bluuebunny/crossref_metadata_2025 huggingface dataset:
Stable Epigenetic Programming of Effector and Central Memory CD4 T Cells Occurs Within 7 Days of Antigen Exposure In Vivo
Authors: Bevington Sarah L. , Fiancette Remi , Gajdasik Dominika W. , Keane Peter , Soley Jake K. , Willis Claire M. , Coleman Daniel J. L. , Withers David R. , Cockerill Peter N.
Published: May 2021

T cell immunological memory is established within days of an infection, but little is known about thein vivochanges in gene regulatory networks accounting for their ability to respond more efficiently to secondary infections. To decipher the timing and nature of immunological memory we performed genome-wide analyses of epigenetic and transcriptional changes in a mouse model generating antigen-specific T cells. Epigenetic reprogramming for Th differentiation and memory T cell formation was already established by the peak of the T cell response after 7 days. The Th memory T cell program was associated with a gain of open chromatin regions, enriched for RUNX, ETS and T-bet motifs, which remained stable for 56 days. The epigenetic programs for both effector memory, associated with T-bet, and central memory, associated with TCF-1, were established in parallel. Memory T cell-specific regulatory elements were associated with greatly enhanced inducible Th1-biased responses during secondary exposures to antigen. Furthermore, memory T cells respondedin vivoto re-exposure to antigen by rapidly reprograming the entire ETS factor gene regulatory network, by suppressingEts1and activatingEtv6expression. These data show that gene regulatory networks are epigenetically reprogrammed towards memory during infection, and undergo substantial changes upon re-stimulation.
Macrophage Function in Calcium Oxalate Kidney Stone Formation: A Systematic Review of Literature
Authors: Taguchi Kazumi , Okada Atsushi , Unno Rei , Hamamoto Shuzo , Yasui Takahiro
Published: May 2021

Background

The global prevalence and recurrence rate of kidney stones is very high. Recent studies of Randall plaques and urinary components in vivo, and in vitro including gene manipulation, have attempted to reveal the pathogenesis of kidney stones. However, the evidence remains insufficient to facilitate the development of novel curative therapies. The involvement of renal and peripheral macrophages in inflammatory processes offers promise that might lead to the development of therapeutic targets. The present systematic literature review aimed to determine current consensus about the functions of macrophages in renal crystal development and suppression, and to synthesize evidence to provide a basis for future immunotherapy.

Methods

We systematically reviewed the literature during February 2021 according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Articles investigating the relationship between macrophages and urolithiasis, particularly calcium oxalate (CaOx) stones, were extracted from PubMed, MEDLINE, Embase, and Scopus. Study subjects, languages, and publication dates were unrestricted. Two authors searched and screened the publications.

Results

Although several studies have applied mixed modalities, we selected 10, 12, and seven (total, n = 29) of 380 articles that respectively described cultured cells, animal models, and human samples.

The investigative trend has shifted to macrophage phenotypes and signaling pathways, including micro (m)-RNAs since the discovery of macrophage involvement in kidney stones in 1999. Earlier studies of mice-associated macrophages with the acceleration and suppression of renal crystal formation. Later studies found that pro-inflammatory M1- and anti-inflammatory M2-macrophages are involved. Studies of human-derived and other macrophages in vitro and ex vivo showed that M2-macrophages (stimulated by CSF-1, IL-4, and IL-13) can phagocytose CaOx crystals, which suppresses stone development. The signaling mechanisms that promote M2-like macrophage polarization toward CaOx nephrocalcinosis, include the ﻿NLRP3, PPARγ-miR-23-Irf1/Pknox1, miR-93-TLR4/IRF1, and miR-185-5p/CSF1 pathways.

Proteomic findings have indicated that patients who form kidney stones mainly express M1-like macrophage-related proteins, which might be due to CaOx stimulation of the macrophage exosomal pathway.

