusion: Among patients taking DPP-4i′s for T2DM, concurrent use of such inhibitors with bumetanide, captopril, acetaminophen, and pantoprazole was associated with an increased risk of hypoglycemia compared with the use of DPP-4i′s alone. Physicians prescribing DPP-4i′s should consider the potential risks associated with their concomitant use with other drugs.
Hydroxypropyl-β-Cyclodextrin-Complexed Resveratrol Enhanced Antitumor Activity in a Cervical Cancer Model: In Vivo Analysis
Authors: Hao Xincai , Sun Xiaodong , Zhu Haizhen , Xie Lixia , Wang Xuanbin , Jiang Nan , Fu Pan , Sang Ming
Published: April 2021

Trans-resveratrol (RES) exhibits a wide range of biological activities. Various methodological approaches have been established to improve the pharmacokinetic properties of RES. Moreover, additional in vivo studies are required to support clinical application. In this study, RES/HP-β-CD (RHSD) inclusion complex was prepared and characterized by FTIR, PXRD, DSC and NMR data. The effect and potential mechanism of RHSD against cervical cancer were investigated in a mouse xenograft tumor model by qPCR assay, Western blot assay, and immunohistochemical assay. Results showed that RHSD significantly decreased tumor growth compared with free RES, while the effect of preventing tumor growth was more prominent in vivo. Notably, RHSD could inhibit tumor development by suppressing the expression of HPV E6 and E7 oncogenes and upregulating P53 and Rb1 protein in cervical cancer. These findings demonstrated that RHSD was safe and potential for development of a new oral administration drug to treat cervical cancer.
Atorvastatin Upregulates microRNA-186 and Inhibits the TLR4-Mediated MAPKs/NF-κB Pathway to Relieve Steroid-Induced Avascular Necrosis of the Femoral Head
Authors: Zhang Yusong , Ma Limin , Lu Erhai , Huang Wenhua
Published: April 2021

Steroid-induced avascular necrosis of the femoral head (SANFH) is caused by the death of active components of the femoral head owing to hormone overdoses. The use of lipid-lowering drugs to prevent SANFH in animals inspired us to identify the mechanisms involving Atorvastatin (Ato) in SANFH. However, it is still not well understood how and to what extent Ato affects SANFH. This study aimed to figure out the efficacy of Ato in SANFH and the underlying molecular mechanisms. After establishment of the SANFH model, histological evaluation, lipid metabolism, inflammatory cytokines, oxidative stress, apoptosis, and autophagy of the femoral head were evaluated. The differentially expressed microRNAs (miRs) after Ato treatment were screened out using microarray analysis. The downstream gene and pathway of miR-186 were predicted and their involvement in SANFH rats was analyzed. OB-6 cells were selected to simulate SANFH in vitro. Cell viability, cell damage, inflammation responses, apoptosis, and autophagy were assessed. Ato alleviated SANFH, inhibited apoptosis, and promoted autophagy. miR-186 was significantly upregulated after Ato treatment. miR-186 targeted TLR4 and inactivated the MAPKs/NF-κB pathway. Inhibition of miR-186 reversed the protection of Ato on SANFH rats, while inhibition of TLR4 restored the protective effect of Ato. Ato reduced apoptosis and promoted autophagy of OB-6 cells by upregulating miR-186 and inhibiting the TLR4/MAPKs/NF-κB pathway. In conclusion, Ato reduced apoptosis and promoted autophagy, thus alleviating SANFH via miR-186 and the TLR4-mediated MAPKs/NF-κB pathway.
Glycyrrhizic Acid Promotes Osteogenic Differentiation of Human Bone Marrow Stromal Cells by Activating the Wnt/β-Catenin Signaling Pathway
Authors: Bai Jinwu , Xu Jianxiang , Hang Kai , Kuang Zhihui , Ying Li , Zhou Chenwei , Ni Licheng , Wang Yibo , Xue Deting
Published: April 2021

