bluuebunny/crossref_metadata_2025 huggingface dataset:
Design and Synthesis of New Quinoxaline Derivatives as Potential Histone Deacetylase Inhibitors Targeting Hepatocellular Carcinoma: In Silico, In Vitro, and SAR Studies
Authors: Ma Chao , Taghour Mohammed S. , Belal Amany , Mehany Ahmed B. M. , Mostafa Naglaa , Nabeeh Ahmed , Eissa Ibrahim H. , Al-Karmalawy Ahmed A.
Published: September 2021

Guided by the structural optimization principle and the promising anticancer effect of the quinoxaline nucleus, a new series of novel HDAC inhibitors were designed and synthesized. The synthesized compounds were designed to bear the reported pharmacophoric features of the HDAC inhibitors in addition to an extra moiety to occupy the non-used vacant deep pocket of the HDAC receptor. The newly prepared compounds were evaluated for theirin vitroanti-proliferative activities against HepG-2 and HuH-7 liver cancer cell lines. The tested compounds showed promising anti-proliferative activities against both cell lines. The most active ten candidates (6c,6d,6f,6g,6k,6l,7b,8,10h, and12) were further evaluated for their effect on the gene expression levels of Bax as an apoptotic marker and Bcl-2 as an anti-apoptotic one. Moreover, they were evaluated for their ability to inhibit histone deacetylase (HDAC1, HDAC4, and HDAC6) activities. Compound6cachieved the best cytotoxic activities on both HepG-2 and HuH-7 cell lines with IC50values of 1.53 and 3.06 µM, respectively, and also it showed the most inhibitory activities on HDAC1, HDAC4, and HDAC6 with IC50values of 1.76, 1.39, and 3.46 µM, respectively, compared to suberoylanilide hydroxamic acid (SAHA) as a reference drug (IC50= 0.86, 0.97, and 0.93 µM, respectively). Furthermore, it achieved a more characteristic arrest in the growth of cell population of HepG-2 at both G0/G1 and S phases with 1.23-, and 1.18-fold, respectively, compared to that of the control, as determined by cell cycle analysis. Also, compound6cshowed a marked elevation in the AnxV-FITC apoptotic HepG-2 cells percentage in both early and late phases increasing the total apoptosis percentage by 9.98-, and 10.81-fold, respectively, compared to the control. Furthermore, docking studies were carried out to identify the proposed binding mode of the synthesized compounds towards the prospective target (HDAC4).In silicoADMET and toxicity studies revealed that most of the synthesized compounds have accepted profiles of drug-likeness with low toxicity. Finally, an interesting SAR analysis was concluded to help the future design of more potent HDACIs in the future by medicinal chemists.
Integrated Cobaloxime and Mesoporous Silica-Supported Ruthenium/Diamine Co-Catalysis for One-Pot Hydration/Reduction Enantioselective Sequential Reaction of Alkynes
Authors: Liu Zeyang , Wang Yongjie , Liu Kaihong , Wang Shanshan , Liao Haocheng , Zhu Yuanli , Hou Baoming , Tan Chunxia , Liu Guohua
Published: September 2021

This study developed a cost-efficient hydration/asymmetric transfer hydrogenation (ATH) process for the one-pot synthesis of valuable chiral alcohols from alkynes. During this process, the initial homogeneous cobaloxime-catalyzed hydration of alkynes was followed by heterogeneous Ru/diamine-catalyzed ATH transformation of the in-situ generated ketones, which provided varieties of chiral alcohols in good yields with up to 99% ee values. The immobilized Ru/diamine catalyst could be recycled at least three times before its deactivation in the sequential reaction system. This work shows a general method for developing one-pot asymmetric sequential catalysis towards sustainable organic synthesis.
Cysteamine Inhibits Glycine Utilisation and Disrupts Virulence in Pseudomonas aeruginosa
Authors: Fraser-Pitt Douglas J. , Dolan Stephen K. , Toledo-Aparicio David , Hunt Jessica G. , Smith Daniel W. , Lacy-Roberts Niamh , Nupe Hewage Piumi Sara , Stoyanova Teodora N. , Manson Erin , McClean Kevin , Inglis Neil F. , Mercer Derry K. , O’Neil Deborah A.
Published: September 2021

Pseudomonas aeruginosa is a major opportunistic human pathogen which employs a myriad of virulence factors. In people with cystic fibrosis (CF) P. aeruginosa frequently colonises the lungs and becomes a chronic infection that evolves to become less virulent over time, but often adapts to favour persistence in the host with alginate-producing mucoid, slow-growing, and antibiotic resistant phenotypes emerging. Cysteamine is an endogenous aminothiol which has been shown to prevent biofilm formation, reduce phenazine production, and potentiate antibiotic activity against P. aeruginosa, and has been investigated in clinical trials as an adjunct therapy for pulmonary exacerbations of CF. Here we demonstrate (for the first time in a prokaryote) that cysteamine prevents glycine utilisation by P. aeruginosa in common with previously reported activity blocking the glycine cleavage system in human cells. Despite the clear inhibition of glycine metabolism, cysteamine also inhibits hydrogen cyanide (HCN) production by P. aeruginosa, suggesting a direct interference in the regulation of virulence factor synthesis. Cysteamine impaired chemotaxis, lowered pyocyanin, pyoverdine and exopolysaccharide production, and reduced the toxicity of P. aeruginosa secreted factors in a Galleria mellonella infection model. Thus, cysteamine has additional potent anti-virulence properties targeting P. aeruginosa, further supporting its therapeutic potential in CF and other infections.
Comparison of the Direct Oral Anticoagulants and Warfarin in Patients With Atrial Fibrillation and Valvular Heart Disease: Updated Systematic Review and Meta-Analysis of Randomized Controlled Trials
Authors: Bitar Yasmin de Souza Lima , Duraes Andre Rodrigues , Roever Leonardo , Gomes Neto Mansueto , Lins-Kusterer Liliane , Bocchi Edimar Alcides
Published: September 2021

Background: Direct oral anticoagulants (DOACS) are approved for use in non-valvular atrial fibrillation (AF). This systematic review and meta-analysis aimed to evaluate the efficacy and safety of DOACs vs. warfarin and update the evidence for treatment of AF and valvular heart disease (VHD).

