bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of Fecal Microbiota Transplantation Combined With Mediterranean Diet on Insulin Sensitivity in Subjects With Metabolic Syndrome
Authors: Koopen Annefleur M. , Almeida Eduardo L. , Attaye Ilias , Witjes Julia J. , Rampanelli Elena , Majait Soumia , Kemper Marleen , Levels Johannes H. M. , Schimmel Alinda W. M. , Herrema Hilde , Scheithauer Torsten P. M. , Frei Werner , Dragsted Lars , Hartmann Bolette , Holst Jens J. , O’Toole Paul W. , Groen Albert K. , Nieuwdorp Max
Published: June 2021

Background

Recent studies demonstrate that a Mediterranean diet has beneficial metabolic effects in metabolic syndrome subjects. Since we have shown that fecal microbiota transplantation (FMT) from lean donors exerts beneficial effects on insulin sensitivity, in the present trial, we investigated the potential synergistic effects on insulin sensitivity of combining a Mediterranean diet with donor FMT in subjects with metabolic syndrome.

Design

Twenty-four male subjects with metabolic syndrome were put on a Mediterranean diet and after a 2-week run-in phase, the subjects were randomized to either lean donor (n = 12) or autologous (n = 12) FMT. Changes in the gut microbiota composition and bacterial strain engraftment after the 2-week dietary regimens and 6 weeks post-FMT were the primary endpoints. The secondary objectives were changes in glucose fluxes (both hepatic and peripheral insulin sensitivity), postprandial plasma incretin (GLP-1) levels, subcutaneous adipose tissue inflammation, and plasma metabolites.

Results

Consumption of the Mediterranean diet resulted in a reduction in body weight, HOMA-IR, and lipid levels. However, no large synergistic effects of combining the diet with lean donor FMT were seen on the gut microbiota diversity after 6 weeks. Although we did observe changes in specific bacterial species and plasma metabolites, no significant beneficial effects on glucose fluxes, postprandial incretins, or subcutaneous adipose tissue inflammation were detected.

Conclusions

In this small pilot randomized controlled trial, no synergistic beneficial metabolic effects of combining a Mediterranean diet with lean donor FMT on glucose metabolism were achieved. However, we observed engraftment of specific bacterial species. Future trials are warranted to test the combination of other microbial interventions and diets in metabolic syndrome.
Transcriptional Responses of Herbaspirillum seropedicae to Environmental Phosphate Concentration
Authors: Grillo-Puertas Mariana , Villegas Josefina M. , Pankievicz Vânia C. S. , Tadra-Sfeir Michelle Z. , Teles Mota Francisco J. , Hebert Elvira M. , Brusamarello-Santos Liziane , Pedraza Raul O. , Pedrosa Fabio O. , Rapisarda Viviana A. , Souza Emanuel M.
Published: June 2021

Herbaspirillum seropedicae is a nitrogen-fixing endophytic bacterium associated with important cereal crops, which promotes plant growth, increasing their productivity. The understanding of the physiological responses of this bacterium to different concentrations of prevailing nutrients as phosphate (Pi) is scarce. In some bacteria, culture media Pi concentration modulates the levels of intracellular polyphosphate (polyP), modifying their cellular fitness. Here, global changes of H. seropedicae SmR1 were evaluated in response to environmental Pi concentrations, based on differential intracellular polyP levels. Cells grown in high-Pi medium (50 mM) maintained high polyP levels in stationary phase, while those grown in sufficient Pi medium (5 mM) degraded it. Through a RNA-seq approach, comparison of transcriptional profiles of H. seropedicae cultures revealed that 670 genes were differentially expressed between both Pi growth conditions, with 57% repressed and 43% induced in the high Pi condition. Molecular and physiological analyses revealed that aspects related to Pi metabolism, biosynthesis of flagella and chemotaxis, energy production, and polyhydroxybutyrate metabolism were induced in the high-Pi condition, while those involved in adhesion and stress response were repressed. The present study demonstrated that variations in environmental Pi concentration affect H. seropedicae traits related to survival and other important physiological characteristics. Since environmental conditions can influence the effectiveness of the plant growth-promoting bacteria, enhancement of bacterial robustness to withstand different stressful situations is an interesting challenge. The obtained data could serve not only to understand the bacterial behavior in respect to changes in rhizospheric Pi gradients but also as a base to design strategies to improve different bacterial features focusing on biotechnological and/or agricultural purposes.
Development and Application of a Multiple Cross Displacement Amplification Combined With Nanoparticle-Based Lateral Flow Biosensor Assay to Detect Candida tropicalis
Authors: Wang Yu , Zhao Xue , Cheng Jinzhi , Tang Xiaomin , Chen Xu , Yu Honglan , Li Shijun
Published: June 2021