Conclusions

This systematic review provides an update regarding the current status of macrophage involvement in CaOx nephrolithiasis. Targeting M2-like macrophage function might offer a therapeutic strategy with which to prevent stones via crystal phagocytosis.
Host-Microbiome Interaction in Lung Cancer
Authors: Dong Qiang , Chen Eric S. , Zhao Chen , Jin Chengcheng
Published: May 2021

Commensal microbiota has emerged as an essential biomarker and regulator of both tumorigenesis and response to cancer therapy. However, our current knowledge about microbiota in cancer has been largely limited to intestinal microbiota. As a mucosal organ harboring one of the largest surface areas in the body, the lung is exposed to a variety of microbes through inhalation and micro-aspiration, and is colonized by a diverse bacterial community in both physiological and pathological conditions. Importantly, increasing evidence has linked the lung microbiome to cancer development. Studies in lung cancer patients and mouse models have revealed tumor-associated dysregulation of the local microbiome in the lung, which in turn impacts cancer progression by shaping the tumor microenvironment and modulating the activity of tumor-infiltrating immune cells. These findings not only provide novel mechanistic insight into the biology of lung cancer but also shed light on new therapeutic targets and strategies for lung cancer prevention and treatment. The goal of this review is to discuss the key findings, remaining questions, and future directions in this new and exciting field.
Clinical Characteristics of Patients With Chronic Stevens-Johnson Syndrome Treated at a Major Tertiary Eye Hospital Within the United Kingdom
Authors: Jabbour Samir , Din Nizar , Logeswaran Abison , Taberno Sanchez Sara , Ahmad Sajjad
Published: May 2021

The purpose of this study is to provide a comprehensive review of the clinical characteristics in chronic Stevens-Johnson syndrome (SJS) patients within the United Kingdom population, their causative factors, treatment profile and prognosis. This retrospective series included 91 patients with chronic SJS treated at Moorfields Eye Hospital (London, United Kingdom). A chart review included visual acuity and presence of clinical findings (including lid abnormalities and ocular surface findings). All medical and surgical treatments were also recorded. Approximately a half of patients were White British but there were significant numbers of patients from other ethnic groups, South Asian and Black in particular. Oral antibiotics were the causative agent in almost a half of the patients with SJS, systemic infections in 14%, non-steroidal anti-inflammatory drugs in 8% and anticonvulsants in 7%. The age of onset was varied but a significant proportion of patients developed acute SJS in childhood. There was a significant correlation between visual acuity at initial referral to final recorded vision. Vision was found to continue to significantly deteriorate over time despite therapeutic interventions. Our regression model shows that ~62% of the variance in final vision can be explained by the initial vision and duration disease. The majority of our patients were on advanced ocular surface treatments including serum drops, topical ciclosporin and retinoic acid drops. Of particular significance, approximately a third of our patient cohort was also on systemic immune suppression. In conclusion, chronic SJS within the UK population under tertiary care remains an area of unmet clinical need. Current medical and surgical modalities prevent worsening of vision in severe ocular disease from SJS.
Influence of Peanut, Sorghum, and Soil Salinity on Microbial Community Composition in Interspecific Interaction Zone
Authors: Shi Xiaolong , Zhao Xinhua , Ren Jinyao , Dong Jiale , Zhang He , Dong Qiqi , Jiang Chunji , Zhong Chao , Zhou Yufei , Yu Haiqiu
Published: May 2021

Soil microorganisms play important roles in crop production and sustainable agricultural management. However, soil conditions and crop selection are key determining factors for soil microbial communities. This study investigated the effect of plant types and soil salinity on the microbial community of interspecific interaction zone (II) based on the sorghum/peanut intercropping system. Microbial community diversity and composition were determined through PacBio single molecule, real-time sequencing of 16S rDNA and internal transcribed spacer (ITS) genes. Results showed Proteobacteria, Bacteroidota, and Acidobacteriota to be the dominant bacterial phyla in IP, II, and IS, whereas Ascomycota, Basidiomycota, and Mucoromycota were the dominant fungal phyla. Under salt-treated soil conditions, the plants-specific response altered the composition of the microbial community (diversity and abundance). Additionally, the interspecific interactions were also helpful for maintaining the stability and ecological functions of microbial communities by restructuring the otherwise stable core microbiome. The phylogenetic structure of the bacterial community was greatly similar between IP and II while that of the fungal community was greatly similar between IP and IS; however, the phylogenetic distance between IP and IS increased remarkably upon salinity stress. Overall, salinity was a dominant factor shaping the microbial community structure, although plants could also shape the rhizosphere microenvironment by host specificity when subjected to environmental stresses. In particular, peanut still exerted a greater influence on the microbial community of the interaction zone than sorghum.
cAMP-Dependent Signaling Pathways as Potential Targets for Inhibition of Plasmodium falciparum Blood Stages
Authors: Lasonder Edwin , More Kunal , Singh Shailja , Haidar Malak , Bertinetti Daniela , Kennedy Eileen J. , Herberg Friedrich W. , Holder Anthony A. , Langsley Gordon , Chitnis Chetan E.
Published: May 2021