Methods: We identified randomized clinical trials (RCTs) and post-hoc analyses comparing the use of DOACS and Warfarin in AF and VHD, including biological and mechanical heart valves (MHV), updating from 2010 to 2020. Through systematic review and meta-analysis, by using the “Rev Man” program 5.3, the primary effectiveness endpoints were stroke and systemic embolism (SE). The primary safety outcome was major bleeding, while the secondary outcome included intracranial hemorrhage. We performed prespecified subgroup analyses. Data were analyzed by risk ratio (RR) and 95% confidence interval (CI) and the I-square (I2) statistic as a quantitative measure of inconsistency. Risk of bias and methodological quality assessment of included trials was evaluated with the modified Cochrane risk-of-bias tool.

Results: We screened 326 articles and included 8 RCTs (n = 14.902). DOACs significantly reduced the risk of stroke/SE (RR 0.80, 95% CI: 0.68–0.94; P = 0.008; moderate quality evidence; I2 = 2%) and intracranial hemorrhage (RR 0.40, 95% CI: 0.24–0.66; P = 0.0004; I2 = 49%) with a similar risk of major bleeding (RR 0.83, 95% CI: 0.56–1.24; P = 0.36; I2 = 88%) compared to Warfarin.

Conclusions: In this update, DOACs remained with similar efficacy and safety compared to warfarin in thromboprophylaxis for AF and VHD.
Frozen Embryo Transfer in Mildly Stimulated Cycle With Letrozole Compared to Natural Cycle in Ovulatory Women: A Large Retrospective Study
Authors: Li Danjun , Khor Shuzin , Huang Jialyu , Chen Qiuju , Lyu Qifeng , Cai Renfei , Kuang Yanping , Lu Xuefeng
Published: September 2021

Objective

To evaluate the clinical effect of mild stimulation with letrozole on pregnancy outcomes in ovulatory women undergoing frozen embryo transfer (FET) compared to natural cycle.

Design

Retrospective observational study.

Setting

Tertiary care academic medical center.

Population

A total of 6,874 infertile women with regular menstrual cycles (21-35 days) met the criteria for this study in the period from 2013 to 2020.

Methods

All patients who were prepared for and underwent FET were divided into two groups: a modified natural cycle (NC) group (n=3,958) and a letrozole cycle group (n=2,916).

Main Outcome Measures

The primary outcome of the study was clinical pregnancy rate. Secondary outcome measures were endometrial thickness, rates of implantation, positive HCG test, live birth, early miscarriage and ectopic pregnancy.

Results

The clinical pregnancy rate was not statistically different between the modified NC-FET group and the letrozole-FFT group before (crude OR 0.99, 95% CI 0.90-1.09, P=0.902>0.05) and after propensity score matching (PSM) (crude OR 1.01, 95% CI 0.91-1.12, P=0.870>0.05). After multivariable logistic regression analysis, the clinical pregnancy rate remained insignificant before (adjusted OR 1.00, 95% CI 0.91-1.10, P=0.979>0.05) and after matching (adjusted OR 1.00, 95% CI 0.89-1.11, P=0.936>0.05), respectively. Similarly, in the crude and adjusted analysis, the positive HCG test, implantation, live birth and early miscarriage rates were also comparable in the letrozole-FFT group and modified NC-FET group before and after matching. Furthermore, the endometrial thickness of letrozole-FFT group was similar to that of modified NC-FET group with adjusted analysis.

Conclusion

Our observation suggests that mild stimulation with letrozole could produce similar pregnancy outcomes in ovulatory patients who undergo FET when compared with a natural cycle.
Joint Analysis of Genome-Wide Association Data Reveals No Genetic Correlations Between Low Back Pain and Neurodegenerative Diseases
Authors: Wu Pengfei , Du Bing , Wang Bing , Yin Rui , Lv Xin , Dai Yuliang , Zhang Wan , Xia Kun
Published: September 2021

Background: We aimed to explore the genetic correlation and bidirectional causal relationships between low back pain (LBP) and three neurodegenerative diseases, Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS).

Methods: Summary-level statistics were obtained from genome-wide association studies of LBP (n = 177,860), AD (n = 63,926), PD (n = 482,730), and ALS (n = 80,610). We implemented linkage disequilibrium score regression to calculate heritability estimates and genetic correlations. To investigate possible causal associations between LBP and three neurodegenerative diseases, we also conducted a bidirectional two-sample Mendelian randomization (MR) study. Inverse variance-weighted MR was employed as the primary method to generate overall estimates, whereas complementary approaches and sensitivity analyses were conducted to confirm the consistency and robustness of the findings.

Results: There was no evidence of genetic correlations between LBP and AD (Rg = −0.033, p = 0.766). MR analyses did not support the causal effect of LBP on AD (OR = 1.031; 95% CI, 0.924–1.150; p = 0.590) or the effect of AD on LBP (OR = 0.963; 95% CI, 0.923–1.006; p = 0.090). Likewise, this study failed to identify genetic correlations between LBP and two other neurodegenerative diseases. MR results of the associations of LBP with PD and ALS, and the reverse associations, did not reach Bonferroni-corrected significance.