Candida tropicalis is an increasingly opportunistic pathogen that causes serious invasive candidiasis threatening a patient’s life. Traditional methods to detect C. tropicalis infection depends on time-consuming, culture-based gold-standard methods. So, we sought to establish a new method that could detect target pathogens quickly, accurately, and straightforwardly. Herein, a combination of multiple cross displacement amplification (MCDA) and lateral flow biosensors (LFB) was employed to detect C. tropicalis. In the MCDA system, 10 primers were designed to identify the specific genes of C. tropicalis and amplify the genes in an isothermal amplification device. Then, MCDA amplification reaction products could be identified visibly by color change, and all the amplification products would be tested by LFB with no special equipment. The results demonstrated that the optimal reaction condition of C. tropicalis-MCDA assay was 64°C within 30 min, and only 10 fg DNA was required in each reaction. No cross-reaction was found between C. tropicalis strains and non-C. tropicalis strains. For 300 sputum samples, the results showed that MCDA-LFB assay could rapidly and successfully detect all of the C. tropicalis-positive (28/300) samples detected by the gold-standard method. The entire procedure, including specimen processing (40 min), isothermal reaction (30 min) and result reporting (within 2 min), could be completed within 75 min. Briefly, the study results demonstrated that the detection ability of C. tropicalis-MCDA-LFB assay was better than culture methods with more simplicity, rapidity, sensitivity and specificity. Hence, MCDA-LFB strategy is an effective tool to rapidly detect C. tropicalis in clinical samples, especially in resource-poor areas.
Evidence of Horizontal Gene Transfer of 50S Ribosomal Genes rplB, rplD, and rplY in Neisseria gonorrhoeae
Authors: Manoharan-Basil Sheeba Santhini , Laumen Jolein Gyonne Elise , Van Dijck Christophe , De Block Tessa , De Baetselier Irith , Kenyon Chris
Published: June 2021

Horizontal gene transfer (HGT) in the penA and multidrug efflux pump genes has been shown to play a key role in the genesis of antimicrobial resistance in Neisseria gonorrhoeae. In this study, we evaluated if there was evidence of HGT in the genes coding for the ribosomal proteins in the Neisseria genus. We did this in a collection of 11,659 isolates of Neisseria, including N. gonorrhoeae and commensal Neisseria species (N. cinerea, N. elongata, N. flavescens, N. mucosa, N. polysaccharea, and N. subflava). Comparative genomic analyses identified HGT events in three genes: rplB, rplD, and rplY coding for ribosomal proteins L2, L4 and L25, respectively. Recombination events were predicted in N. gonorrhoeae and N. cinerea, N. subflava, and N. lactamica were identified as likely progenitors. In total, 2,337, 2,355, and 1,127 isolates possessed L2, L4, and L25 HGT events. Strong associations were found between HGT in L2/L4 and the C2597T 23S rRNA mutation that confers reduced susceptibility to macrolides. Whilst previous studies have found evidence of HGT of entire genes coding for ribosomal proteins in other bacterial species, this is the first study to find evidence of HGT-mediated chimerization of ribosomal proteins.
Virulence Gene Expression of Staphylococcus aureus in Human Skin
Authors: Cruz Ana Rita , van Strijp Jos A. G. , Bagnoli Fabio , Manetti Andrea G. O.
Published: June 2021

Staphylococcus aureus is the main cause of human skin and soft tissue infections. However, S. aureus pathogenicity within the skin is not fully characterized. Here, we implemented an S. aureus cutaneous infection model using human skin explants and performed a time-course infection to study the gene expression profile of a large panel of virulence-related factors of S. aureus USA300 LAC strain, by high-throughput RT-PCR. We pinpointed the genes that were differentially regulated by the bacteria in the skin tissues and identified 12 virulence factors that were upregulated at all time points assessed. Finally, using confocal microscopy, we show that the expression of alpha-hemolysin by S. aureus varies dependent on the skin niche and that the bacteria preferentially accumulates inside sweat glands and ducts. Taken together, our study gives insights about the pathogenic lifestyle of S. aureus within human skin tissues, which may contribute for the development of anti-S. aureus therapeutic strategies.
Varied Contribution of Phospholipid Shedding From Membrane to Daptomycin Tolerance in Staphylococcus aureus
Authors: Shen Tianwei , Hines Kelly M. , Ashford Nathaniel K. , Werth Brian J. , Xu Libin
Published: June 2021

It has been suggested that daptomycin can be inactivated by lipids released by Staphylococcus aureus and that this effect is antagonized by phenol soluble modulins (PSMs), which bind to the shed lipids. PSM production is regulated by the Agr system, and others have shown that loss of the Agr function enhances S. aureus survival in the presence of daptomycin. Here we assessed the impact of Agr function on daptomycin activity and lipid metabolism under various conditions. Daptomycin activity was evaluated against three sets of isogenic strain series with wild-type or dysfunctional Agr using static daptomycin time-kills over 24 h and against one strain pair using in vitro pharmacokinetic/pharmacodynamic (PK/PD) models simulating clinical daptomycin exposure for 48 h. We performed comprehensive lipidomics on bacterial membranes and the spent media to correlate lipid shedding with survival. In static time-kill experiments, two agr-deficient strains (SH1000- and USA300 LAC ΔagrA) showed improved survival for 8 h compared with their corresponding wild-type strains as seen in previous studies, but this difference did not persist for 24 h. However, four other agr-deficient strains (SH1001 and JE2 agr KOs) did not demonstrate improved survival compared to isogenic wild-type strains at any time in the time-kills. Lipidomics analysis of SH1000, SH1001, and SH1000- strains showed daptomycin exposure increased lipid shedding compared to growth controls in all strains with phosphatidylglycerols (PGs), lysylPGs and cardiolipins predominating. In the cell pellets, PGs and lysylPGs decreased but cardiolipins were unchanged with daptomycin exposure. The shed lipid profiles in SH1001 and SH1000- were similar, suggesting that the inability to resist daptomycin by SH1001 was not because of differences in lipid shedding. In the PK/PD model, the agr mutant SH1000- strain did not show improved survival relative to SH1000 either. In conclusion, inactivation of daptomycin by shed lipids may be dependent on genetic background, the specific agr mutations, or the techniques used to generate these KOs rather than the overall function of the Agr system, and its contribution to daptomycin tolerance seems to be varied, transient, and growth-condition dependent.
Predictors of Functional Outcome in a Cohort of Hispanic Patients Using Exoskeleton Rehabilitation for Cerebrovascular Accidents and Traumatic Brain Injury
Authors: Treviño Lisa R. , Roberge Peter , Auer Michael E. , Morales Angela , Torres-Reveron Annelyn
Published: June 2021

