bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of Cost-Related Medication Non-adherence Among Older Adults With Medication Therapy Management
Authors: Zhang Weiwei , Lv Gang , Xiong Xiaomo , Li Minghui
Published: June 2021

Background: Medication therapy management (MTM) was established by the Center for Medicare and Medicaid Services (CMS) with the aim to improve medication adherence. However, the national prevalence of cost-related medication non-adherence (CRN) is still unknown and there is a literature gap in the association between MTM services and CRN.

Methods: A cross-sectional study was conducted. A nationally representative study sample from Medicare Current Beneficiary Surveys (MCBS) was used. Survey sampling weights were applied for national estimates of CRN. Weighted multivariable logistic regressions controlling for covariates were conducted to investigate the effect of the MTM on the CRN.

Results: The study identified 1,549 MTM-eligible beneficiaries. The prevalence of CRN was higher in MTM-eligible individuals than in non-MTM eligible individuals (24.14 vs. 13.44%; P < 0.001). According to the results of multivariable logistic regressions, we found that MTM eligibility was significantly associated with a higher prevalence of CRN (OR: 1.59; 95% CI: 1.28–1.96). Additionally, some other variables such as health status, with or without low-income subsidy are also associated with CRN.

Conclusions: Our findings suggest that the prevalence of CRN in MTM-eligible beneficiaries was higher than in non-MTM eligible beneficiaries. Further studies with the longitudinal design are warranted to clarify the relationship between MTM and CRN. Alternative strategies to improve CRN should be considered in future Medicare Part D Enhanced MTM Models.
An Integrated Database of Small RNAs and Their Interplay With Transcriptional Gene Regulatory Networks in Corynebacteria
Authors: Parise Mariana Teixeira Dornelles , Parise Doglas , Aburjaile Flavia Figueira , Pinto Gomide Anne Cybelle , Kato Rodrigo Bentes , Raden Martin , Backofen Rolf , Azevedo Vasco Ariston de Carvalho , Baumbach Jan
Published: June 2021

Small RNAs (sRNAs) are one of the key players in the post-transcriptional regulation of bacterial gene expression. These molecules, together with transcription factors, form regulatory networks and greatly influence the bacterial regulatory landscape. Little is known concerning sRNAs and their influence on the regulatory machinery in the genus Corynebacterium, despite its medical, veterinary and biotechnological importance. Here, we expand corynebacterial regulatory knowledge by integrating sRNAs and their regulatory interactions into the transcriptional regulatory networks of six corynebacterial species, covering four human and animal pathogens, and integrate this data into the CoryneRegNet database. To this end, we predicted sRNAs to regulate 754 genes, including 206 transcription factors, in corynebacterial gene regulatory networks. Amongst them, the sRNA Cd-NCTC13129-sRNA-2 is predicted to directly regulate ydfH, which indirectly regulates 66 genes, including the global regulator glxR in C. diphtheriae. All of the sRNA-enriched regulatory networks of the genus Corynebacterium have been made publicly available in the newest release of CoryneRegNet(www.exbio.wzw.tum.de/coryneregnet/) to aid in providing valuable insights and to guide future experiments.
Efficient Preparation of Chitooligosaccharide With a Potential Chitosanase Csn-SH and Its Application for Fungi Disease Protection
Authors: Cui Dandan , Yang Jin , Lu Bosi , Shen Hong
Published: June 2021

Chitosanase plays a vital role in bioactive chitooligosaccharide preparation. Here, we characterized and prepared a potential GH46 family chitosanase from Bacillus atrophaeus BSS. The purified recombinant enzyme Csn-SH showed a molecular weight of 27.0 kDa. Csn-SH displayed maximal activity toward chitosan at pH 5.0 and 45°C. Thin-layer chromatography and electrospray ionization–mass spectrometry indicated that Csn-SH mainly hydrolyzed chitosan into (GlcN)2, (GlcN)3, and (GlcN)4 with an endo-type cleavage pattern. Molecular docking analysis demonstrated that Csn-SH cleaved the glycoside bonds between subsites −2 and + 1 of (GlcN)6. Importantly, the chitosan hydrolysis rate of Csn-SH reached 80.57% within 40 min, which could reduce time and water consumption. The hydrolysates prepared with Csn-SH exhibited a good antifungal activity against Magnaporthe oryzae and Colletotrichum higginsianum. The above results suggested that Csn-SH could be used to produce active chitooligosaccharides efficiently that are biocontrol agents applicable for safe and sustainable agricultural production.
Brevibacillin 2V, a Novel Antimicrobial Lipopeptide With an Exceptionally Low Hemolytic Activity
Authors: Zhao Xinghong , Wang Xiaoqi , Shukla Rhythm , Kumar Raj , Weingarth Markus , Breukink Eefjan , Kuipers Oscar P.
Published: June 2021

Bacterial non-ribosomally produced peptides (NRPs) form a rich source of antibiotics, including more than 20 of these antibiotics that are used in the clinic, such as penicillin G, colistin, vancomycin, and chloramphenicol. Here we report the identification, purification, and characterization of a novel NRP, i.e., brevibacillin 2V (lipo-tridecapeptide), fromBrevibacillus laterosporusDSM 25. Brevibacillin 2V has a strong antimicrobial activity against Gram-positive bacterial pathogens (minimum inhibitory concentration = 2 mg/L), including difficult-to-treat antibiotic-resistantEnterococcus faecium,Enterococcus faecalis, andStaphylococcus aureus. Notably, brevibacillin 2V has a much lower hemolytic activity (HC50> 128 mg/L) and cytotoxicity (CC50= 45.49 ± 0.24 mg/L) to eukaryotic cells than previously reported NRPs of the lipo-tridecapeptide family, including other brevibacillins, which makes it a promising candidate for antibiotic development. In addition, our results demonstrate that brevibacillins display a synergistic action with established antibiotics against Gram-negative bacterial pathogens. Probably due to the presence of non-canonical amino acids and D-amino acids, brevibacillin 2V showed good stability in human plasma. Thus, we identified and characterized a novel and promising antimicrobial candidate (brevibacillin 2V) with low hemolytic activity and cytotoxicity, which can be used either on its own or as a template for further total synthesis and modification.
Proteostasis Dysfunction in Aged Mammalian Cells. The Stressful Role of Inflammation
Authors: Ruano Diego
Published: June 2021