Glycyrrhizic acid (GA) is a major triterpene glycoside isolated from liquorice root that has been shown to inhibit osteoclastogenesis. However, there have been no reports regarding the effect of GA on osteogenic differentiation. Therefore, this study was performed to explore the effects and mechanism of action of GA on osteogenesis. A CCK-8 array was used to assess cell viability. The osteogenic capability was investigated by real-time quantitative PCR, western blotting and immunofluorescence analyses. ALP staining and ARS were used to evaluate ALP activity and mineralization, respectively. GA-GelMA hydrogels were designed to verify the therapeutic effects of GA in vivo by radiographic analysis and histological evaluation. Our results show that GA had no significant influence on the viability or proliferation of human bone marrow stromal cells (hBMSCs). GA promoted osteogenic differentiation and enhanced calcium deposition. Furthermore, ratio of active β-catenin and total β-catenin protein increased after treatment with GA. Wnt/catenin signaling inhibitor partially attenuated the effects of GA on osteogenic differentiation. In a mouse femoral fracture model, GA-GelMA hydrogels accelerated bone healing. Our results show that GA promotes the osteogenic differentiation of hBMSCs by modulating the Wnt/β-catenin signaling pathway. GA-GelMA hydrogels promoted bone fracture healing. GA has potential as a cost-effective treatment of bone defects.
Chemopreventive and Anticancer Property of Selenoproteins in Obese Breast Cancer
Authors: Bevinakoppamath Supriya , Saleh Ahmed Adel Mohammed , Ramachandra Shobha Chikkavaddaraguddi , Vishwanath Prashant , Prashant Akila
Published: April 2021

Obesity is a significant risk factor for various cancers including breast cancer resulting in an increased risk of recurrence as well as morbidity and mortality. Extensive studies on various pathways have been successful in establishing a biological relationship between obesity and breast cancer. The molecular classification of breast cancer includes five groups each having different responses to treatment. Increased levels of inflammatory cytokines seen in obese conditions drive the pro-proliferative pathways, such as the influx of macrophages, angiogenesis, and antiapoptotic pathways. Increased peripheral aromatization of androgens by aromatase increases the circulating estrogen levels which are also responsible for the association of obesity with breast cancer. Also, increased oxidative stress due to chronic low-grade inflammation in obese women plays an important role in carcinogenesis. Despite the availability of safe and effective treatment options for breast cancer, obese women are at increased risk of adverse outcomes including treatment-related toxicities. In the recent decade, selenium compounds have gained substantial interest as chemopreventive and anticancer agents. The chemical derivatives of selenium include inorganic and organic compounds that exhibit pro-oxidant properties and alter cellular redox homeostasis. They target more than one metabolic pathway by thiol modifications, induction of reactive oxygen species, and chromatin modifications to exert their chemopreventive and anticancer activities. The primary functional effectors of selenium that play a significant role in human homeostasis are selenoproteins like glutathione peroxidase, thioredoxin reductase, iodothyronine deiodinases, and selenoprotein P. Selenoproteins play a significant role in adipose tissue physiology by modulating preadipocyte proliferation and adipogenic differentiation. They correlate negatively with body mass index resulting in increased oxidative stress that may lead to carcinogenesis in obese individuals. Methylseleninic acid effectively suppresses aromatase activation thus reducing the estrogen levels and acting as a breast cancer chemopreventive agent. Adipose-derived inflammatory mediators influence the selenium metabolites and affect the proliferation and metastatic properties of cancer cells. Recently selenium nanoparticles have shown potent anticancer activity which may lead to a major breakthrough in the management of cancers caused due to multiple pathways. In this review, we discuss the possible role of selenoproteins as chemopreventive and an anticancer agent in obese breast cancer.
Targeted Therapy in Cardiovascular Disease: A Precision Therapy Era
Authors: Xu Mengda , Zhang Kailun , Song Jiangping
Published: April 2021

Targeted therapy refers to exploiting the specific therapeutic drugs against the pathogenic molecules (a protein or a gene) or cells. The drug specifically binds to disease-causing molecules or cells without affecting normal tissue, thus enabling personalized and precision treatment. Initially, therapeutic drugs included antibodies and small molecules, (e.g. nucleic acid drugs). With the advancement of the biology technology and immunotherapy, the gene editing and cell editing techniques are utilized for the disease treatment. Currently, targeted therapies applied to treat cardiovascular diseases (CVDs) mainly include protein drugs, gene editing technologies, nucleic acid drugs and cell therapy. Although targeted therapy has demonstrated excellent efficacy in pre-clinical and clinical trials, several limitations need to be recognized and overcome in clinical application, (e.g. off-target events, gene mutations, etc.). This review introduces the mechanisms of different targeted therapies, and mainly describes the targeted therapy applied in the CVDs. Furthermore, we made comparative analysis to clarify the advantages and disadvantages of different targeted therapies. This overview is expected to provide a new concept to the treatment of the CVDs.
Efficacy of Antiangiogenic Drugs in the Treatment of Diabetic Macular Edema: A Bayesian Network Analysis
Authors: Zhang Xuexue , Liu Yi , Wang Miaoran , Li Qiuyan , Zhang Wantong , Zhang Rui , Wu Yufei
Published: April 2021