Traumatic brain injury (TBI) and cerebrovascular accidents (CVA) are two of the leading causes of disability in the United States. Robotic exoskeletons (RE) have been approved for rehabilitation by the Federal Drug Administration (FDA) for use after a CVA, and recently received approval for use in patients with TBI. The aim of the study was to determine which factors predict the improvement in functional independence measure (FIM) score after using RE rehabilitation in a population of patients with CVA or TBI. We carried out a retrospective chart-review analysis of the use of the RE (Ekso® GT) in the rehabilitation of patients with TBI and CVA using data from a single, private rehabilitation hospital for patients admitted and discharged between 01/01/2017 and 04/30/2020. From the medical records, we collected presentation date, Glasgow Coma Scale score (GCS) on the date of injury, rehabilitation start date, age, diabetes status on presentation (Yes or No), injury category (TBI or CVA), and both admission and discharge FIM scores. Matching algorithms resulted in one TBI patient matched to three CVA patients resulting in a sample size of 36. The diabetic and non-diabetic populations showed significant differences between age and days from injury to the start of rehabilitation. A multivariate linear regression assessed predictors for discharge motor FIM and found admission motor FIM score and total RE steps to be statistically significant predictors. For each point scored higher on the admission motor FIM the discharge FIM was increased by 1.19 FIM points, and for each 1,000 steps taken in the RE, the discharge motor FIM increased by three points. The type of acquired brain injury (CVA or TBI) was not found to affect functional outcome. The presented results show that key clinic-biologic factors including diabetic status, together with start to rehabilitation play key roles in discharge FIM scores for patients using RE.

Clinical Trial Registration:ClinicalTrials.gov, NCT04465019
Dynamic Characteristics and Anti-slip Grasping of Two-Finger Translational Manipulator
Authors: Liu Wei , Cheng Jin , Wan Ping , Jing Cheng , Ma Yongheng , Chen Keshiting
Published: June 2021

Aiming at the problem of deformation and slip of disc-shaped rubber gasket in the process of grasping, a two-finger translational manipulator based on ABB1410 robot is designed. The kinematics model of the two-finger translational manipulator is established, and the geometric relationship between the motor angle and grasp position is obtained. Based on the two-dimensional force sensor, the dynamic characteristics of the two-finger translational manipulator were studied, and the relationship between the grasping force and the deformation and slip of the disc-shaped rubber gasket was obtained. A prototype of two-finger translational manipulator is developed. The experimental results show that when the grasping force is 5 N, small deformation and stable grasping can be achieved. The grasping and handling process of disk-shaped rubber gasket is designed based on Robot Studio software, and the verification experiments were carried out. The experimental results show that the system can achieve the small deformation and stable grasping of flexible objects, which is consistent with the simulation results. The research can provide theoretical and experimental basis for the design of automation system structure and process control.
White Matter Injury After Intracerebral Hemorrhage
Authors: Fu Xiongjie , Zhou Guoyang , Zhuang Jianfeng , Xu Chaoran , Zhou Hang , Peng Yucong , Cao Yang , Zeng Hanhai , Li Jianru , Yan Feng , Wang Lin , Chen Gao
Published: June 2021

Spontaneous intracerebral hemorrhage (ICH) accounts for 15% of all stroke cases. ICH is a devastating form of stroke associated with high morbidity, mortality, and disability. Preclinical studies have explored the mechanisms of neuronal death and gray matter damage after ICH. However, few studies have examined the development of white matter injury (WMI) following ICH. Research on WMI indicates that its pathophysiological presentation involves axonal damage, demyelination, and mature oligodendrocyte loss. However, the detailed relationship and mechanism between WMI and ICH remain unclear. Studies of other acute brain insults have indicated that WMI is strongly correlated with cognitive deficits, neurological deficits, and depression. The degree of WMI determines the short- and long-term prognosis of patients with ICH. This review demonstrates the structure and functions of the white matter in the healthy brain and discusses the pathophysiological mechanism of WMI following ICH. Our review reveals that the development of WMI after ICH is complex; therefore, comprehensive treatment is essential. Understanding the relationship between WMI and other brain cells may reveal therapeutic targets for the treatment of ICH.
Biomarkers for Antiplatelet Therapies in Acute Ischemic Stroke: A Clinical Review
Authors: Alhazzani Adel , Venkatachalapathy Poongothai , Padhilahouse Sruthi , Sellappan Mohan , Munisamy Murali , Sekaran Mangaiyarkarasi , Kumar Amit
Published: June 2021