We review the role of signaling pathways in regulation of the key processes of merozoite egress and red blood cell invasion by Plasmodium falciparum and, in particular, the importance of the second messengers, cAMP and Ca2+, and cyclic nucleotide dependent kinases. cAMP-dependent protein kinase (PKA) is comprised of cAMP-binding regulatory, and catalytic subunits. The less well conserved cAMP-binding pockets should make cAMP analogs attractive drug leads, but this approach is compromised by the poor membrane permeability of cyclic nucleotides. We discuss how the conserved nature of ATP-binding pockets makes ATP analogs inherently prone to off-target effects and how ATP analogs and genetic manipulation can be useful research tools to examine this. We suggest that targeting PKA interaction partners as well as substrates, or developing inhibitors based on PKA interaction sites or phosphorylation sites in PKA substrates, may provide viable alternative approaches for the development of anti-malarial drugs. Proximity of PKA to a substrate is necessary for substrate phosphorylation, but the P. falciparum genome encodes few recognizable A-kinase anchor proteins (AKAPs), suggesting the importance of PKA-regulatory subunit myristylation and membrane association in determining substrate preference. We also discuss how Pf14-3-3 assembles a phosphorylation-dependent signaling complex that includes PKA and calcium dependent protein kinase 1 (CDPK1) and how this complex may be critical for merozoite invasion, and a target to block parasite growth. We compare altered phosphorylation levels in intracellular and egressed merozoites to identify potential PKA substrates. Finally, as host PKA may have a critical role in supporting intracellular parasite development, we discuss its role at other stages of the life cycle, as well as in other apicomplexan infections. Throughout our review we propose possible new directions for the therapeutic exploitation of cAMP-PKA-signaling in malaria and other diseases caused by apicomplexan parasites.
ZEB1 Mediates Bone Marrow Mesenchymal Stem Cell Osteogenic Differentiation Partly via Wnt/β-Catenin Signaling
Authors: Xu Cuidi , Shi Hongli , Jiang Xin , Fan Yongqian , Huang Donghui , Qi Xinming , Cheng Qun
Published: May 2021

Zinc finger E-box-binding homebox 1 (ZEB1) is a zinc-finger transcription factor best known for its role in promoting the epithelial-mesenchymal transition, which is also related to osteogenesis. Here, ZEB1 was investigated for its role in the commitment of bone marrow mesenchymal stem cells (BMSCs) to osteoblasts. In vitro, ZEB1 expression decreased following osteogenic differentiation. Furthermore, silencing of ZEB1 in BMSCs promoted osteogenic activity and mineralization. The increase in osteogenic differentiation induced by si-ZEB1 could be partly rescued by the inhibition of Wnt/β-catenin (si-β-catenin). In vivo, knockdown of ZEB1 in BMSCs inhibited the rapid bone loss of ovariectomized (OVX) mice. ZEB1 expression has also been negatively associated with bone mass and bone formation in postmenopausal women. In conclusion, ZEB1 is an essential transcription factor in BMSC differentiation and may serve as a potential anabolic strategy for treating and preventing postmenopausal osteoporosis (PMOP).
BACHD Mice Recapitulate the Striatal Parvalbuminergic Interneuron Loss Found in Huntington’s Disease
Authors: Rallapalle Vyshnavi , King Annesha C. , Gray Michelle
Published: May 2021