Aims: To compare the efficacy of five kinds of antiangiogenic drugs in the treatment of diabetic macular edema

Methods: A comprehensive search of seven databases without language restrictions includes PubMed, EMBASE, Web of Science, CBM, the Cochrane Library, CNKI, and WanFang date. All literature used was published before October 2020. Eligible randomized trials were screened for inclusion in this study, and Bayesian framework was used to perform a network meta-analysis (NMA). Data on the mean change of best-corrected visual acuity (BCVA), central macular thickness (CMT) and intraocular pressure (IOP) at 6 months were extracted.

Results: 25 randomized controlled trials (RCTs) that covered 2214 eyes, which received treatment of more than 3 months durations were included. In the pooled pair-wise meta-analysis, there was no statistically significant difference between all treatments. The same result was observed in the network meta-analysis with 0–37.82% Global I-squared. For BCVA at 6 months, conbercept and ranibizumab may be favorable than bevacizumab, aflibercept, triamcinolone acetonide and sham injections according to the ranking probabilities. As for CMT at 6 months, ranibizumab may be the most effective compared to bevacizumab, aflibercept and triamcinolone acetonide. In terms of IOP at 6 months, ranibizumab have better effect than bevacizumab, triamcinolone acetonide and sham injections. The results of sensitivity analysis also confirm it.

Conclusion: The analysis confirms that ranibizumab may be the most favorable for BCVA improvement and have a stronger efficacy in decreasing CMT and IOP than other drugs when taking all the indicators into consideration. This conclusion may provide clinical evidence to guide treatment decisions. However, more high-quality randomized controlled trials will be necessary to further confirm this.
Resveratrol Prevents Campylobacter jejuni-Induced Leaky gut by Restoring Occludin and Claudin-5 in the Paracellular Leak Pathway
Authors: Lobo de Sá F. D. , Heimesaat M. M. , Bereswill S. , Nattramilarasu P. K. , Schulzke J. D. , Bücker R.
Published: April 2021

Campylobacter jejuni is a bacterial human pathogen causing gastroenteritis and sequelae like irritable bowel syndrome. Epidemiologists count the human campylobacteriosis by C. jejuni as the most common foodborne zoonosis and bacterial diarrheal disease worldwide. Based on bioinformatics predictions for potential protective compounds in campylobacteriosis, the question was raised whether the plant-based polyphenol resveratrol is sufficient to attenuate intestinal epithelial damage induced by C. jejuni. We investigated this by performing experimental infection studies in an epithelial cell culture and the secondary abiotic IL-10−/− mouse model. In C. jejuni-infected human colonic HT-29/B6 cell monolayers, transepithelial electrical resistance (TER) was decreased and the paracellular marker flux of fluorescein (332 Da) increased. Concomitantly, the tight junction (TJ) proteins occludin and claudin-5 were re-distributed off the tight junction domain. This was accompanied by an increased induction of epithelial apoptosis, both changes contributing to compromised barrier function and the opening of the leak pathway induced by C. jejuni. In parallel, the recovery experiments with the application of resveratrol revealed a functional improvement of the disturbed epithelial barrier in both models in vitro and in vivo. During treatment with resveratrol, TJ localization of occludin and claudin-5 was fully restored in the paracellular domain of HT-29/B6 cells. Moreover, resveratrol decreased the rate of epithelial apoptosis. These resveratrol-induced molecular and cellular effects would therefore be expected to improve epithelial barrier function, thereby minimizing the so-called leaky gut phenomenon. In conclusion, the induction of the leak pathway by C. jejuni and the restoration of barrier function by resveratrol demonstrates its effectiveness as a potential preventive or therapeutic method of mitigating the leaky gut associated with campylobacteriosis.
Cardiac Protection by Oral Sodium Thiosulfate in a Rat Model of L-NNA-Induced Heart Disease
Authors: Nguyen Isabel T. N. , Wiggenhauser Lucas M. , Bulthuis Marian , Hillebrands Jan-Luuk , Feelisch Martin , Verhaar Marianne C. , van Goor Harry , Joles Jaap A.
Published: April 2021