Stroke is one of the world's leading causes of disability and death. Antiplatelet agents are administered to acute ischemic stroke patients as secondary prevention. Clopidogrel involves biotransformation by cytochrome P450 (CYP) enzymes into an active metabolite, and single nucleotide polymorphisms (SNPs) can influence the efficacy of this biotransformation. Despite the therapeutic advantages of aspirin, there is significant inter-individual heterogeneity in response to this antiplatelet drug. In this clinical review, the recent advances in the biomarkers of antiplatelet agents in acute ischemic stroke are discussed. The studies reviewed herein highlight the clinical relevance of antiplatelet resistance, pharmacotherapy of antiplatelet agents predicting drug response, strategies for identifying aspirin resistance, pharmacogenetic variants of antiplatelet agents, miRNAs, and extracellular vesicles (EVs) as biomarkers toward the personalized approach in the management of acute ischemic stroke. The precise pathways contributing to antiplatelet resistance are not very well known but are presumably multi-factorial. It is essential to understand the clinical relevance of clopidogrel and aspirin-related single nucleotide polymorphism (SNPs) as potential predictive and prognostic biomarkers. Prasugrel is a next-generation antiplatelet agent that prevents ADP-platelet activation by binding irreversibly to P2Y12 receptor. There are sporadic reports of prasugrel resistance and polymorphisms in the Platelet endothelial aggregation receptor-1 (PEAR1) that may contribute to a change in the pharmacodynamics response. Ticagrelor, a direct-acting P2Y12-receptor antagonist, is easily absorbed and partly metabolized to major AR-C124910XX metabolite (ARC). Ticagrelor's primary active metabolite, ARC124910XX (ARC), is formed via the most abundant hepatic cytochrome P450 (CYP) enzyme, CYP3A4, and CYP3A5. The integration of specific biomarkers, genotype as well as phenotype-related data in antiplatelet therapy stratification in patients with acute ischemic stroke will be of great clinical significance and could be used as a guiding tool for more effective, personalized therapy.
Predictive Value of Upper Extremity Outcome Measures After Stroke—A Systematic Review and Metaregression Analysis
Authors: Wolf Silke , Gerloff Christian , Backhaus Winifried
Published: June 2021

A better understanding of motor recovery after stroke requires large-scale, longitudinal trials applying suitable assessments. Currently, there is an abundance of upper limb assessments used to quantify recovery. How well various assessments can describe upper limb function change over 1 year remains uncertain. A uniform and feasible standard would be beneficial to increase future studies' comparability on stroke recovery. This review describes which assessments are common in large-scale, longitudinal stroke trials and how these quantify the change in upper limb function from stroke onset up to 1 year. A systematic search for well-powered stroke studies identified upper limb assessments classifying motor recovery during the initial year after a stroke. A metaregression investigated the association between assessments and motor recovery within 1 year after stroke. Scores from nine common assessments and 4,433 patients were combined and transformed into a standardized recovery score. A mixed-effects model on recovery scores over time confirmed significant differences between assessments (P< 0.001), with improvement following the weeks after stroke present when measuring recovery using the Action Research Arm Test (β = 0.013), Box and Block test (β = 0.011), Fugl–Meyer Assessment (β = 0.007), or grip force test (β = 0.023). A last-observation-carried-forward analysis also highlighted the peg test (β = 0.017) and Rivermead Assessment (β = 0.011) as additional, valuable long-term outcome measures. Recovery patterns and, thus, trial outcomes are dependent on the assessment implemented. Future research should include multiple common assessments and continue data collection for a full year after stroke to facilitate the consensus process on assessments measuring upper limb recovery.
Cerebellum and Prematurity: A Complex Interplay Between Disruptive and Dysmaturational Events
Authors: Spoto Giulia , Amore Greta , Vetri Luigi , Quatrosi Giuseppe , Cafeo Anna , Gitto Eloisa , Nicotera Antonio Gennaro , Di Rosa Gabriella
Published: June 2021

The cerebellum plays a critical regulatory role in motor coordination, cognition, behavior, language, memory, and learning, hence overseeing a multiplicity of functions. Cerebellar development begins during early embryonic development, lasting until the first postnatal years. Particularly, the greatest increase of its volume occurs during the third trimester of pregnancy, which represents a critical period for cerebellar maturation. Preterm birth and all the related prenatal and perinatal contingencies may determine both dysmaturative and lesional events, potentially involving the developing cerebellum, and contributing to the constellation of the neuropsychiatric outcomes with several implications in setting-up clinical follow-up and early intervention.
Protein Intake, IGF-1 Concentrations, and Growth in the Second Year of Life in Children Receiving Growing Up Milk – Lite (GUMLi) or Cow's Milk (CM) Intervention
Authors: Lovell Amy L. , Milne Tania , Matsuyama Misa , Hill Rebecca J. , Davies Peter S. W. , Grant Cameron C. , Wall Clare R.
Published: June 2021

The relationship of protein intake with insulin-like growth factor 1 (IGF-1) concentrations in well-nourished children during the second year of life is poorly understood. The aim of this study was to explore the effect of a reduced-protein Growing Up Milk Lite (GUMLi) or unfortified cow's milk (CM) on protein intake, growth, and plasma IGF-1 at 2 y. An exploratory analysis of a sub-sample of Auckland-based children (n = 79) in the GUMLi trial (a double-blind, randomised control trial, N = 160) completed in Auckland and Brisbane (2015–2017) was conducted. One-year old children were randomised to receive a reduced-protein GUMLi (1.7 g protein/100 mL) or a non-fortified CM (3.1 g protein/100 mL) for 12 months. Blood sampling and anthropometric measurements were made at 1 and 2 y. Diet was assessed using a validated food frequency questionnaire. Total protein intake (g/d) from all cow's milk sources was 4.6 g (95% CI: −6.7, −2.4; p < 0.005) lower in the GUMLi group after 12 months of the intervention, with a significant group-by-time interaction (p = 0.005). Length-for-age (LAZ) and weight-for-length (WLZ) z-scores did not differ between groups, however, mean body fat % (BF%) was 3.2% (95%CI: −6.2, −0.3; p = 0.032) lower in the GUMLi group at 2 y. There was no difference between the intervention groups in relation to IGF-1 and IGF-BP3 (p = 0.894 and 0.698, respectively), with no group-by-sex interaction. After combining the groups, IGF-1 concentration at 2 y was positively correlated with parameters of growth (all p < 0.05), total cow's milk intake (p = 0.032) after adjusting for sex, breastfeeding status, and gestation. Randomisation to a reduced protein GUMLi resulted in small reduction in %BF and lower total protein intakes but had no effect on growth. Plasma IGF-1 concentrations were independently associated with total protein intake from cow's milk at 2 y, highlighting a potential area of the diet to target when designing future protein-related nutrition interventions.