Conclusion: The study did not support genetic correlations or causations between LBP and three common neurodegenerative diseases, AD, PD, and ALS in the European population.
Dietary Analysis Based on 18S rDNA, and Stable Carbon and Nitrogen Isotopes in Juvenile Eriocheir sinensis Crabs Reared Under Three Feeding Modes
Authors: Lu Zhenzhen , Sun Yunfei , Xiao Changlun , Cheng Yongxu
Published: September 2021

To investigate the growth and feeding conditions of the Chinese mitten crab Eriocheir sinensis under different feeding modes: traditional (mainly consisting of wheat, bran, and soybean meal), formulated, and mixed feeds (1:1 mixture of traditional and formulated feeds) were fed in different crab breeding ponds in this study. During the experiment, the stomach contents of juvenile crabs under the different feeding modes were collected. The main potential eukaryotic food components were studied using 18S ribosomal DNA sequencing, and the contribution of different feeding modes to the feeding source of juvenile crabs were analyzed using C and N stable isotopes. The terminal weight and weight gain rate of crabs under the formulated feeding mode were significantly higher than those in the traditional and mixed feeding modes (P < 0.05). No differences were observed in the diversity and abundance of the main potential eukaryotic feed components of male and female crabs under different feeding modes (P > 0.05). Thirty-four phyla, composed mainly of benthic organisms, were identified, with Arthropoda (mainly including Malacostraca, 30.25–51.48%), Phragmoplastophyta (mainly including Embryophyta and Trebouxiophyceae, 5.08–24.74%), and Diatomea (3.13–8.43%) being the most abundant. The δ13C and δ15N values of the feeding sources and muscle of crabs ranged from −34.45 to −22.21‰, and from 0.27 to 5.66‰, respectively, varying greatly among the three feeding modes and δ15N value of muscle under formulated feeding mode was significantly higher than that in traditional feeding mode (P < 0.05). The proportion of particulate organic matter (11.92–17.50%) is similar to Alternanthera philoxeroides (11.24–16.03%) in three feeding modes. There was no significant difference in feeding habits between male and female crabs under the same and different feeding modes. Juvenile crabs feed on both plant- and animal-based feeds in an aquaculture pond, but they are not complete predators and selectively feed on animal or plant feeds as supplements of that which is deficient, in addition to their main feed.
An Italian Disease-Based Registry of Axial and Peripheral Spondyloarthritis: The SIRENA Study
Authors: Zabotti Alen , Luchetti Michele Maria , Selmi Carlo Francesco , Ramonda Roberta , Grembiale Rosa Daniela , Dagna Lorenzo , D'Angelo Salvatore , Cafaro Giacomo , De Vita Salvatore , Felicetti Mara , Marelli Silvia , Frigerio Daniela , Favalli Ennio Giulio
Published: September 2021

Introduction: Data about the clinical presentation and management of early and mild spondyloarthritis (SpA) are limited.

Objectives: The objective of this study was to describe the baseline characteristics of disease-modifying antirheumatic drug (DMARD)-naïve patients with axial or peripheral SpA.

Methods: The Spondyloarthritis Italian Registry: Evidence from a National Pathway (SIRENA) study is an ongoing, Italian, multicenter, prospective registry of patients with a first or newly confirmed diagnosis of SpA according to the Assessment of SpondyloArthritis International Society (ASAS) criteria. To be included, patients had to be naïve to conventional, targeted, and biological DMARDs for SpA. Patients were enrolled between June 2017 and June 2019 and classified into groups according to disease presentation: predominantly axial or peripheral manifestations. The study is ongoing, and patients are being followed for 2 years, with an evaluation every 6 months according to clinical practice. Differences in baseline demographics, lifestyle, and clinical characteristics between axial and peripheral SpA were evaluated.

Results: In this study, 350 patients were enrolled, of which 123 (35.1%) were axial and 227 (64.9%) were peripheral patients. Patients with axial SpA were significantly younger at enrollment (median age: 44 vs. 53 years), had significantly more anxiety/depression (13 vs. 2.6%), and expressed higher disease activity compared to patients with peripheral SpA. Patients with peripheral SpA had significantly more cardiometabolic disorders (33 vs. 18.7%), skin psoriasis (65.2 vs. 21.1%), and nail psoriasis (35.5 vs. 17.1%) than patients with axial SpA. Dactylitis, enthesitis, and fibromyalgia were observed, respectively, in 17.6, 51.2, and 5.7% of patients with axial SpA and 24.3, 40, and 3.1% of patients with peripheral SpA. In both disease groups, women tended to report depression, joint tenderness, and higher disease activity more frequently than their male counterparts. At inclusion, a new diagnosis of SpA was performed in 58% of axial and 77% of peripheral patients, with a median time from symptom onset to diagnosis of 36 and 24 months, respectively. At baseline, most patients with axial SpA (77%) started a biological DMARD, while over half of the peripheral patients started a conventional DMARD.

Conclusions: Based on a well-characterized clinical registry of SpA, we provided real-world insights on the clinical features of DMARD-naïve SpA patients, pointing out major differences between axial and peripheral disease in terms of clinical characteristics and treatment pattern. Future prospective evaluations within the SIRENA study will improve knowledge on SpA and contribute to defining the best therapeutic approach.
Long-Term Survival Outcomes and Comparison of Different Treatment Modalities for Stage I-III Cervical Esophageal Carcinoma
Authors: Lu Yanwei , Xu Chenwang , Wang Haitao , Song Tao , Wu Shixiu , Liang Xiaodong , Xu Hong'en
Published: September 2021

Purpose: To investigate the survival outcomes, prognostic factors and treatment modalities of stage I-III cervical esophageal carcinoma (CEC) patients using data from the Surveillance, Epidemiology, and End Results (SEER) database from the period 2004–2016.