Aging is a biological and multifactorial process characterized by a progressive and irreversible deterioration of the physiological functions leading to a progressive increase in morbidity. In the next decades, the world population is expected to reach ten billion, and globally, elderly people over 80 are projected to triple in 2050. Consequently, it is also expected an increase in the incidence of age-related pathologies such as cancer, diabetes, or neurodegenerative disorders. Disturbance of cellular protein homeostasis (proteostasis) is a hallmark of normal aging that increases cell vulnerability and might be involved in the etiology of several age-related diseases. This review will focus on the molecular alterations occurring during normal aging in the most relevant protein quality control systems such as molecular chaperones, the UPS, and the ALS. Also, alterations in their functional cooperation will be analyzed. Finally, the role of inflammation, as a synergistic negative factor of the protein quality control systems during normal aging, will also be addressed. A better comprehension of the age-dependent modifications affecting the cellular proteostasis, as well as the knowledge of the mechanisms underlying these alterations, might be very helpful to identify relevant risk factors that could be responsible for or contribute to cell deterioration, a fundamental question still pending in biomedicine.
Case Report: Clinical Features of Childhood Leukoencephalopathy With Cerebral Calcifications and Cysts Due to SNORD118 Variants
Authors: Jin Hong , Ren Xiaotun , Wu Husheng , Hou Yanqi , Fang Fang
Published: June 2021

Background: Leukoencephalopathy with cerebral calcifications and cysts (LCC) is a rare autosomal recessive cerebral microangiopathy. Recently, biallelic variants in a non-protein-coding gene SNORD118 have been discovered to cause LCC.

Case Presentation: We here report a genetically confirmed childhood case of LCC. The patient was a 4-year-and-1-month-old boy with focal seizures. The age at onset of his seizure was 10 days after birth. The seizures were well-controlled by antiepileptic treatment but reoccurred twice due to a head impact accident and a fever, respectively. He suffered from a self-limited esotropia and unsteady running gait during the seizure onset. He had the typical neuroimaging triad of multifocal intracranial calcifications, cysts, and leukoencephalopathy. Genetic analysis indicated that he carried compound heterozygous variants of n.*9C>T and n.3C>T in SNORD118, which were inherited from his parents.

Conclusion: We report a childhood LCC case with compound heterozygous variants in SNORD118. To the best of our knowledge, the patient reported in our case had the youngest onset age of LCC with a determined genotype. The triad cerebral-imaging findings of calcifications, cysts, and leukoencephalopathy provide a crucial diagnostic basis. Moreover, the gene assessment, together with the clinical investigations, should be considered for the diagnosis of LCC.
Simultaneous Assessment of Electroencephalography Microstates and Resting State Intrinsic Networks in Alzheimer's Disease and Healthy Aging
Authors: Teipel Stefan J. , Brüggen Katharina , Temp Anna Gesine Marie , Jakobi Kristina , Weber Marc-André , Berger Christoph
Published: June 2021

Electroencephalography (EEG) microstate topologies may serve as building blocks of functional brain activity in humans. Here, we studied the spatial and temporal correspondences between simultaneously acquired EEG microstate topologies and resting state functional MRI (rs-fMRI) intrinsic networks in 14 patients with Alzheimer's disease (AD) and 14 healthy age and sex matched controls. We found an anteriorisation of EEG microstates' topologies in AD patients compared with controls; this corresponded with reduced spatial expression of default mode and increased expression of frontal lobe networks in rs-fMRI. In a hierarchical cluster analysis the time courses of the EEG microstates were associated with the time courses of spatially corresponding rs-fMRI networks. We found prevalent negative correlations of time courses between anterior microstate topologies and posterior rs-fMRI components as well as between posterior microstate topology and anterior rs-fMRI components. These negative correlations were significantly more expressed in controls than in AD patients. In conclusion, our data support the notion that the time courses of EEG microstates underlie the temporal expression of rs-fMRI networks. Furthermore, our findings indicate that the anterior-to-posterior connectivity of microstates and rs-fMRI components may be reduced in AD, indicative of a break-down of long-reaching intrahemispheric connections.
Behavioral Assessment of Sensory, Motor, Emotion, and Cognition in Rodent Models of Intracerebral Hemorrhage
Authors: Shi Xiaoyu , Bai Huiying , Wang Junmin , Wang Jiarui , Huang Leo , He Meimei , Zheng Xuejun , Duan Zitian , Chen Danyang , Zhang Jiaxin , Chen Xuemei , Wang Jian
Published: June 2021