Clinical Trial Registration: Australian New Zealand Clinical Trials Registry number: ACTRN12614000918628. Date registered: 27/08/2014.
Germline Variants and Genetic Interactions of Several EMT Regulatory Genes Increase the Risk of HBV-Related Hepatocellular Carcinoma
Authors: Liu Wen-Xuan , Yang Lei , Yan Hui-Min , Yan Li-Na , Zhang Xiao-Lin , Ma Ning , Tang Long-Mei , Gao Xia , Liu Dian-Wu
Published: June 2021

Epithelial-mesenchymal transition (EMT) plays an important role in the development of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). We hypothesized that germline variants in the major EMT regulatory genes (SNAIL1, ZEB1, ZEB2, TWIST1) may influence the development of HBV-related HCC. We included 421 cases of HBsAg-positive patients with HCC, 1371 cases of HBsAg-positive subjects without HCC [patients with chronic hepatitis B (CHB) or liver cirrhosis (LC)] and 618 cases of healthy controls in the case-control study. Genotype, allele, and haplotype associations in the major EMT regulatory genes were tested. Environment-gene and gene-gene interactions were analysed using the non-parametric model-free multifactor dimensionality reduction (MDR) method. The SNAIL1rs4647958T>C was associated with a significantly increased risk of both HCC (CT+CC vs. TT: OR=1.559; 95% confidence interval [CI], 1.073-2.264; P=0.020) and CHB+LC (CT+CC vs. TT: OR=1.509; 95% CI, 1.145-1.988; P=0.003). Carriers of the TWIST1rs2285681G>C (genotypes CT+CC) had an increased risk of HCC (CG+CC vs. GG: OR=1.407; 95% CI, 1.065-1.858; P=0.016). The ZEB2rs3806475T>C was associated with significantly increased risk of both HCC (Precessive =0.001) and CHB+LC (Precessive<0.001). The CG haplotype of the rs4647958/rs1543442 haplotype block was associated with significant differences between healthy subjects and HCC patients (P=0.0347). Meanwhile, the CT haplotype of the rs2285681/rs2285682 haplotype block was associated with significant differences between CHB+LC and HCC patients (P=0.0123). In MDR analysis, the combination of TWIST1rs2285681, ZEB2rs3806475, SNAIL1rs4647958 exhibited the most significant association with CHB+LC and Health control in the three-locus model. Our results suggest significant single-gene associations and environment-gene/gene-gene interactions of EMT-related genes with HBV-related HCC.
Construction and Validation of a Reliable Six-Gene Prognostic Signature Based on the TP53 Alteration for Hepatocellular Carcinoma
Authors: Huo Junyu , Wu Liqun , Zang Yunjin
Published: June 2021

Background

The high mutation rate of TP53 in hepatocellular carcinoma (HCC) makes it an attractive potential therapeutic target. However, the mechanism by which TP53 mutation affects the prognosis of HCC is not fully understood.

Material and Approach

This study downloaded a gene expression profile and clinical-related information from The Cancer Genome Atlas (TCGA) database and the international genome consortium (ICGC) database. We used Gene Set Enrichment Analysis (GSEA) to determine the difference in gene expression patterns between HCC samples with wild-type TP53 (n=258) and mutant TP53 (n=116) in the TCGA cohort. We screened prognosis-related genes by univariate Cox regression analysis and Kaplan–Meier (KM) survival analysis. We constructed a six-gene prognostic signature in the TCGA training group (n=184) by Lasso and multivariate Cox regression analysis. To assess the predictive capability and applicability of the signature in HCC, we conducted internal validation, external validation, integrated analysis and subgroup analysis.

Results

A prognostic signature consisting of six genes (EIF2S1, SEC61A1, CDC42EP2, SRM, GRM8, and TBCD) showed good performance in predicting the prognosis of HCC. The area under the curve (AUC) values of the ROC curve of 1-, 2-, and 3-year survival of the model were all greater than 0.7 in each independent cohort (internal testing cohort, n = 181; TCGA cohort, n = 365; ICGC cohort, n = 229; whole cohort, n = 594; subgroup, n = 9). Importantly, by gene set variation analysis (GSVA) and the single sample gene set enrichment analysis (ssGSEA) method, we found three possible causes that may lead to poor prognosis of HCC: high proliferative activity, low metabolic activity and immunosuppression.