Methods: Patients with a histopathologic diagnosis of CEC were included. The primary endpoint was overall survival (OS). Univariate and multivariate analyses of OS were performed using Cox proportional hazards models, and OS was compared using the Kaplan-Meier method and log-rank test.

Results: A total of 347 patients in the SEER database were enrolled. The median OS was 14.0 months, with a 5-year OS rate of 20.9%. The parameters that were found to significantly correlate with OS in the multivariate analysis were age at diagnosis [P < 0.001, hazard ratio (HR) = 1.832], sex [P < 0.001, HR= 1.867], histology [P = 0.001, HR = 0.366], surgery at the primary site [P = 0.021, HR = 0.553], radiotherapy (RT, P = 0.017, HR = 0.637) and chemotherapy (CT, P < 0.001, HR = 0.444). Comparison among the three treatment modalities demonstrated that a triple therapy regimen consisting of surgery, RT and CT was associated with a longer survival time than the other two treatment modalities before and after propensity score matching (PSM). However, triple therapy showed no significant survival benefit over double therapy (P = 0.496 before PSM and P = 0.184 after PSM).

Conclusions: The survival of patients with CEC remains poor. Surgery, RT and CT were all strongly correlated with OS. We recommend a triple therapy regimen for select CEC patients based on the findings of the current study, although this recommendation should be further confirmed by prospective studies with large sample sizes.
Symbiosis and Dysbiosis of the Human Mycobiome
Authors: Mishra Kirtishri , Bukavina Laura , Ghannoum Mahmoud
Published: September 2021

The influence of microbiological species has gained increased visibility and traction in the medical domain with major revelations about the role of bacteria on symbiosis and dysbiosis. A large reason for these revelations can be attributed to advances in deep-sequencing technologies. However, the research on the role of fungi has lagged. With the continued utilization of sequencing technologies in conjunction with traditional culture assays, we have the opportunity to shed light on the complex interplay between the bacteriome and the mycobiome as they relate to human health. In this review, we aim to offer a comprehensive overview of the human mycobiome in healthy and diseased states in a systematic way. The authors hope that the reader will utilize this review as a scaffolding to formulate their understanding of the mycobiome and pursue further research.
Microfluidic Synthesis of Indomethacin-Loaded PLGA Microparticles Optimized by Machine Learning
Authors: Damiati Safa A. , Damiati Samar
Published: September 2021

Several attempts have been made to encapsulate indomethacin (IND), to control its sustained release and reduce its side effects. To develop a successful formulation, drug release from a polymeric matrix and subsequent biodegradation need to be achieved. In this study, we focus on combining microfluidic and artificial intelligence (AI) technologies, alongside using biomaterials, to generate drug-loaded polymeric microparticles (MPs). Our strategy is based on using Poly (D,L-lactide-co-glycolide) (PLGA) as a biodegradable polymer for the generation of a controlled drug delivery vehicle, with IND as an example of a poorly soluble drug, a 3D flow focusing microfluidic chip as a simple device synthesis particle, and machine learning using artificial neural networks (ANNs) as an in silico tool to generate and predict size-tunable PLGA MPs. The influence of different polymer concentrations and the flow rates of dispersed and continuous phases on PLGA droplet size prediction in a microfluidic platform were assessed. Subsequently, the developed ANN model was utilized as a quick guide to generate PLGA MPs at a desired size. After conditions optimization, IND-loaded PLGA MPs were produced, and showed larger droplet sizes than blank MPs. Further, the proposed microfluidic system is capable of producing monodisperse particles with a well-controllable shape and size. IND-loaded-PLGA MPs exhibited acceptable drug loading and encapsulation efficiency (7.79 and 62.35%, respectively) and showed sustained release, reaching approximately 80% within 9 days. Hence, combining modern technologies of machine learning and microfluidics with biomaterials can be applied to many pharmaceutical applications, as a quick, low cost, and reproducible strategy.
LECT2, A Novel and Direct Biomarker of Liver Fibrosis in Patients With CHB
Authors: Xu Honghai , Li Xutong , Wu Zihao , Zhao Linyan , Shen Jiapei , Liu Jiaying , Qin Jiangfeng , Shen Yuanlong , Ke Jing , Wei Yuanyuan , Li Jiabin , Gao Yufeng
Published: September 2021

Chronic hepatitis B (CHB) patients with severe liver fibrosis would be more likely to progress to a poorer prognosis. Treatment is considered once the liver fibrosis reaches significant liver fibrosis (≥S2). Leukocyte cell-derived chemotaxin-2 (LECT2) has been shown to contribute to liver fibrosis progression. No research has focused on the role of LECT2 in liver fibrosis in CHB patients. This study enrolled 227 CHB patients and divided them into the training group (n = 147) and validation group (n = 80), respectively. The expression of LECT2 in serum, protein and mRNA of the human liver tissues was detected to analyze the possible associations between LECT2 and liver fibrosis. A receiver operating characteristic curve (ROC) was used to estimate the efficacy of LECT2 for predicting liver fibrosis. The data showed that there was a positive relationship between LECT2 and the progression of liver fibrosis. In the training group, LECT2 was demonstrated to have better effectiveness than APRI and FIB-4. The AUC was 0.861, 0.698, and 0.734 for significant liver fibrosis, and 0.855, 0.769, and 0.752 for advanced liver fibrosis. Besides, the efficacy of LECT2 in different statuses of patients with CHB was examined and the effectiveness of LECT2 had also been confirmed in the validation group. All the results confirmed that LECT2 could act as a perfect predictor and thus offers a novel and direct biomarker to estimate liver fibrosis more accurately.
Microstimulation Is a Promising Approach in Achieving Better Lead Placement in Subthalamic Nucleus Deep Brain Stimulation Surgery
Authors: Shi Lin , Fan Shiying , Yuan Tianshuo , Fang Huaying , Zheng Jie , Xiao Zunyu , Diao Yu , Zhu Guanyu , Zhang Quan , Liu Huanguang , Zhang Hua , Meng Fangang , Zhang Jianguo , Yang Anchao
Published: September 2021