Huntington’s disease (HD) is a dominantly inherited, adult-onset neurodegenerative disease characterized by motor, psychiatric, and cognitive abnormalities. Neurodegeneration is prominently observed in the striatum where GABAergic medium spiny neurons (MSN) are the most affected neuronal population. Interestingly, recent reports of pathological changes in HD patient striatal tissue have identified a significant reduction in the number of parvalbumin-expressing interneurons which becomes more robust in tissues of higher disease grade. Analysis of other interneuron populations, including somatostatin, calretinin, and cholinergic, did not reveal significant neurodegeneration. Electrophysiological experiments in BACHD mice have identified significant changes in the properties of parvalbumin and somatostatin expressing interneurons in the striatum. Furthermore, their interactions with MSNs are altered as the mHTT expressing mouse models age with increased input onto MSNs from striatal somatostatin and parvalbumin-expressing neurons. In order to determine whether BACHD mice recapitulate the alterations in striatal interneuron number as observed in HD patients, we analyzed the number of striatal parvalbumin, somatostatin, calretinin, and choline acetyltransferase positive cells in symptomatic 12–14 month-old mice by immunofluorescent labeling. We observed a significant decrease in the number of parvalbumin-expressing interneurons as well as a decrease in the area and perimeter of these cells. No significant changes were observed for somatostatin, calretinin, or cholinergic interneuron numbers while a significant decrease was observed for the area of cholinergic interneurons. Thus, the BACHD mice recapitulate the degenerative phenotype observed in the parvalbumin interneurons in HD patient striata without affecting the number of other interneuron populations in the striatum.
Exercise Factors Released by the Liver, Muscle, and Bones Have Promising Therapeutic Potential for Stroke
Authors: Stephan Joseph S. , Sleiman Sama F.
Published: May 2021

Stroke is one of the leading causes of death and disability in the world. Stroke not only affects the patients, but also their families who serve as the primary caregivers. Discovering novel therapeutic targets for stroke is crucial both from a quality of life perspective as well as from a health economic perspective. Exercise is known to promote neuroprotection in the context of stroke. Indeed, exercise induces the release of blood-borne factors that promote positive effects on the brain. Identifying the factors that mediate the positive effects of exercise after ischemic stroke is crucial for the quest for novel therapies. This approach will yield endogenous molecules that normally cross the blood brain barrier (BBB) and that can mimic the effects of exercise. In this minireview, we will discuss the roles of exercise factors released by the liver such as beta-hydroxybutyrate (DBHB), by the muscle such as lactate and irisin and by the bones such as osteocalcin. We will also address their therapeutic potential in the context of ischemic stroke.
Smiling, Yawning, Jaw Functional Limitations and Oral Behaviors With Respect to General Health Status in Patients With Temporomandibular Disorder—Myofascial Pain With Referral
Authors: Kuć Joanna , Szarejko Krzysztof Dariusz , Gołȩbiewska Maria
Published: May 2021

Background: The temporomandibular joint is the one of the most important joints in the human body. It enables numerous orofacial functions such as mastication, swallowing, breathing, speech, emotional communication, and facial expressions. The aim of the study was to evaluate the prevalence of jaw functional limitations and oral behaviors with respect to general health status in patients with temporomandibular joint disorders—myofascial pain with referral.

Materials and methods: The study group consisted of 50 individuals (37 females and 13 males) with complete natural dentition. The average age was 23.36 years with ± 0.30 as a standard error. All subjects underwent clinical examination and were diagnosed with myofascial pain with referral according to the Diagnostic Criteria for Temporomandibular Disorders. The survey was conducted in connection with the Jaw Functional Limitation Scale-8 (JFLS-8), Jaw Functional Limitation Scale-20 (JFLS-20), Patient Health Questionnaire-4 (PHQ-4), Patient Health Questionnaire-9 (PHQ-9), Generalized Anxiety Disorder-7 (GAD-7), Patient Health Questionnaire-15 (PHQ-15), and Oral Behaviors Checklist (OBC).