Conclusion

Our study provides a reliable method for the prognostic risk assessment of HCC and has great potential for clinical transformation.
DDX60 Is Associated With Glioma Malignancy and Serves as a Potential Immunotherapy Biomarker
Authors: Zhang Jingwen , Fu Minjie , Zhang Mengli , Zhang Jinsen , Du Zunguo , Zhang Hongyi , Hua Wei , Mao Ying
Published: June 2021

DDX60, an interferon (IFN)-inducible gene, plays a promotional role in many tumors. However, its function in glioma remains unknown. In this study, bioinformatic analysis (TCGA, CGGA, Rembrandt) illustrated the upregulation and prognostic value of DDX60 in gliomas. Immunohistochemical staining of clinical samples (n = 49) validated the DDX60 expression is higher in gliomas than in normal tissue (n = 20, P < 0.0001). It also could be included in nomogram as a parameter to predict the 3- and 5-year survival risk (C-index = 0.86). The biological process of DDX60 in glioma was mainly enriched in the inflammatory and immune response by GSEA and GO analysis. DDX60 expression had a positive association with most inflammatory-related functions, such as hematopoietic cell kinase (HCK) (R = 0.31), interferon (R = 0.72), STAT1 (R = 54), and a negative correlation with IgG (R = −0.24). Furthermore, DDX60 expression tends to be positively related to multiple infiltrating immune cells, while negatively related to CD56 dim nature killer cell in glioma. Some important immune checkpoints, like CTLA-4, PD-L1, EGF, CD96, and CD226, were all positively related with DDX60 (all Pearson correlation R > 0.26). The expression and correlation between DDX60, EGF, and PD-L1 were confirmed by western blot in clinical samples (n = 14, P < 0.0001) and GBM cells. These results indicated that DDX60 might have important clinical significance in glioma and could serve as a potential immune therapeutic target.
Partial Nephrectomy Versus Radical Nephrectomy for Clinical T2 or Higher Stage Renal Tumors: A Systematic Review and Meta-Analysis
Authors: Huang Ruizhen , Zhang Chiyu , Wang Xing , Hu Honglin
Published: June 2021

Objective

The choice of surgical method for clinically diagnosed T2 or higher stage kidney cancer remains controversial. Here, we systematically reviewed and collected published comparative studies on renal function, oncologic outcomes, and perioperative results of partial nephrectomy (PN) versus radical nephrectomy (RN) for larger renal tumors (T2 and above), and performed a meta-analysis.

Evidence Acquisition

Following searches of PubMed, Web of Science, and Embase, the original studies on PN vs. RN in the treatment of T2 renal cancer were screened through strict inclusion and exclusion criteria. RevMan 5.4 was used for data analysis of the perioperative results, renal function, and oncologic outcomes of the two surgical methods for T2 renal tumor therapy. The weighted mean difference was used as the combined effect size for continuous variables, while the odds ratio (OR) or risk ratio (RR) was used as the combined effect size for binary variables. Both variables used a 95% confidence interval (CI) to estimate statistical accuracy. In cases with low heterogeneity, the fixed-effects model was used to pool the estimated value; otherwise, the random-effects model was used when significant heterogeneity was detected.

Results

Fifteen retrospective studies including 5,056 patients who underwent nephrectomy (PN: 1975, RN: 3081) were included. The decline in estimated GFR (eGFR) after PN was lower than RN [(MD: −11.74 ml/min/1.73 m2; 95% CI: −13.15, −10.32; p < 0.00001)]. The postoperative complication rate of PN was higher than that of PN (OR: 2.09; 95% CI: 1.56, 2.80; p < 0.00001)], and the postoperative overall survival (OS) of PN was higher than that of RN (HR: 0.77; 95% CI: 0.65, 0.90; p = 0.002), and tumor recurrence (RR, 0.69; 95% CI: 0.53, 0.90; p = 0.007). No obvious publication bias was found in the funnel chart of the OS rates of the two groups of patients.

Conclusions

PN is beneficial for patients with T2 renal tumors in terms of OS and renal function protection. However, it is also associated with a higher risk of surgical complications.
Predicting Microsatellite Instability Status in Colorectal Cancer Based on Triphasic Enhanced Computed Tomography Radiomics Signatures: A Multicenter Study
Authors: Cao Yuntai , Zhang Guojin , Zhang Jing , Yang Yingjie , Ren Jialiang , Yan Xiaohong , Wang Zhan , Zhao Zhiyong , Huang Xiaoyu , Bao Haihua , Zhou Junlin
Published: June 2021

Background

This study aimed to develop and validate a computed tomography (CT)-based radiomics model to predict microsatellite instability (MSI) status in colorectal cancer patients and to identify the radiomics signature with the most robust and high performance from one of the three phases of triphasic enhanced CT.

Methods

In total, 502 colorectal cancer patients with preoperative contrast-enhanced CT images and available MSI status (441 in the training cohort and 61 in the external validation cohort) were enrolled from two centers in our retrospective study. Radiomics features of the entire primary tumor were extracted from arterial-, delayed-, and venous-phase CT images. The least absolute shrinkage and selection operator method was used to retain the features closely associated with MSI status. Radiomics, clinical, and combined Clinical Radiomics models were built to predict MSI status. Model performance was evaluated by receiver operating characteristic curve analysis.

Results

Thirty-two radiomics features showed significant correlation with MSI status. Delayed-phase models showed superior predictive performance compared to arterial- or venous-phase models. Additionally, age, location, and carcinoembryonic antigen were considered useful predictors of MSI status. The Clinical Radiomics nomogram that incorporated both clinical risk factors and radiomics parameters showed excellent performance, with an AUC, accuracy, and sensitivity of 0.898, 0.837, and 0.821 in the training cohort and 0.964, 0.918, and 1.000 in the validation cohort, respectively.

Conclusions

The proposed CT-based radiomics signature has excellent performance in predicting MSI status and could potentially guide individualized therapy.
Resveratrol Ameliorates Cardiac Remodeling in a Murine Model of Heart Failure With Preserved Ejection Fraction
Authors: Zhang Liyun , Chen Juan , Yan Lianhua , He Qin , Xie Han , Chen Manhua
Published: June 2021

Objective: Accumulating evidence suggested that resveratrol (RES) could protect against adverse cardiac remodeling induced by several cardiovascular diseases. However, the role of RES in the setting of heart failure with preserved ejection fraction (HFpEF) and the underlying mechanisms of its action remain understood. This study was to determine whether RES could ameliorate HFpEF-induced cardiac remodeling and its mechanisms.