Background: The successful application of subthalamic nucleus (STN) deep brain stimulation (DBS) surgery relies mostly on optimal lead placement, whereas the major challenge is how to precisely localize STN. Microstimulation, which can induce differentiating inhibitory responses between STN and substantia nigra pars reticulata (SNr) near the ventral border of STN, has indicated a great potential of breaking through this barrier.

Objective: This study aims to investigate the feasibility of localizing the boundary between STN and SNr (SSB) using microstimulation and promote better lead placement.

Methods: We recorded neurophysiological data from 41 patients undergoing STN-DBS surgery with microstimulation in our hospital. Trajectories with typical STN signal were included. Microstimulation was applied near the bottom of STN to determine SSB, which was validated by the imaging reconstruction of DBS leads.

Results: In most trajectories with microstimulation (84.4%), neuronal firing in STN could not be inhibited by microstimulation, whereas in SNr long inhibition was observed following microstimulation. The success rate of localizing SSB was significantly higher in trajectories with microstimulation than those without. Moreover, results from imaging reconstruction and intraoperative neurological assessments demonstrated better lead location and higher therapeutic effectiveness in trajectories with microstimulation and accurately identified SSB.

Conclusion: Microstimulation on microelectrode recording is an effective approach to localize the SSB. Our data provide clinical evidence that microstimulation can be routinely employed to achieve better lead placement.
Involvement of Specialist Palliative Care in a Stroke Unit in Austria—Challenges for Families and Stroke Teams
Authors: Riesinger Renate , Altmann Klaus , Lorenzl Stefan
Published: September 2021

Purpose: Severe stroke poses vast challenges. Appropriate goals of care according to individual preferences and values have to be developed under time restrictions—often impeded by limited ability to communicate and the need for decisions by surrogates. The aim of our study was to explore the decision-making process and the involvement of specialist palliative care in the acute phase of severe stroke.

Methods: Twenty patients suffering from severe ischemic stroke treated in an Austrian acute inpatient stroke unit were included in a prospective study. Their families were interviewed with a questionnaire (FS-ICU 24), which covered satisfaction with care and decision-making. With a second questionnaire, decision-making processes within the stroke team were investigated.

Results: A palliative approach and early integration of specialist palliative care in severe ischemic stroke results in individualized therapeutic goals, including withholding therapeutic or life-sustaining measures, especially in patients with pre-existing illness.

Conclusions: Family members benefit from understandable and consistent information, emotional support, and a professional team identifying their needs. Stroke unit professionals need skills as well as knowledge and strategies in order to make decisions and provide treatment at the end-of-life, when there may be ethical or legal issues. Close cooperation with specialist palliative care services supports both treatment teams and families with communication and decision-making for patients with severe ischemic stroke.
Gene Therapy Overexpressing Neuregulin 1 Type I in Combination With Neuregulin 1 Type III Promotes Functional Improvement in the SOD1G93A ALS Mice
Authors: Mòdol-Caballero Guillem , Herrando-Grabulosa Mireia , Verdés Sergi , García-Lareu Belén , Hernández Neus , Francos-Quijorna Isaac , López-Vales Rubén , Bosch Assumpció , Navarro Xavier
Published: September 2021

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting the neuromuscular system for which currently there is no effective therapy. Motoneuron (MN) degeneration involves several complex mechanisms, including surrounding glial cells and skeletal muscle contributions. Neuregulin 1 (NRG1) is a trophic factor present particularly in MNs and neuromuscular junctions. Our previous studies revealed that gene therapy overexpressing the isoform I (NRG1-I) in skeletal muscles as well as overexpressing the isoform III (NRG1-III) directly in the central nervous system are both effective in preserving MNs in the spinal cord of ALS mice, opening novel therapeutic approaches. In this study, we combined administration of both viral vectors overexpressing NRG1-I in skeletal muscles and NRG1-III in spinal cord of the SOD1G93A mice in order to obtain a synergistic effect. The results showed that the combinatorial gene therapy increased preservation of MNs and of innervated neuromuscular junctions and reduced glial reactivity in the spinal cord of the treated SOD1G93A mice. Moreover, NRG1 isoforms overexpression improved motor function of hindlimb muscles and delayed the onset of clinical disease. However, this combinatory gene therapy did not produce a synergic effect compared with single therapies, suggesting an overlap between NRG1-I and NRG1-III activated pathways and their beneficial effects.
Infantile-Onset Charcot–Marie–Tooth Disease With Pyramidal Features and White Matter Abnormalities Due to a De novo MORC2 Gene Variant: A Case Report and Brief Review of the Literature
Authors: Frongia Ivana , Rizzi Susanna , Baga Margherita , Ceteroni Laura Maria , Spagnoli Carlotta , Salerno Grazia Gabriella , Frattini Daniele , Kaare Milja , Pisani Francesco , Fusco Carlo
Published: September 2021

Background: Charcot–Marie–Tooth (CMT) is the most frequent group of inherited neuropathies and includes several heterogeneous phenotypes. Over 80 causative genes have been described so far. Variants in the microrchidia family CW-type zinc finger 2 (MORC2) gene have been described in several axonal polyneuropathy (CMT2) patients with childhood or adult onset. Occasionally more complex phenotypes with delayed milestones, severe hypotonia, intellectual disability, dystonic postures, pyramidal signs, and neuroimaging abnormalities have been reported.