Hypertension contributes to cardiac damage and remodeling. Despite the availability of renin-angiotensin system inhibitors and other antihypertensive therapies, some patients still develop heart failure. Novel therapeutic approaches are required that are effective and without major adverse effects. Sodium Thiosulfate (STS), a reversible oxidation product of hydrogen sulfide (H2S), is a promising pharmacological entity with vasodilator and anti-oxidant potential that is clinically approved for the treatment of calciphylaxis and cyanide poisoning. We hypothesized that Sodium Thiosulfate improves cardiac disease in an experimental hypertension model and sought to investigate its cardioprotective effects by direct comparison to the ACE-inhibitor lisinopril, alone and in combination, using a rat model of chronic nitric oxide (NO) deficiency. Systemic nitric oxide production was inhibited in Sprague Dawley rats by administering N-ω-nitro-l-arginine (L-NNA) with the food for three weeks, leading to progressive hypertension, cardiac dysfunction and remodeling. We observed that STS, orally administered via the drinking water, ameliorated L-NNA-induced heart disease. Treatment with STS for two weeks ameliorated hypertension and improved systolic function, left ventricular hypertrophy, cardiac fibrosis and oxidative stress, without causing metabolic acidosis as is sometimes observed following parenteral administration of this drug. STS and lisinopril had similar protective effects that were not additive when combined. Our findings indicate that oral intervention with a H2S donor such as STS has cardioprotective properties without noticeable side effects.
Therapies for Chronic Allograft Rejection
Authors: Kim Min Young , Brennan Daniel C.
Published: April 2021

Remarkable advances have been made in the pathophysiology, diagnosis, and treatment of antibody-mediated rejection (ABMR) over the past decades, leading to improved graft outcomes. However, long-term failure is still high and effective treatment for chronic ABMR, an important cause of graft failure, has not yet been identified. Chronic ABMR has a relatively different phenotype from active ABMR and is a slowly progressive disease in which graft injury is mainly caused byde novodonor specific antibodies (DSA). Since most trials of current immunosuppressive therapies for rejection have focused on active ABMR, treatment strategies based on those data might be less effective in chronic ABMR. A better understanding of chronic ABMR may serve as a bridge in establishing treatment strategies to improve graft outcomes. In this in-depth review, we focus on the pathophysiology and characteristics of chronic ABMR along with the newly revised Banff criteria in 2017. In addition, in terms of chronic ABMR, we identify the reasons for the resistance of current immunosuppressive therapies and look at ongoing research that could play a role in setting better treatment strategies in the future. Finally, we review non-invasive biomarkers as tools to monitor for rejection.
The Tetramethylpyrazine Derivative Statmp-151: A Novel Small Molecule Stat3 Inhibitor With Promising Activity Against Breast Cancer
Authors: Fan Chen , Wang Yijie , Huang Hui , Li Wenzhen , Ma Jialin , Yao Dongping , Tang Zijun , Xue Taixiong , Ha Liyang , Ren Yan , Zhang Yiwen , Wang Qin , Xie Yongmei , Luo Yi , Tan Rui , Gu Jian
Published: April 2021

Breast cancer is the most common malignancy in women and is a molecularly heterogeneous disease. Signal transducer and activator of transcription 3 (Stat3) is overexpressed and hyperactivated in a variety of human tumours, including breast cancer, thus representing a promising target for breast cancer treatment. In the present study, we evaluated the activities of a novel Stat3 inhibitor named Statmp-151 in the human breast cancer cell lines MCF-7 and MDA-MB-231 and the murine mammary carcinoma cell line 4T1. The in vitro results showed that Statmp-151 inhibited the proliferation of breast cancer cell lines in a dose- and time-dependent manner and suppressed the phosphorylation of Stat3 in a dose-dependent manner. Flow cytometry (FCM) assays revealed that Statmp-151 affected mitochondrial membrane potential and reactive oxygen species (ROS) production. Furthermore, Statmp-151 inhibited cell migration, as shown by analysis of the matrix metalloproteinases MMP2 and MMP9. Finally, in a 4T1 tumour-bearing mouse model, intraperitoneal injection of 30 mg/kg/day Statmp-151 significantly suppressed the growth of tumours without obvious toxicity. These results indicated that Statmp-151 might be a potential candidate for the treatment of breast cancer.
Pregnancy-Related Hormones Increase UGT1A1-Mediated Labetalol Metabolism in Human Hepatocytes
Authors: Khatri Raju , Fallon John K. , Sykes Craig , Kulick Natasha , Rementer Rebecca J. B. , Miner Taryn A. , Schauer Amanda P. , Kashuba Angela D. M. , Boggess Kim A. , Brouwer Kim L. R. , Smith Philip C. , Lee Craig R.
Published: April 2021