Methods:In vivo, C57BL/6 mice served as either the sham or the HFpEF model. The HFpEF mice model was induced by uninephrectomy surgery and d-aldosterone infusion. RES (10 mg/kg/day, ig) or saline was administered to the mice for four weeks. In vitro, transforming growth factor β1 (TGF-β1) was used to stimulate neonatal rat cardiac fibroblasts (CFs) and Ex-527 was used to inhibit sirtuin 1 (Sirt1) in CFs. Echocardiography, hemodynamics, western blotting, quantitative real-time PCR, histological analysis, immunofluorescence, and ELISA kits were used to evaluate cardiac remodeling induced by HFpEF. Sirt1 and Smad3 expressions were measured to explore the underlying mechanisms of RES.

Results: HFpEF mice developed left ventricular hypertrophy, preserved ejection fraction, diastolic dysfunction, and pulmonary congestion. Moreover, HFpEF mice showed increased infiltration of neutrophils and macrophages into the heart, including increased interleukin (IL)-1β, IL-6, and TNF-α. We also observed elevated M1 macrophages and decreased M2 macrophages, which were exhibited by increased mRNA expression of M1 markers (iNOS, CD86, and CD80) and decreased mRNA expression of M2 markers (Arg1, CD163, and CD206) in HFpEF hearts. Moreover, HFpEF hearts showed increased levels of intracellular reactive oxygen species (ROS). Importantly, HFpEF mice depicted increased collagen-I and -III and TGF-β mRNA expressions and decreased protein expression of phosphorylated endothelial nitric-oxide synthase (p-eNOS). Results of western blot revealed that the activated TGF-β/Smad3 signaling pathway mediated HFpEF-induced cardiac remodeling. As expected, this HFpEF-induced cardiac remodeling was reversed when treated with RES. RES significantly decreased Smad3 acetylation and inhibited Smad3 transcriptional activity induced by HFpEF via activating Sirt1. Inhibited Sirt1 with Ex-527 increased Smad3 acetylation, enhanced Smad3 transcriptional activity, and offset the protective effect of RES on TGF-β–induced cardiac fibroblast–myofibroblast transformation in CFs.

Conclusion: Our results suggested that RES exerts a protective action against HFpEF-induced adverse cardiac remodeling by decreasing Smad3 acetylation and transcriptional activity via activating Sirt1. RES is expected to be a novel therapy option for HFpEF patients.
Investigation on the Efficiency of Chinese Herbal Injections combined with Concurrent Chemoradiotherapy for Treating Nasopharyngeal Carcinoma based on Multidimensional Bayesian Network Meta-analysis
Authors: Wu Zhishan , Wang Haojia , Wu Jiarui , Guo Siyu , Zhou Wei , Wu Chao , Lu Shan , Wang Miaomiao , Zhang Xiaomeng , Li Jialin , Tan Yingying , Fan Xiaotian , Huang Zhihong
Published: June 2021

Introduction: Given the wide utilization of Chinese herbal injections in the treatment of nasopharyngeal carcinoma (NPC), this network meta-analysis (NMA) was devised to compare the clinical efficacy and safety of different Chinese herbal injections combined with concurrent chemoradiotherapy (CCRT) against NPC.

Methods: Randomized controlled trials (RCTs) were retrieved from seven electronic databases from the date of database establishment to October 5, 2020. Study selection and data extraction conformed to a priori criteria. Focusing on clinical effective rate, performance status, grade ≥3 oral mucositis, nausea and vomiting, leukopenia, and thrombopenia, this NMA was performed with Review Manager 5.3.5, Stata 13.1, WinBUGS 1.4.3, and R 4.0.3 software.

Results: Ten inventions from 37 RCTs involving 2,581 participants with NPC that evaluated the clinical effective rate, nausea and vomiting, leukopenia, thrombopenia, and grade ≥3 oral mucositis were included. Compared with CCRT alone, Elemene injection and Compound Kushen injection were associated with significantly improved clinical effective rates, and Elemene injection plus CCRT had the highest probability in terms of clinical effective rate (78.07%) compared with the other interventions. Shenqifuzheng injection, Xiaoaiping injection, and Shenmai injection ranked the best in terms of performance status (79.02%), nausea and vomiting (86.35%), and grade ≥3 oral mucositis (78.14%) when combined with CCRT. Kangai injection combined with CCRT ranked ahead of the other injections in terms of leukopenia (90.80%) and thrombopenia (91.04%), and had a better impact on improving performance status and reducing leukopenia, thrombopenia, grade ≥3 oral mucositis, and nausea and vomiting in the multidimensional cluster analysis.