Intracerebral hemorrhage (ICH) is the second most common type of stroke and has one of the highest fatality rates of any disease. There are many clinical signs and symptoms after ICH due to brain cell injury and network disruption resulted from the rupture of a tiny artery and activation of inflammatory cells, such as motor dysfunction, sensory impairment, cognitive impairment, and emotional disturbance, etc. Thus, researchers have established many tests to evaluate behavioral changes in rodent ICH models, in order to achieve a better understanding and thus improvements in the prognosis for the clinical treatment of stroke. This review summarizes existing protocols that have been applied to assess neurologic function outcomes in the rodent ICH models such as pain, motor, cognition, and emotion tests. Pain tests include mechanical, hot, and cold pain tests; motor tests include the following 12 types: neurologic deficit scale test, staircase test, rotarod test, cylinder test, grid walk test, forelimb placing test, wire hanging test, modified neurologic severity score, beam walking test, horizontal ladder test, and adhesive removal test; learning and memory tests include Morris water maze, Y-maze, and novel object recognition test; emotion tests include elevated plus maze, sucrose preference test, tail suspension test, open field test, and forced swim test. This review discusses these assessments by examining their rationale, setup, duration, baseline, procedures as well as comparing their pros and cons, thus guiding researchers to select the most appropriate behavioral tests for preclinical ICH research.
Frequency-Domain Optical Coherence Tomography for Intracranial Atherosclerotic Stenosis: Feasibility, Safety, and Preliminary Experience
Authors: Yang Bin , Feng Yiding , Ma Yan , Wang Yabing , Chen Jian , Li Long , Dong Jia , Zhang Bairu , Gao Peng , Chen Yanfei , Dmytriw Adam A. , Jiao Liqun
Published: June 2021

Background: Despite advances in non-invasive imaging, the characterization of atherosclerotic plaque remains superior with frequency-domain optical coherence tomography (FD-OCT) in the clinical coronary and experimental cerebrovascular literature. An assessment of the feasibility and safety of FD-OCT for intracranial atherosclerotic stenosis (ICAS) is desirable.

Methods: We analyzed a cohort of all consecutive FD-OCT evaluations for ICAS performed at our institution from April 2017 to August 2018 (16 months) in patients who suffered from transient ischemic attack (TIA) or non-disabling stroke despite optimal medical management within 90 days of admission attributable to angiographically verified 70–99% stenosis of an intracranial artery.

Results: Thirty-three patients harboring 36 lesions with an average age of (57.6 ± 7.1) years (male sex 27 cases) comprising nine cases of lesions located within the anterior circulation and 24 cases within the posterior circulation were identified. Of the 33 patients with 36 lesions, the FD-OCT imaging catheter detected 35/36 (97%) lesions except in one case in which the FD-OCT catheter failed to navigate excessively tortuous vessels, and FD-OCT images in 27 patients (81.8%) were finally obtained successful, where the target lesion was fully visible, and image quality under at least one pullback was graded 2 or 3. There were no symptomatic complications. Blood flow was the most common artifact encountered (51.9%).

Conclusion: FD-OCT is safe and feasible for the assessment of ICAS in the anterior and posterior circulation. The use of diagnostic interferometry will have to be weighed against its cost, and these preliminary findings should be verified by prospective large-scale studies.
Low-Expressing Synucleinopathy Mouse Models Based on Oligomer-Forming Mutations and C-Terminal Truncation of α-Synuclein
Authors: Martinez Hernandez Ana , Silbern Ivan , Geffers Insa , Tatenhorst Lars , Becker Stefan , Urlaub Henning , Zweckstetter Markus , Griesinger Christian , Eichele Gregor
Published: June 2021

α-synuclein (αSyn) is the main protein component of Lewy bodies, intracellular inclusions found in the brain of Parkinson’s disease (PD) patients. Neurotoxic αSyn species are broadly modified post-translationally and, in patients with genetic forms of PD, carry genetically encoded amino acid substitutions. Mutations and C-terminal truncation can increase αSyn oligomerization and fibrillization. Although several genetic mouse models based on αSyn mutations and/or truncations exist, there is still a lack of mouse models for synucleinopathies not relying on overexpression. We report here two synucleinopathy mouse models, which are based on a triple alanine to proline mutation and a C-terminal truncation of αSyn, but do not overexpress the mutant protein when compared to the endogenous mouse protein. We knocked hαSynTP or hαSynΔ119 (h stands for “human”) into the murine αSyn locus. hαSynTP is a structure-based mutant with triple alanine to proline substitutions that favors oligomers, is neurotoxic and evokes PD-like symptoms in Drosophila melanogaster. hαSynΔ119 lacks 21 amino acids at the C-terminus, favors fibrillary aggregates and occurs in PD. Knocking-in of hαSynTP or hαSynΔ119 into the murine αSyn locus places the mutant protein under the control of the endogenous regulatory elements while simultaneously disrupting the mαSyn gene. Mass spectrometry revealed that hαSynTP and hαSynΔ119 mice produced 12 and 10 times less mutant protein, compared to mαSyn in wild type mice. We show phenotypes in 1 and 1.5 years old hαSynTP and hαSynΔ119 mice, despite the lower levels of hαSynTP and hαSynΔ119 expression. Direct comparison of the two mouse models revealed many commonalities but also aspects unique to each model. Commonalities included strong immunoactive state, impaired olfaction and motor coordination deficits. Neither model showed DAergic neuronal loss. Impaired climbing abilities at 1 year of age and a deviant gait pattern at 1.5 years old were specific for hαSynΔ119 mice, while a compulsive behavior was exclusively detected in hαSynTP mice starting at 1 year of age. We conclude that even at very moderate levels of expression the two αSyn variants evoke measurable and progressive deficiencies in mutant mice. The two transgenic mouse models can thus be suitable to study αSyn-variant-based pathology in vivo and test new therapeutic approaches.
Comparative Proteomic Characterization of Ventral Hippocampus in Susceptible and Resilient Rats Subjected to Chronic Unpredictable Stress
Authors: Zhang Yani , Zhang Xiaoling , Liu Nuo , Ren Siyu , Xia Congyuan , Yang Xiong , Lou Yuxia , Wang Huiqin , Zhang Ningning , Yan Xu , Zhang Zhao , Zhang Yi , Wang Zhenzhen , Chen Naihong
Published: June 2021