Case Presentation: We report on a patient with a de novo MORC2 gene variant (c.1181A>G p.Tyr394Cys) with a history of developmental delay, axial hypotonia, progressive gait disorder with dystonic features, and intentional tremor. At the age of 8 years, he showed bilateral pyramidal signs (clonus, increased tendon reflexes, and Babinski sign) and bilateral pes cavus. The first neuroimaging performed at the age of 3 years demonstrated white matter abnormalities in the posterior periventricular zone, in the frontal lobes bilaterally and at the midbrain, stable during childhood and adolescence. Nerve conduction studies (NCS) were negative until the age of 15 years, when a sensory axonal neuropathy appeared. The association between pyramidal signs and neuropathy due to the MORC2 gene variant is increasingly being highlighted, although a neuroradiological correlate is evident only in about half of the cases. Longitudinal nerve conduction velocity (NCV) are helpful to identify late-onset features and provide useful information for diagnosis in patients with rare neurogenetic disorders.

Conclusions: Characterization of complex neurological disorders is important to delineate the expanding phenotypic spectrum of MORC2-related disease, to confirm if possible the pathogenicity of the variants and to deepen the genotype–phenotype correlation.
Efficacy and Safety of Adherence to dl-3-n-Butylphthalide Treatment in Patients With Non-disabling Minor Stroke and TIA—Analysis From a Nationwide, Multicenter Registry
Authors: Tan Zefeng , Zhao Yin , Yang Wanyong , He Shenwen , Ding Yan , Xu Anding
Published: September 2021

Background: Dl-3-n-Butylphthalide (NBP) has the potential to improve clinical outcomes in acute ischemic stroke patients by improving collateral circulation. We aimed to evaluate the efficacy and safety of NBP in patients with non-disabling minor ischemic stroke and transient ischemic attack (TIA).

Methods: The BRIDGE (the observation study on clinical effectiveness of NBP on patients with non-disabling ischemic cerebrovascular disease) is a prospective registry to monitor the efficacy and safety of NBP therapy in acute non-disabling ischemic stroke or high-risk TIA. Non-disabling minor ischemic stroke patients within 48 h were enrolled across 51 stroke centers in China. We divided patients into NBP compliance or non-compliance groups according to their adherence to NBP. The primary outcome was the favorable functional outcome at 90 days, defined as a modified Rankin scale (mRS) <2.

Results: Between 10th October 2016 and 25th June 2019, 3,118 patients were included in this analysis. In multivariable analysis, after adjusting for common risk factors and demographic factors, NBP-compliance group has a higher proportion of favorable functional outcome (92.1 vs. 87.4%, adjusted odds ratio 2.00, 95% confidence interval, 1.50–2.65), and a higher stroke recurrence rate (2.40 vs. 0.31%, adjusted odds ratio 8.86, 95% confidence interval, 3.37–23.30) than the NBP-non-compliance group. There was no significant difference in death and intracranial hemorrhage rate between the two groups. In subgroup analysis, patients with National Institutes of Health Stroke Scale (NIHSS) scores from 3 to 5 who complied to NBP therapy had a higher rate of favorable functional outcomes than the NBP-non-compliance group. [88.82 vs. 76.21%, adjusted odds ratio 2.52 (1.81–3.50), adjusted interaction P = 0.00].

Conclusion: In non-disabling minor ischemic stroke or TIA patients, compliance with NBP therapy led to better 90-day functional outcomes despite a higher risk of recurrence, and this effect seems to be stronger in patients with NIHSS scores of 3–5. Further large randomized, double-blind controlled studies to analyse the association between NBP and functional outcome is warranted in the coming future.
CRMP5 Antibodies—Diagnostic Challenges
Authors: Totland Cecilie , Haugen Mette , Vedeler Christian
Published: September 2021

CRMP5-associated paraneoplastic neurological syndromes (PNS) are rare, and only few studies describe larger cohorts of patients with CRMP5 antibodies. We have included 24 patients with CRMP5 antibodies and compared clinical findings with diagnostic findings from two different line assays (Ravo and Euroimmun), staining of cerebellar sections and results of a newly developed cell-based assay for detection of CRMP5 antibodies, CRMP5-CBA. We found that peripheral neuropathy and cerebellar ataxia together with lung cancer were the most common diagnoses associated with CRMP5 antibodies. CRMP5-CBA was easy to perform, identified all relevant cases for CRMP5-associated PNS and is therefore a valuable add-on for verification of CRMP5 positivity in diagnosis of PNS.
Association Between Genetic Risks for Obesity and Working Memory in Children
Authors: Takahashi Nagahide , Nishimura Tomoko , Harada Taeko , Okumura Akemi , Iwabuchi Toshiki , Rahman Md. Shafiur , Kuwabara Hitoshi , Takagai Shu , Nomura Yoko , Takei Nori , Tsuchiya Kenji J.
Published: September 2021

Introduction: Obesity is highly heritable, and recent evidence demonstrates that obesity is associated with cognitive deficits, specifically working memory. However, the relationship between genetic risks for obesity and working memory is not clear. In addition, whether the effect of these genetic risks on working memory in children is mediated by increased body mass index (BMI) has not been elucidated.