Conclusion: Current clinical evidence indicates that Elemene injection combined with CCRT has the best clinical effective rate and that Kangai injection might have a comprehensively better impact on improving performance status and reducing adverse reactions against NPC. Additionally, due to the limitations of this NMA, more multicenter, high-quality, and head-to-head RCTs are needed to properly support our findings.
A Skin Lipidomics Study Reveals the Therapeutic Effects of Tanshinones in a Rat Model of Acne
Authors: Chen Tingting , Zhu Zhaoming , Du Qunqun , Wang Zhuxian , Wu Wenfeng , Xue Yaqi , Wang Yuan , Wu Yufan , Zeng Quanfu , Jiang Cuiping , Shen Chunyan , Liu Li , Zhu Hongxia , Liu Qiang
Published: June 2021

Tanshinone (TAN), a class of bioactive components in traditional Chinese medicinal plant Salvia miltiorrhiza, has antibacterial and anti-inflammatory effects, can enhance blood circulation, remove blood stasis, and promote wound healing. For these reasons it has been developed as a drug to treat acne. The purpose of this study was to evaluate the therapeutic effects of TAN in rats with oleic acid-induced acne and to explore its possible mechanisms of action through the identification of potential lipid biomarkers. In this study, a rat model of acne was established by applying 0.5 ml of 80% oleic acid to rats’ back skin. The potential metabolites and targets involved in the anti-acne effects of TAN were predicted using lipidomics. The results indicate that TAN has therapeutic efficacy for acne, as supported by the results of the histological analyses and biochemical index assays for interleukin (IL)-8, IL-6, IL-β and tumor necrosis factor alpha. The orthogonal projection of latent structure discriminant analysis score was used to analyze the lipidomic profiles between control and acne rats. Ninety-six potential biomarkers were identified in the skin samples of the acne rats. These biomarkers were mainly related to glycerophospholipid and sphingolipid metabolism, and the regulation of their dysfunction is thought to be a possible therapeutic mechanism of action of TAN on acne.
Effects of Sinusoidal Vibrations on the Motion Response of Honeybees
Authors: Stefanec Martin , Oberreiter Hannes , Becher Matthias A. , Haase Gundolf , Schmickl Thomas
Published: June 2021

Vibratory signals play a major role in the organization of honeybee colonies. Due to the seemingly chaotic nature of the mechano-acoustic landscape within the hive, it is difficult to understand the exact meaning of specific substrate-borne signals. Artificially generated vibrational substrate stimuli not only allow precise frequency and amplitude control for studying the effects of specific stimuli, but could also provide an interface for human-animal interaction for bee-keeping-relevant colony interventions. We present a simple method for analyzing motion activity of honeybees and show that specifically generated vibrational signals can be used to alter honeybee behavior. Certain frequency-amplitude combinations can induce a significant decrease and other signals might trigger an increase in honeybees’ motion activity. Our results demonstrate how different subtle local modulatory signals on the comb can influence individual bees in the local vicinity of the emitter. Our findings could fundamentally impact our general understanding of a major communication pathway in honeybee colonies. This pathway is based on mechanic signal emission and mechanic proprio-reception of honeybees in the bee colony. It is a candidate to be a technologically accessible gateway into the self-regulated system of the colony and thus may offer a novel information transmission interface between humans and honeybees for the next generation of “smart beehives” in future beekeeping.
Nicotine Causes Mitochondrial Dynamics Imbalance and Apoptosis Through ROS Mediated Mitophagy Impairment in Cardiomyocytes
Authors: Meng Ting-ting , Wang Wei , Meng Fan-liang , Wang Shu-ya , Wu Hui-hui , Chen Jia-min , Zheng Yan , Wang Guang-xin , Zhang Mao-xiu , Li Ying , Su Guo-hai
Published: June 2021

Nicotine contained in traditional cigarettes, hookahs, and e-cigarettes is an important risk factor for cardiovascular disease. Our previous study showed that macroautophagic flux impairment occurred under nicotine stimulation. However, whether nicotine influences mitochondrial dynamics in neonatal rat ventricular myocytes (NRVMs) is unclear. The purpose of this study was to explore the effects and potential mechanism of nicotine on mitophagy, mitochondrial dynamics, apoptosis, and the relationship between these processes in NRVMs. Our results showed that nicotine exposure increased mitochondria-derived superoxide production, decreased mitochondrial membrane potential, and impaired PINK1/Parkin-mediated mitophagic flux in NRVMs. Interestingly, nicotine significantly promoted dynamin-related protein 1 (Drp1)-mediated mitochondrial fission and suppressed mitofusin (MFN)-mediated fusion, which was also observed in the bafilomycin A1-treated group. These results suggest that mitophagic flux impairment may contribute to Drp-1-mediated mitochondrial fission. Finally, nicotine caused excessive mitochondrial fission and contributed to apoptosis, which could be alleviated by mdivi-1, an inhibitor of Drp1. In addition to CTSB, as we previously reported, the enzyme activity of cathepsin L (CTSL) was also decreased in lysosomes after stimulation with nicotine, which may be the main cause of the hindered mitophagic flux induced by nicotine in NRVMs. Pretreatment with Torin 1, which is an inhibitor of mTOR, activated CTSL and ameliorated nicotine-induced mTOR activation and mitophagy impairment, decreased mitochondria-derived superoxide production, and blunted mitochondrial fission and apoptosis. Pretreatment with the ROS scavenger N-acetyl-cysteine (NAC) or inhibitors of p38 and JNK, which could also alleviate mitophagy impairment, exhibited similar effects as Torin1 on mitochondria. Taken together, our study demonstrated that nicotine treatment may lead to an increase in Drp1-mediated mitochondrial fission by blocking mitophagic flux by weakening the enzyme activity of CTSL and activating the ROS/p38/JNK signaling pathway. Excessive mitochondrial fission induced by nicotine ultimately leads to apoptosis. Torin1 restored the decreased CTSL enzyme activity by removing excessive ROS and alleviated the effects of nicotine on mitophagic flux, mitochondrial dynamics, and apoptosis. These results may provide new evidence on the relationship between mitophagic flux and mitochondrial dynamics and new perspectives on nicotine’s effects on mitochondrial dynamics in cardiomyocytes.