Chronic stress is an essential factor leading to depression. However, there exist individual differences in people exposed to the same stressful stimuli. Some people display negative psychology and behavior, while others are normal. Given the importance of individual difference, finding differentially expressed proteins in stress-resistant and stress-susceptible groups has great significance for the study of pathogenesis and treatment of depression. In this study, stress-susceptible rats and stress-resilient rats were first distinguished by sucrose preference test. These stress-susceptible rats also displayed depression-like behaviors in forced swimming test and open field test. Then, we employed label-free quantitative proteomics to analyze proteins in the ventral hippocampus. There were 4,848 proteins totally identified. Based on statistical analysis, we found 276 differentially expressed proteins. Bioinformatics analysis revealed that the biological processes of these differential proteins were related to mitochondrion organization, protein localization, coenzyme metabolic process, cerebral cortex tangential migration, vesicle-mediated transport, and so on. The KEGG pathways were mainly involved in metabolic pathways, axon guidance, autophagy, and tight junction. Furthermore, we ultimately found 20 stress-susceptible proteins and two stress-resilient proteins. These stress-related proteins could not only be potential biomarkers for depression diagnosis but also contribute to finding new therapeutic targets and providing personalized medicine.
Broad Influence of Mutant Ataxin-3 on the Proteome of the Adult Brain, Young Neurons, and Axons Reveals Central Molecular Processes and Biomarkers in SCA3/MJD Using Knock-In Mouse Model
Authors: Wiatr Kalina , Marczak Łukasz , Pérot Jean-Baptiste , Brouillet Emmanuel , Flament Julien , Figiel Maciej
Published: June 2021

Spinocerebellar ataxia type 3 (SCA3/MJD) is caused by CAG expansion mutation resulting in a long polyQ domain in mutant ataxin-3. The mutant protein is a special type of protease, deubiquitinase, which may indicate its prominent impact on the regulation of cellular proteins levels and activity. Yet, the global model picture of SCA3 disease progression on the protein level, molecular pathways in the brain, and neurons, is largely unknown. Here, we investigated the molecular SCA3 mechanism using an interdisciplinary research paradigm combining behavioral and molecular aspects of SCA3 in the knock-in ki91 model. We used the behavior, brain magnetic resonance imaging (MRI) and brain tissue examination to correlate the disease stages with brain proteomics, precise axonal proteomics, neuronal energy recordings, and labeling of vesicles. We have demonstrated that altered metabolic and mitochondrial proteins in the brain and the lack of weight gain in Ki91 SCA3/MJD mice is reflected by the failure of energy metabolism recorded in neonatal SCA3 cerebellar neurons. We have determined that further, during disease progression, proteins responsible for metabolism, cytoskeletal architecture, vesicular, and axonal transport are disturbed, revealing axons as one of the essential cell compartments in SCA3 pathogenesis. Therefore we focus on SCA3 pathogenesis in axonal and somatodendritic compartments revealing highly increased axonal localization of protein synthesis machinery, including ribosomes, translation factors, and RNA binding proteins, while the level of proteins responsible for cellular transport and mitochondria was decreased. We demonstrate the accumulation of axonal vesicles in neonatal SCA3 cerebellar neurons and increased phosphorylation of SMI-312 positive adult cerebellar axons, which indicate axonal dysfunction in SCA3. In summary, the SCA3 disease mechanism is based on the broad influence of mutant ataxin-3 on the neuronal proteome. Processes central in our SCA3 model include disturbed localization of proteins between axonal and somatodendritic compartment, early neuronal energy deficit, altered neuronal cytoskeletal structure, an overabundance of various components of protein synthesis machinery in axons.
Polyphenol-Rich Aronia melanocarpa Juice Consumption Affects LINE-1 DNA Methylation in Peripheral Blood Leukocytes in Dyslipidemic Women
Authors: Stojković Ljiljana , Zec Manja , Zivkovic Maja , Bundalo Maja , Bošković Maja , Glibetić Marija , Stankovic Aleksandra
Published: June 2021