Pregnancy-related hormones (PRH) are recognized as important regulators of hepatic cytochrome P450 enzyme expression and function. However, the impact of PRH on the hepatic expression and function of uridine diphosphate glucuronosyltransferases (UGTs) remains unclear. Using primary human hepatocytes, we evaluated the effect of PRH exposure on mRNA levels and protein concentrations of UGT1A1, UGT2B7, and other key UGT enzymes, and on the metabolism of labetalol (a UGT1A1 and UGT2B7 substrate commonly prescribed to treat hypertensive disorders of pregnancy). Sandwich-cultured human hepatocytes (SCHH) from female donors were exposed to the PRH estradiol, estriol, estetrol, progesterone, and cortisol individually or in combination. We quantified protein concentrations of UGT1A1, UGT2B7, and four additional UGT1A isoforms in SCHH membrane fractions and evaluated the metabolism of labetalol to its glucuronide metabolites in SCHH. PRH exposure increased mRNA levels and protein concentrations of UGT1A1 and UGT1A4 in SCHH. PRH exposure also significantly increased labetalol metabolism to its UGT1A1-derived glucuronide metabolite in a concentration-dependent manner, which positively correlated with PRH-induced changes in UGT1A1 protein concentrations. In contrast, PRH did not alter UGT2B7 mRNA levels or protein concentrations in SCHH, and formation of the UGT2B7-derived labetalol glucuronide metabolite was decreased following PRH exposure. Our findings demonstrate that PRH alter expression and function of UGT proteins in an isoform-specific manner and increase UGT1A1-mediated labetalol metabolism in human hepatocytes by inducing UGT1A1 protein concentrations. These results provide mechanistic insight into the increases in labetalol clearance observed in pregnant individuals.
Different Pharmacokinetics of Tramadol, O-Demethyltramadol and N-Demethyltramadol in Postoperative Surgical Patients From Those Observed in Medical Patients
Authors: Neskovic Nenad , Mandic Dario , Marczi Saska , Skiljic Sonja , Kristek Gordana , Vinkovic Hrvoje , Mraovic Boris , Debeljak Zeljko , Kvolik Slavica
Published: April 2021

Background: Most studies examining tramadol metabolism have been carried out in non-surgical patients and with oral tramadol. The aim of this study was 1) to measure concentrations of tramadol, O-demethyltramadol (ODT), and N-demethyltramadol (NDT) in the surgical patients admitted to the intensive care unit (ICU) within the first 24 postoperative hours after intravenous application of tramadol, and 2) to examine the effect of systemic inflammation on tramadol metabolism and postoperative pain.

Methods: A prospective observational study was carried out in the surgical ICU in the tertiary hospital. In the group of 47 subsequent patients undergoing major abdominal surgery, pre-operative blood samples were taken for CYP2D6 polymorphism analysis. Systemic inflammation was assessed based on laboratory and clinical indicators. All patients received 100 mg of tramadol intravenously every 6 h during the first postoperative day. Postoperative pain was assessed before and 30 min after tramadol injections. Tramadol, ODT, and NDT concentrations were determined by high-performance liquid chromatography.

Results:CYP2D6 analysis revealed 2 poor (PM), 22 intermediate (IM), 22 extensive (EM), and 1 ultrafast metabolizer. After a dose of 100 mg of tramadol, t1/2 of 4.8 (3.2–7.6) h was observed. There were no differences in tramadol concentration among metabolic phenotypes. The area under the concentration–time curve at the first dose interval (AUC1-6) of tramadol was 1,200 (917.9–1944.4) μg ×h ×L−1. NDT concentrations in UM were below the limit of quantification until the second dose of tramadol was administrated, while PM had higher NDT concentrations compared to EM and IM. ODT concentrations were higher in EM, compared to IM and PM. ODT AUC1-6 was 229.6 (137.7–326.2) μg ×h ×L−1 and 95.5 (49.1–204.3) μg ×h ×L−1 in EM and IM, respectively (p = 0.004). Preoperative cholinesterase activity (ChE) of ≤4244 U L−1 was a cut-off value for a prediction of systemic inflammation in an early postoperative period. NDT AUC1-6 were significantly higher in patients with low ChE compared with normal ChE patients (p = 0.006). Pain measurements have confirmed that sufficient pain control was achieved in all patients after the second tramadol dose, except in the PM.