Results: The most common functional problems in the entire study group were chewing tough food and yawning. In terms of gender, statistically significant differences were noted for chewing tough food and smiling (p = 0.015451; p = 0.035978, respectively). With respect to Bonferroni correction and Benjamini-Hochberg procedure, the observed differences were not statistically significant. There were no statistically considerable differences in mastication, mandibular mobility, verbal and emotional communication, or global limitations (p > 0.05). Over half (56%) of the respondents had depression of varying severity. Somatic symptoms of different severity were found in 78% of the patients, and 44% of the respondents declared anxiety disorders. The score of the Oral Behavior Checklist (OBC = 27.18) highlighted a high tendency for developing craniomandibular disorders.

Conclusion: Patients with myofascial pain with referral, demonstrated a disturbed biopsychosocial profile. The restrictions in yawning and smiling as well as limitations in mastication, mobility, verbal and emotional communication, and global limitations appear to be significant predictors of craniomandibular dysfunction. Depression, stress, and somatic disorders are important factors predisposing patients to the occurrence of myofascial pain with referral. The progression of oral behaviors may indicate the role of somatosensory amplification.
Anti-seizure Medication Prescription in Adult Outpatients With Epilepsy in China, 2013–2018
Authors: Yu Lingyan , Zhu Wenjie , Zhu Xiuping , Lu Yan , Yu Zhenwei , Dai Haibin
Published: May 2021

This study aimed to assess the national trends in anti-seizure medication (ASM) prescription in Chinese adult outpatients with epilepsy over a 6-year period from 2013 to 2018. Prescriptions for adult outpatients with epilepsy from hospitals in six major cities were extracted from the database of the Hospital Prescription Analysis Cooperative Project. Trends in the annual prescriptions and expenditure of ASM were analyzed. Prescription patterns (monotherapy or combination therapy) were also assessed. A total of 225,767 prescriptions from 60 hospitals were eligible and extracted for analysis. The number of ASM prescriptions increased from 28,360 in 2013 to 44,110 in 2018, and the corresponding cost increased from 9,452,990 Chinese Yuan (CNY) in 2013 to 14,627,865 CNY in 2018. The share of newer ASM use increased continuously, accounting for 56.75% of prescriptions and 85.03% of expenditure in 2018. The most frequently prescribed ASMs were sodium valproate and levetiracetam. The proportion of sodium valproate use decreased, while the proportion of levetiracetam use increased dramatically in terms of both ASM prescriptions and expenditure. Monotherapy was more frequent than combination therapy. The three most common combination therapies were sodium valproate/lamotrigine, levetiracetam/oxcarbazepine, and sodium valproate/levetiracetam. In summary, ASM use increased rapidly in terms of the number of ASM prescriptions and cost during the 6-year period, which raises concern regarding the rational use and pharma-economic profiles of ASMs. In place of valproate, levetiracetam became the most frequently used ASM. The development of ASM prescription is in line with therapy guidelines and reflects the current state of research in China.
Intravitreal Gene Therapy vs. Natural History in Patients With Leber Hereditary Optic Neuropathy Carrying the m.11778G>A ND4 Mutation: Systematic Review and Indirect Comparison
Authors: Newman Nancy J. , Yu-Wai-Man Patrick , Carelli Valerio , Biousse Valerie , Moster Mark L. , Vignal-Clermont Catherine , Sergott Robert C. , Klopstock Thomas , Sadun Alfredo A. , Girmens Jean-François , La Morgia Chiara , DeBusk Adam A. , Jurkute Neringa , Priglinger Claudia , Karanjia Rustum , Josse Constant , Salzmann Julie , Montestruc François , Roux Michel , Taiel Magali , Sahel José-Alain
Published: May 2021

Objective: This work aimed to compare the evolution of visual outcomes in Leber hereditary optic neuropathy (LHON) patients treated with intravitreal gene therapy to the spontaneous evolution in prior natural history (NH) studies.