Cardiovascular disease (CVD) is associated with alterations in DNA methylation and polyunsaturated fatty acid (PUFA) profile, both modulated by dietary polyphenols. The present parallel, placebo-controlled study (part of the original clinical study registered as NCT02800967 at www.clinicaltrials.gov) aimed to determine the impact of 4-week daily consumption of polyphenol-rich Aronia melanocarpa juice (AMJ) treatment on Long Interspersed Nucleotide Element-1 (LINE-1) methylation in peripheral blood leukocytes and on plasma PUFAs, in subjects (n = 54, age range of 40.2 ± 6.7 years) at moderate CVD risk, including an increased body mass index, central obesity, high normal blood pressure, and/or dyslipidemia. The goal was also to examine whether factors known to affect DNA methylation (folate intake levels, MTHFR C677T gene variant, anthropometric and metabolic parameters) modulated the LINE-1 methylation levels upon the consumption of polyphenol-rich aronia juice. Experimental analysis of LINE-1 methylation was done by MethyLight method. MTHFR C677T genotypes were determined by the polymerase chain reaction–restriction fragment length polymorphism method, and folate intake was assessed by processing the data from the food frequency questionnaire. PUFAs were measured by gas–liquid chromatography, and serum lipid profile was determined by using Roche Diagnostics kits. The statistical analyses were performed using Statistica software package. In the comparison after vs. before the treatment period, in dyslipidemic women (n = 22), we observed significant decreases in LINE-1 methylation levels (97.54 ± 1.50 vs. 98.39 ± 0.86%, respectively; P = 0.01) and arachidonic acid/eicosapentaenoic acid ratio [29.17 ± 15.21 vs. 38.42 (25.96–89.58), respectively; P = 0.02]. The change (after vs. before treatment) in LINE-1 methylation directly correlated with the presence of MTHFR 677T allele, average daily folate intake, and the change in serum low-density lipoprotein cholesterol but inversely correlated with the change in serum triacylglycerols (R = 0.72, R2 = 0.52, adjusted R2 = 0.36, P = 0.03). The current results imply potential cardioprotective effects of habitual polyphenol-rich aronia juice consumption achieved through the modifications of DNA methylation pattern and PUFAs in subjects at CVD risk, which should be further confirmed. Hence, the precision nutrition-driven modulations of both DNA methylation and PUFA profile may become targets for new approaches in the prevention of CVD.
Explant Modeling of the Immune Environment of Head and Neck Cancer
Authors: Sharon Shay , Duhen Thomas , Bambina Shelly , Baird Jason , Leidner Rom , Bell Bryan , Casap Nardy , Crittenden Marka , Vasudevan Swetha , Jubran Maria , Kravchenko-Balasha Nataly , Gough Michael
Published: June 2021

Patients exhibit distinct responses to immunotherapies that are thought to be linked to their tumor immune environment. However, wide variations in outcomes are also observed in patients with matched baseline tumor environments, indicating that the biological response to treatment is not currently predictable using a snapshot analysis. To investigate the relationship between the immune environment of tumors and the biological response to immunotherapies, we characterized four murine head and neck squamous cell carcinoma (HNSCC) models on two genetic backgrounds. Using tumor explants from those models, we identified correlations between the composition of infiltrating immune cells and baseline cytokine profiles prior to treatment. Following treatment with PD-1 blockade, CTLA-4 blockade, or OX40 stimulation, we observed inter-individual variability in the response to therapy between genetically identical animals bearing the same tumor. These distinct biological responses to treatment were not linked to the initial tumor immune environment, meaning that outcome would not be predictable from a baseline analysis of the tumor infiltrates. We similarly performed the explant assay on patient HNSCC tumors and found significant variability between the baseline environment of the tumors and their response to therapy. We propose that tumor explants provide a rapid biological assay to assess response to candidate immunotherapies that may allow matching therapies to individual patient tumors. Further development of explant approaches may allow screening and monitoring of treatment responses in HNSCC.
M6A “Writer” Gene METTL14: A Favorable Prognostic Biomarker and Correlated With Immune Infiltrates in Rectal Cancer
Authors: Cai Changjing , Long Jie , Huang Qiaoqiao , Han Ying , Peng Yinghui , Guo Cao , Liu Shanshan , Chen Yihong , Shen Edward , Long Kexin , Wang Xinwen , Yu Jian , Shen Hong , Zeng Shan
Published: June 2021

Rectal cancer (RC) is the leading cause of tumor-related death among both men and women. The efficacy of immunotherapy for rectal cancer is closely related to the immune infiltration level. The N6-methyladenosine (m6A) modification may play a pivotal role in tumor-immune interactions. However, the roles of m6A-related genes in tumor-immune interactions of rectal cancer remain largely unknown. After an evaluation on the expression levels of m6A-related genes and their correlations with the prognosis of rectal cancer patients, we found that METTL14 was the only gene to be significantly correlated with prognosis in rectal cancer patients. Therefore, we further observed the impact of METTL14 expression and m6A modification on the immune infiltration in rectal cancer. Our study indicates that low expression of the m6A “writer” gene METTL14 in rectal cancer may lead to the downregulation of m6A RNA modification, thus reducing the level of immune cell infiltration and resulting in poor prognosis. METTL14 expression level is an independent prognostic factor in rectal cancer and is positively correlated with the immune infiltration level. Our study identified METTL14 as a potential target for enhancing immunotherapy efficacy in rectal cancer.
Post-Diagnostic Beta Blocker Use and Prognosis of Ovarian Cancer: A Systematic Review and Meta-Analysis of 11 Cohort Studies With 20,274 Patients
Authors: Wen Zhao-Yan , Gao Song , Gong Ting-Ting , Jiang Yu-Ting , Zhang Jia-Yu , Zhao Yu-Hong , Wu Qi-Jun
Published: June 2021

Objectives

Previous experimental studies have indicated that exposure to beta blocker provides protective effects against ovarian cancer (OC). However, findings from epidemiologic studies have still been controversial. Therefore, we carried out a meta-analysis to update and quantify the correlation between post-diagnostic beta blocker usage and OC prognosis.

Methods

The meta-analysis had been registered at PROSPEPO. The number of registration is CRD42020188806. A comprehensive search of available literatures in English prior to April 16, 2020, was conducted in PubMed, EMBASE, and the Web of Science databases. Random-effects models were used to calculate overall hazard ratios (HRs) and 95% confidence intervals (CIs). Publication bias assessments, and subgroup, sensitivity, and meta-regression analyses were also performed.