Conclusions:CYP2D6 polymorphism is a major factor in O-demethylation, while systemic inflammation accompanied by low ChE has an important role in the N-demethylation of tramadol in postoperative patients. Concentrations of tramadol, ODT, and NDT are lower in surgical patients than previously reported in non-surgical patients.

Clinical Trial Registration: ClinicalTrials.gov, NCT04004481.
Pharmacogenetics in Psychiatry: Perceived Value and Opinions in a Chilean Sample of Practitioners
Authors: Undurraga Juan , Bórquez-Infante Ignacio , Crossley Nicolás A. , Prieto Miguel L. , Repetto Gabriela M.
Published: April 2021

Use of pharmacogenetics (PGx) testing to guide clinical decisions is growing in developed countries. Published guidelines for gene–drug pair analysis are available for prescriptions in psychiatry, but information on their utilization, barriers, and health outcomes in Latin America is limited. As a result, this work aimed at exploring current use, opinions, and perceived obstacles on PGx testing among psychiatrists in Chile, via an online, anonymous survey. Among 123 respondents (5.9% of registered psychiatrists in the country), 16.3% reported ever requesting a PGx test. The vast majority (95%) of tests were ordered by clinicians practicing in the Metropolitan Region of Santiago. Having more than 20 years in practice was positively associated with prior use of PGx (p 0.02, OR 3.74 (1.19–11.80)), while working in the public health system was negatively associated (OR 0.30 (0.10–0.83)). Perceived barriers to local implementation included insufficient evidence of clinical utility, limited clinicians’ knowledge on PGx and on test availability, and health systems’ issues, such as costs and reimbursement. Despite the recognition of these barriers, 80% of respondents asserted that it is likely that they will incorporate PGx tests in their practice in the next five years. Given these results, we propose next steps to facilitate implementation such as further research in health outcomes and clinical utility of known and novel clinically actionable variants, growth in local sequencing capabilities, education of clinicians, incorporation of clinical decision support tools, and economic evaluations, all in local context.
Probiotic Lactobacilli Isolated from Kefir Promote Down-Regulation of Inflammatory Lamina Propria T Cells from Patients with Active IBD
Authors: Curciarello Renata , Canziani Karina E. , Salto Ileana , Barbiera Romero Emanuel , Rocca Andrés , Doldan Ivan , Peton Emmanuel , Brayer Santiago , Sambuelli Alicia M. , Goncalves Silvina , Tirado Pablo , Correa Gustavo J. , Yantorno Martín , Garbi Laura , Docena Guillermo H. , Serradell María de los Ángeles , Muglia Cecilia I.
Published: April 2021

Ulcerative colitis and Crohn’s disease, the two main forms of inflammatory bowel disease (IBD), are immunologically mediated disorders. Several therapies are focused on activated T cells as key targets. Although Lactobacillus kefiri has shown anti-inflammatory effects in animal models, few studies were done using human mucosal T cells. The aim of this work was to investigate the immunomodulatory effects of this bacterium on intestinal T cells from patients with active IBD. Mucosal biopsies and surgical samples from IBD adult patients (n = 19) or healthy donors (HC; n = 5) were used. Lamina propria mononuclear cells were isolated by enzymatic tissue digestion, and entero-adhesive Escherichia coli-specific lamina propria T cells (LPTC) were expanded. The immunomodulatory properties of L. kefiri CIDCA 8348 strain were evaluated on biopsies and on anti-CD3/CD28-activated LPTC. Secreted cytokines were quantified by ELISA, and cell proliferation and viability were assessed by flow cytometry. We found that L. kefiri reduced spontaneous release of IL-6 and IL-8 from inflamed biopsies ex vivo. Activated LPTC from IBD patients showed low proliferative rates and reduced secretion of TNF-α, IL-6, IFN-γ and IL-13 in the presence of L. kefiri. In addition, L. kefiri induced an increased frequency of CD4+FOXP3+ LPTC along with high levels of IL-10. This is the first report showing an immunomodulatory effect of L. kefiri CIDCA 8348 on human intestinal cells from IBD patients. Understanding the mechanisms of interaction between probiotics and immune mucosal cells may open new avenues for treatment and prevention of IBD.