Methods: In order to test whether the polygenic risk score (PRS) for obesity in adulthood (adulthood-BMI-PRS) is associated with working memory at 8 years of age, and whether the effect is mediated by childhood BMI, in children from the general population, participants in the Hamamatsu Birth Cohort for Mothers and Children (HBC) study in Hamamatsu, Japan, underwent testing for association of adulthood-BMI-PRS with working memory. HBC data collection began in December 2007 and is ongoing. Adulthood-BMI-PRS values were generated using summary data from the recent genome-wide association study (GWAS) undertaken in Japan, and the significance of thresholds was calculated for each outcome. Outcomes measured included the working memory index (WMI) of Weschler Intelligence Scale-4 (WISC-IV) scores and the BMI at 8 years of age. Gene-set enrichment analysis was conducted to clarify the molecular basis common to adulthood-BMI and childhood-WMI. Mediation analysis was performed to assess whether childhood-BMI of children mediated the association between adulthood-BMI-PRS and working memory.

Results: A total of 734 participants (377 males, 357 females) were analyzed. Adulthood-BMI-PRS was associated with lower childhood-WMI (β[SE], −1.807 [0.668]; p = 0.010, corrected) of WISC-IV. Gene-set enrichment analyses found that regulation of neurotrophin Trk receptor signaling (β[SE], −2.020 [6.39]; p = 0.002, corrected), negative regulation of GTPase activity (β[SE], 2.001 [0.630]; p = 0.002, corrected), and regulation of gene expression epigenetic (β[SE], −2.119 [0.664]; p = 0.002, corrected) were enriched in BMI in adulthood and WMI in childhood. Mediation analysis showed that there is no mediation effect of childhood-BMI between the adulthood-BMI-PRS and working memory deficits in children.

Conclusion: Adulthood-BMI-PRS was associated with working memory among children in the general population. These genetic risks were not mediated by the childhood-BMI itself and were directly associated with working memory deficits.
CCNDBP1, a Prognostic Marker Regulated by DNA Methylation, Inhibits Aggressive Behavior in Dedifferentiated Liposarcoma via Repressing Epithelial Mesenchymal Transition
Authors: Yang Lingge , Wu Zhiqiang , Sun Wei , Luo Peng , Chen Shiqi , Chen Yong , Yan Wangjun , Li Yan , Wang Chunmeng
Published: September 2021

The present study aimed to explore the prognostic value, function, and mechanism of CCNDBP1 in dedifferentiated liposarcoma (DDL). Immunohistochemistry staining was used to analyze the protein expression of CCNDBP1 in tissue specimens. After silencing CCNDBP1 in LPS853 and overexpressing CCNDBP1 in LPS510, CCK-8, clone formation, transwell migration, and invasion assays were used to detect cell proliferation, migration, and invasion ability. CCNDBP1-induced cell apoptosis was analyzed by flow cytometry. The altered expression of epithelial-mesenchymal transition (EMT)-related proteins were detected by Western blot. The methylation, gene expression, and clinical data of 58 samples with DDL were analyzed using the cancer genome atlas (TCGA) database. Low expression of CCNDBP1 was associated with a poor prognosis of patients with DDL and was considered an independent prognostic factor of the progression-free survival (PFS). CCNDBP1 significantly inhibited the clone formation, proliferation, migration, and invasion of cancer cells in vitro and promoted cancer cell apoptosis. CCNDBP1 could repress the pathological EMT, thereby inhibiting the malignant behaviors of DDL cells. The high degree of DNA methylation sites cg05194114 and cg22184989 could decrease the expression of CCNDBP1 and worsen the prognosis of DDL patients. This is the first study reporting that CCNDBP1 is a tumor suppressor gene of DDL and putative prognostic marker in DDL patients. CCNDBP1 might inhibit the ability of cell proliferation and invasion by repressing pathological EMT, and the expression of CCNDBP1 could be regulated by DNA methylation in DDL.
High Expression of SLC16A1 as a Biomarker to Predict Poor Prognosis of Urological Cancers
Authors: Zhang Ling , Song Zheng-Shuai , Wang Zhi-Shun , Guo Yong-Lian , Xu Chang-Geng , Shen Hao
Published: September 2021

Objective

Tumor metabolism has always been the focus of cancer research. SLC16A1, as a key factor in catalysis of monocarboxylate transport across the plasma membrane, has been found to be associated with the occurrence and metastasis of a variety of cancers, but its prognostic significance and mechanism in different tumors are still unclear.

Methods

Based on the gene expression matrix and clinical information of human cancer tissues acquired from TCGA and GTEX databases, the differential expression of SLC16A1 in different tumors and normal tissues was analyzed. To confirm the association between its expression, the mutation of MMRS gene, and the expression level of DNMTs. Univariate Cox regression was applied to analyze the association between SLC16A1 expression and patient prognosis. The effect of SLC16A1 expression on patient survival was examined by Kaplan Meier analysis. GSEA was used to identify related signaling pathways.

Results

The expression of SLC16A1 was differentially expressed in most tumors, especially in the urinary tract where it is commonly highly expressed, and differential expression of SLC16A1 in different clinical stages. SLC16A1 expression was significantly positively correlated with MMRS gene mutation and DNMTS expression. Moreover, high SLC16A1 expression was associated with poorer overall survival (OS) and progression-free survival (PFS) in urological cancers. In particular, the results of the enrichment analysis showed that SLC16A1 was associated with processes such as cell adhesion and many signaling pathways affecting cell cycle were significantly enriched in the group with high-expressed SLC16A1.