Results

Of the 637 initially identified articles, 11 retrospective cohort studies with 20,274 OC patients were included. The summary HRs did not reveal any statistically significant associations between post-diagnostic beta blocker use and OC prognosis characteristics, such as total mortality (HR = 1.08, 95% CI = 0.92–1.27, I2 = 76.5%, n = 9), cancer-specific mortality (HR = 1.22, 95% CI = 0.89–1.67, I2 = 88.1%, n=3), and progression-free survival (HR = 0.88, 95% CI = 0.75–1.05, I2 = 0, n = 4). No evidence of publication bias was observed in current analysis. In our subgroup analyses, the majority of results were consistent with the main findings. However, several positive correlations were detected in studies with ≥800 cases (HR = 1.20, 95% CI = 1.05–1.37), no immortal time bias (HR = 1.28, 95% CI = 1.10–1.49), and adjustment for comorbidity (HR = 1.20, 95% CI = 1.05–1.37). In the meta-regression analysis, no evidence of heterogeneity was detected in the subgroups according to study characteristics and confounding factors.

Conclusions

Post-diagnostic beta blocker use has no statistical correlation with OC prognosis. More prospective cohort studies are necessary to further verify our results.

Systematic Review Registration

Identifier (CRD42020188806).
Evaluation of Preoperative Inflammation-Based Prognostic Scores in Patients With Intrahepatic Cholangiocarcinoma: A Multicenter Cohort Study
Authors: He Chaobin , Zhao Chongyu , Lu Jiawei , Huang Xin , Chen Cheng , Lin Xiaojun
Published: June 2021

Background

Accumulating evidence has indicated the vital role of inflammation-based score (IBS) in predicting the prognostic outcome of cancer patients. Otherwise, their value in intrahepatic cholangiocarcinoma (iCCA) remains indistinct. The present study aimed to evaluate whether IBSs were related to survival outcomes in iCCA patients.

Method

Clinical characteristics were retrospectively collected in 399 patients diagnosed with iCCA from cohorts of Sun Yat-sen University Cancer Center (SYSUCC) and the First Hospital of Dalian Medical University (FHDMU). The survival curves were constructed with the Kaplan-Meier method and compared with the log-rank test. Univariate and multivariate analyses were conducted to determine the prognostic factors of overall survival (OS) and progression-free survival (PFS). The concordance index and the area under the time-dependent receiver operating characteristic (ROC) curves (AUROCs) were used to compare the predictive value of inflammation-based scores in terms of survival outcomes.

Results

The significant survival differences in OS and DFS were observed when patients were stratified by the modified Glasgow Prognostic Score (mGPS) (p<0.001). Multivariate analysis demonstrated that higher mGPS score was independently associated with poor OS and DFS (p<0.001). The predictive accuracy of the mGPS was superior to other IBSs (all p<0.001) in survival prediction in iCCA patients. The findings were further supported by the external validation cohort.

Conclusion

The mGPS is a sensitive, efficient, simple and widely applicable preoperative prognostic factor for iCCA patients. Thus, more effective therapy and frequent surveillance should be conducted after surgical resection in iCCA patients with higher mGPS scores.
Survival Outcomes in Patients With 2018 FIGO Stage IA2–IIA2 Cervical Cancer Treated With Laparoscopic Versus Open Radical Hysterectomy: A Propensity Score-Weighting Analysis
Authors: Zhao Wancheng , Xiao Yunyun , Zhao Wei , Yang Qing , Bi Fangfang
Published: June 2021

Objective

To compare the survival and recurrence outcomes between open and laparoscopic radically hysterectomy (RH) for stage IA2-IIA2 cervical cancer based on Federation International of Gynecology and Obstetrics (FIGO) 2018.

Methods

Data of 1,373 early cervical cancer patients undergoing open or laparoscopic radically hysterectomy at ShengJing Hospital of China Medical University between January 1, 2013, and December 31, 2016, were retrospectively reviewed. Propensity score-based inverse probability of treatment weighting (PS-IPTW) was used to balance the covariates between the two groups.

Results

A total of 705 cervical cancer patients of FIGO 2009 stage IA2-IIA2 were finally enrolled in this study. After IPTW adjustment, the OS (HR = 2.095, 95% CI: 1.233-3.562, P = 0.006) and PFS (HR = 1.950, 95%CI: 1.194-3.184, P = 0.008) rates were significantly higher in the open RH (ORH) group compared with the laparoscopic RH (LRH) group. Then after re-staging according to the FIGO 2018 staging system, 561 patients still belonged to stage IA2-IIA2, 144 patients were upgraded to stage IIIC1p-IIIC2p. The ORH group had a significantly superior OS (HR = 1.977, 95%CI: 1.077-3.626, P = 0.028) and PFS (HR = 1.811, 95%CI: 1.046-3.134, P = 0.034) compared with the LRH group after PS-IPTW analysis. Furthermore, in patients with no high and intermediate risks, difference of the OS (HR = 1.386, 95%CI: 0.287-6.69, P = 0.684) and PFS (HR = 1.524, 95%CI: 0.363-6.396, P = 0.565) rates between the two groups were with no statistical meaning.

Conclusions

Outcomes of this retrospective cohort study were in compliance with indications for ORH recommended by the National Comprehensive Cancer Network guidelines Version 1, 2021. However, LRH showed non-inferiority for patients with no prognostic risk factors compared with ORH.
The Diagnostic Role of 18F-Choline, 18F-Fluciclovine and 18F-PSMA PET/CT in the Detection of Prostate Cancer With Biochemical Recurrence: A Meta-Analysis
Authors: Wang Rang , Shen Guohua , Huang Mingxing , Tian Rong
Published: June 2021

Background

Diagnosing the biochemical recurrence (BCR) of prostate cancer (PCa) is a clinical challenge, and early detection of BCR can help patients receive optimal treatment. We conducted a meta-analysis to define the diagnostic accuracy of PET/CT using 18F-labeled choline, fluciclovine, and prostate-specific membrane antigen (PSMA) in patients with BCR.