Conclusion

SLC16A1 expression was upregulated in urological cancer. SLC16A1 may promote tumor development by regulating the epigenetic process of urological cancer and demonstrated a great potential as a prognostic biomarker of urological cancer patients.
An Injectable Hydrogel for Enhanced FeGA-Based Chemodynamic Therapy by Increasing Intracellular Acidity
Authors: Zeng Wen , Jiang Dazhen , Liu Zeming , Suo Weilong , Wang Ziqi , Zhu Daoming , Huang Qinqin
Published: September 2021

Hydroxyl radical (•OH)-mediated chemodynamic therapy (CDT) is an emerging antitumor strategy, however, acid deficiency in the tumor microenvironment (TME) hampers its efficacy. In this study, a new injectable hydrogel was developed as an acid-enhanced CDT system (AES) for improving tumor therapy. The AES contains iron–gallic acid nanoparticles (FeGA) and α-cyano-4-hydroxycinnamic acid (α-CHCA). FeGA converts near-infrared laser into heat, which results in agarose degradation and consequent α-CHCA release. Then, as a monocarboxylic acid transporter inhibitor, α-CHCA can raise the acidity in TME, thus contributing to an increase in ·OH-production in FeGA-based CDT. This approach was found effective for killing tumor cells both in vitro and in vivo, demonstrating good therapeutic efficacy. In vivo investigations also revealed that AES had outstanding biocompatibility and stability. This is the first study to improve FeGA-based CDT by increasing intracellular acidity. The AES system developed here opens new opportunities for effective tumor treatment.
The Neonatal Assessment Manual scorE: A Reliability Study on Hospitalized Neonates
Authors: Manzotti Andrea , Cerritelli Francesco , Lombardi Erica , La Rocca Simona , Biasi Pamela , Chiera Marco , Galli Matteo , Lista Gianluca
Published: September 2021

Despite clinical improvements in neonatal intensive care units (NICUs), prematurity keeps causing several comorbidities. To enhance the management of such conditions, in previous studies we devised the Neonatal Assessment Manual scorE (NAME) model, a structured touch-based assessment that aims to evaluate how newborns respond to gentle touch-based stimuli. The present study aimed to begin assessing the NAME interrater reliability and specific agreements. At the “Vittore Buzzi” Pediatric Hospital NICU ward in Milan, Italy, we enrolled 144 newborns, 85 male and 59 female, with a mean age of 35.9 weeks (±4.1) and a weight of 2,055.3 g (±750.6). Two experienced manual professionals performed the NAME procedure on all the infants. Regarding the total sample and the analysis by sex, we found moderate and statistically significant results for the interrater reliability (p < 0.001) and the specific agreements (p < 0.05), in particular for the “Marginal” score. Furthermore, interrater reliability significantly (p < 0.05) increased as age and weight increased, whereas there was an almost constant moderate and significant (p < 0.05) agreement especially for the “Marginal” score. Therefore, we found preliminary results showing that the NAME could be a reliable diagnostic tool for assessing the newborns' general condition.
Inflow Occlusion Combined With Bleomycin Sclerotherapy for Management of Macro/Mixed Cystic Lymphatic Malformation in Children
Authors: Han Tao , Ji Yi , Cui Jie , Shen Weimin
Published: September 2021

Background: The link between cystic lymphatic malformation (cLM) and normal lymphatic system has become the focus of research. This study aimed to assess the outcomes of indocyanine green (ICG) lymphography-guided inflow occlusion combined with bleomycin sclerotherapy for the management of macro or mixed cLM in children.

Methods: Between June 2018 and October 2020, inflow occlusion combined with bleomycin sclerotherapy was performed in 81 cLM patients (age range from 6 months to 8 years). All cases were evaluated by the following parameters: cLM location, histological typing, number of afferent lymph vessels, dermal backflow, curative effects, treatment frequency, and postoperative complications. The duration of postoperative follow-up was from 10 to 16 months.

Results: All cLM cases could be found with at least one lymphatic inflow. Excellent outcomes were observed in 68 cases (84.0%), 11 cases (13.6%) experienced good outcomes, and two (2.5%) cases had fair outcome. No case experienced repeated treatment for more than three times. Wound infection, fever, and scar hyperplasia were the independent adverse events, which were managed by symptomatic treatment.

Conclusion: Inflow occlusion combined with bleomycin sclerotherapy renders a safe and efficient approach for the management of macro or mixed cLM.
AK2 Promotes the Migration and Invasion of Lung Adenocarcinoma by Activating TGF-β/Smad Pathway In vitro and In vivo
Authors: Cai Fangfang , Xu Huangru , Zha Daolong , Wang Xiaoyang , Li Ping , Yu Shihui , Yao Yingying , Chang Xiaoyao , Chen Jia , Lu Yanyan , Hua Zi-Chun , Zhuang Hongqin
Published: September 2021

Adenylate kinase 2 (AK2) is a wide-spread and highly conserved protein kinase whose main function is to catalyze the exchange of nucleotide phosphate groups. In this study, we showed that AK2 regulated tumor cell metastasis in lung adenocarcinoma. Positive expression of AK2 is related to lung adenocarcinoma progression and poor survival of patients. Knockdown or knockout of AK2 inhibited, while overexpression of AK2 promoted, human lung adenocarcinoma cell migration and invasion ability. Differential proteomics results showed that AK2 might be closely related to epithelial-mesenchymal transition (EMT). Further research indicated that AK2 regulated EMT occurrence through the Smad-dependent classical signaling pathways as measured by western blot and qPCR assays. Additionally, in vivo experiments showed that AK2-knockout in human lung tumor cells reduced their EMT-like features and formed fewer metastatic nodules both in liver and in lung tissues. In conclusion, we uncover a cancer metastasis-promoting role for AK2 and provide a rationale for targeting AK2 as a potential therapeutic approach for lung cancer.