Methods

Multiple databases were searched until March 30, 2021. We included studies investigating the diagnostic accuracy of 18F-choline, 18F-fluciclovine, and 18F-PSMA PET/CT in patients with BCR. The pooled sensitivity, specificity, and detection rate of 18F-labeled tracers were calculated with a random-effects model.

Results

A total of 46 studies met the included criteria; 17, 16, and 13 studies focused on 18F-choline, fluciclovine, and PSMA, respectively. The pooled sensitivities of 18F-choline and 18F-fluciclovine were 0.93 (95% CI, 0.85–0.98) and 0.80 (95% CI, 0.65–0.897), and the specificities were 0.91 (95% CI, 0.73–0.97) and 0.66 (95% CI, 0.50–0.79), respectively. The pooled detection rates of 18F-labeled choline, fluciclovine and PSMA were 66, 74, and 83%, respectively. Moreover, the detection rates of 18F-labeled choline, fluciclovine, and PSMA were 35, 23, and 58% for a PSA level less than 0.5 ng/ml; 41, 46, and 75% for a PSA level of 0.5–0.99 ng/ml; 62, 57, and 86% for a PSA level of 1.0–1.99 ng/ml; 80, 92, and 94% for a PSA level more than 2.0 ng/ml.

Conclusion

These three 18F-labeled tracers are promising for detecting BCR in prostate cancer patients, with 18F-choline showing superior diagnostic accuracy. In addition, the much higher detection rates of 18F-PSMA showed its superiority over other tracers, particularly in low PSA levels.

Systematic Review Registration

PROSPERO, identifier CRD42020212531.
Comprehensive Landscape of Ovarian Cancer Immune Microenvironment Based on Integrated Multi-Omics Analysis
Authors: Shen Jiacheng , Liu Tingwei , Bei Qiaoli , Xu Shaohua
Published: June 2021

Epithelial ovarian cancer has a low response rate to immunotherapy and a complex immune microenvironment that regulates its treatment outcomes. Understanding the immune microenvironment and its molecular basis is of great clinical significance in the effort to improve immunotherapy response and outcomes. To determine the characteristics of the immune microenvironment in ovarian cancer, we stratified ovarian cancer patients into three immune subtypes (C1, C2, and C3) using immune-related genes based on gene expression data from The Cancer Genome Atlas and found that these three subtypes had significant differences in immune characteristics and prognosis. Methylation and copy number variant analysis showed that the immune checkpoint genes that influenced immune response were significantly hypermethylated and highly deleted in the immunosuppressive C3 subtype, suggesting that epigenetic therapy may be able to reverse the efficacy of immunotherapy. In addition, the mutation frequencies of BRCA2 and CDK12 were significantly higher in the C2 subtype than in the other two subtypes, suggesting that mutation of DNA repair-related genes significantly affects the prognosis of ovarian cancer patients. Our study further elucidated the molecular characteristics of the immune microenvironment of ovarian cancer, which providing an effective hierarchical method for the immunotherapy of ovarian cancer patients, and has clinical relevance to the design of new immunotherapies and a reasonable combination strategies.
Development and Validation of a Prognostic Model for Predicting Overall Survival in Patients With Bladder Cancer: A SEER-Based Study
Authors: Wang Wei , Liu Jianchao , Liu Lihua
Published: June 2021

Objective

To establish a prognostic model for Bladder cancer (BLCA) based on demographic information, the American Joint Commission on Cancer (AJCC) 7th staging system, and additional treatment using the surveillance, epidemiology, and end results (SEER) database.

Methods

Cases with BLCA diagnosed from 2010–2015 were collected from the SEER database, while patient records with incomplete information on pre-specified variables were excluded. All eligible cases were included in the full analysis set, which was then split into training set and test set with a 1:1 ratio. Univariate and multivariate Cox regression analyses were conducted to identify prognostic factors for overall survival (OS) in BLCA patients. With selected independent prognosticators, a nomogram was mapped to predict OS for BLCA. The nomogram was evaluated using receiver operating characteristic (ROC) analysis and calibration plot in both the training and test sets. The area under curve [AUC] of the nomogram was calculated and compared with clinicopathological indicators using the full analysis set. Statistical analyses were conducted using the R software, where P-value <0.05 was considered significant.

Results

The results indicated that age, race, sex, marital status, histology, tumor-node-metastasis (TNM) stages based on the AJCC 7th edition, and additional chemotherapy were independent prognostic factors for OS in patients with BLCA. Patients receiving chemotherapy tend to have better survival outcomes than those without. The proposed nomogram showed decent classification (AUCs >0.8) and prediction accuracy in both the training and test sets. Additionally, the AUC of the nomogram was observed to be better than that of conventional clinical indicators.

Conclusions

The proposed nomogram incorporated independent prognostic factors including age, race, sex, marital status, histology, tumor-node-metastasis (TNM) stages, and additional chemotherapy. Patients with BLCA benefit from chemotherapy on overall survival. The nomogram-based prognostic model could predict overall survival for patients with BLCA with accurate stratification, which is superior to clinicopathological factors.
Comparative Studies on Multi-Component Pharmacokinetics of Polygonum multiflorum Thunb Extract After Oral Administration in Different Rat Models
Authors: Ma Ninghui , Zhang Yong , Sun Liyan , Zhao Yuan , Ding Yue , Zhang Tong
Published: June 2021

The clinical use of Polygonum multiflorum Thunb (PM) has been restricted or banned in many countries, due to its hepatotoxic adverse effects. Its toxicity research has become a hot topic. So far, the pharmacokinetic studies of PM, focusing on prototype compounds such as 2,3,5,4'-tetrahydroxystilbene-2-O-β-D-glucoside (TSG), emodin, and physcion, have been considered the main basis of pharmacodynamic material or of toxic effect. However, pharmacokinetic studies of its phase II metabolites have not yet been reported, mainly because the quantifications of such metabolites are difficult to do without the reference substance. In addition, pharmacokinetic studies on different pathological models treated with PM have also not been reported. On the other hand, toxic effects of PM have been reported in patients diagnosed with different liver pathologies. In the present work, a simultaneous quantitation method for eight prototypes components of PM and their five phase II metabolites has been performed by ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) and used for the pharmacokinetic study of PM in two different liver pathological models in rats (normal, alpha-naphthylisothiocyanate (ANIT), and carbon tetrachloride (CCl4)). The results showed that the main blood-entering components of PM are TSG, emodin, physcion, emodin-8-O-β⁃D⁃glucoside (E-Glu), physcion-8-O-β⁃D⁃glucoside (P-Glu), aloe-emodin, gallic acid, resveratrol and catechin, among which TSG, emodin, and catechin were primary metabolized in phase II, while resveratrol was converted to all phase II metabolites, and the others were metabolized as drug prototypes. Meanwhile, their pharmacokinetic parameters in the different models also exhibited significant differences. For instance, the AUC (0-∞) values of the TSG prototype and its phase II metabolites were higher in the ANIT group, followed by CCl4 group and the normal group, while the AUC (0-∞) values of the emodin prototype and its phase II metabolites were higher in the CCl4 group. To further illustrate the reasons for the pharmacokinetic differences, bilirubin metabolizing enzymes and transporters in the liver were measured, and the correlations with the AUC of the main compounds were analyzed. TSG and aloe-emodin have significant negative correlations with UGT1A1, BSEP, OATP1A4, OCT1, NTCP, MRP2 and MDR1 (p < 0.01). These data suggest that when the expression of metabolic enzymes and transporters in the liver is inhibited, the exposure levels of some components of PM might be promoted in vivo.
Ginkgolide B Alleviates Learning and Memory Impairment in Rats With Vascular Dementia by Reducing Neuroinflammation via Regulating NF-κB Pathway
Authors: Huang Lijuan , Shi Yijie , Zhao Liang
Published: June 2021

Ginkgobalide B (GB) as the main active ingredient of traditional Chinese medicine Ginkgo biloba extract is reported to reduce neuroinflammation, protect neurons and promote cognitive learning ability. To explore that GB can reduce neuroinflammation through regulating nuclear factor-kappaB (NF-κB) signaling pathway and overcome cognitive dysfunction in rats with vascular dementia (VD), we aim at investigating the potential effect of GB on enhancing cognitive function in rats with VD. It was found that GB improved survival of oxygen-glucose deprivation (OGD) treated SH-SY5Y cells by attenuating inflammatory response via Toll-like Receptor 4 (TLR4)/NF-κB pathway. When rats were treated with bilateral common carotid artery occlusion (BCCAO) for 24 h, saline and GB were administered in Sprague-Dawley (SD) rats via a single intraperitoneal injection for consecutive 14 days. The behavioral changes of VD like rats treated with GB were observed through open field test, Morris water maze (MWM) and Y-maze electric maze. Nissl staining and immunofluorescence were used to observe changes of neurons in the hippocampus of rats. Western blot analysis was performed by detecting NF-κB pathway related inflammatory factors. The results found that GB can significantly improve the learning and memory ability of VD rats by reducing TLR4/NF-κB mediated neuroinflammation. In conclusion, GB seemed to be a potential drug for amelioration of learning and memory impairment in rats with VD.
Urolithin A Protects Chondrocytes From Mechanical Overloading-Induced Injuries
Authors: He Yuchen , Yocum Lauren , Alexander Peter G , Jurczak Michael J , Lin Hang
Published: June 2021

Physiological mechanical stimulation has been shown to promote chondrogenesis, but excessive mechanical loading results in cartilage degradation. Currently, the underlying mechanotransduction pathways in the context of physiological and injurious loading are not fully understood. In this study, we aim to identify the critical factors that dictate chondrocyte response to mechanical overloading, as well as to develop therapeutics that protect chondrocytes from mechanical injuries. Specifically, human chondrocytes were loaded in hyaluronic hydrogel and then subjected to dynamic compressive loading under 5% (DL-5% group) or 25% strain (DL-25% group). Compared to static culture and DL-5%, DL-25% reduced cartilage matrix formation from chondrocytes, which was accompanied by the increased senescence level, as revealed by higher expression of p21, p53, and senescence-associated beta-galactosidase (SA-β-Gal). Interestingly, mitophagy was suppressed by DL-25%, suggesting a possible role for the restoration mitophagy in reducing cartilage degeneration with mechanical overloading. Next, we treated the mechanically overloaded samples (DL-25%) with Urolithin A (UA), a natural metabolite previously shown to enhance mitophagy in other cell types. qRT-PCR, histology, and immunostaining results confirmed that UA treatment significantly increased the quantity and quality of cartilage matrix deposition. Interestingly, UA also suppressed the senescence level induced by mechanical overloading, demonstrating its senomorphic potential. Mechanistic analysis confirmed that UA functioned partially by enhancing mitophagy. In summary, our results show that mechanical overloading results in cartilage degradation partially through the impairment of mitophagy. This study also identifies UA’s novel use as a compound that can protect chondrocytes from mechanical injuries, supporting high-quality cartilage formation/maintenance.