Design: A combined analysis of two phase three randomized, double-masked, sham-controlled studies (REVERSE and RESCUE) and their joint long-term extension trial (CLIN06) evaluated the efficacy of rAAV2/2-ND4 vs. 11 pooled NH studies used as an external control.

Subjects: The LHON subjects carried the m.11778G>A ND4 mutation and were aged ≥15 years at onset of vision loss.

Methods: A total of 76 subjects received a single intravitreal rAAV2/2-ND4 injection in one eye and sham injection in the fellow eye within 1 year after vision loss in REVERSE and RESCUE. Both eyes were considered as treated due to the rAAV2/2-ND4 treatment efficacy observed in the contralateral eyes. Best corrected visual acuity (BCVA) from REVERSE, RESCUE, and CLIN06 up to 4.3 years after vision loss was compared to the visual acuity of 208 NH subjects matched for age and ND4 genotype. The NH subjects were from a LHON registry (REALITY) and from 10 NH studies. A locally estimated scatterplot smoothing (LOESS), non-parametric, local regression model was used to modelize visual acuity curves over time, and linear mixed model was used for statistical inferences.

Main Outcome Measures: The main outcome measure was evolution of visual acuity from 12 months after vision loss, when REVERSE and RESCUE patients had been treated with rAAV2/2-ND4.

Results: The LOESS curves showed that the BCVA of the treated patients progressively improved from month 12 to 52 after vision loss. At month 48, there was a statistically and clinically relevant difference in visual acuity of −0.33 logarithm of the minimal angle of resolution (LogMAR) (16.5 ETDRS letters equivalent) in favor of treated eyes vs. NH eyes (p < 0.01). Most treated eyes (88.7%) were on-chart at month 48 as compared to 48.1% of the NH eyes (p < 0.01). The treatment effect at last observation remained statistically and clinically significant when adjusted for age and duration of follow-up (−0.32 LogMAR, p < 0.0001).

Conclusions: The m.11778G>A LHON patients treated with rAAV2/2-ND4 exhibited an improvement of visual acuity over more than 4 years after vision loss to a degree not demonstrated in NH studies.

Clinical Trial Registration: NCT02652767, NCT02652780, NCT03406104, and NCT03295071.
Sirtuin 2 (SIRT2): Confusing Roles in the Pathophysiology of Neurological Disorders
Authors: Chen Xiuqi , Lu Wenmei , Wu Danhong
Published: May 2021

As a type of nicotinamide adenine dinucleotide (NAD+)-dependent deacetylases, sirtuin 2 (SIRT2) is predominantly found in the cytoplasm of cells in the central nervous system (CNS), suggesting its potential role in neurological disorders. Though SIRT2 is generally acknowledged to accelerate the development of neurological pathologies, it protects the brain from deterioration in certain circumstances. This review summarized the complex roles SIRT2 plays in the pathophysiology of diverse neurological disorders, compared and analyzed the discrete roles of SIRT2 in different conditions, and provided possible explanations for its paradoxical functions. In the future, the rapid growth in SIRT2 research may clarify its impacts on neurological disorders and develop therapeutic strategies targeting this protein.
A Systematic Review and Meta-Analysis of Autoantibodies for Diagnosis and Prognosis in Patients With Chronic Inflammatory Demyelinating Polyradiculoneuropathy
Authors: Guo Xiaoqian , Tang Lisha , Huang Qianyi , Tang Xiangqi
Published: May 2021

Objectives: To review the available evidence on sensitivity and specificity of anti-NF155 antibody detection in diagnosing a specific subset of patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and to calculate the frequencies of different autoantibodies to paranodal proteins.

Background: Diagnosis of CIDP relies on clinical and neurophysiologic criteria and lacks useful diagnostic biomarkers. A subset of CIDP patients exhibit atypical clinical phenotypes and impaired response to conventional treatments. These patients were reported as having autoantibodies targeting paranodal protein neurofascin isoform 155 (NF155), contactin-1 (CNTN1), and contactin-associated protein-1 (CASPR1). Here, we conducted a meta-analysis to summarize evidence on the diagnostic and prognostic value of these autoantibodies, especially for anti-NF155 antibody.

Methods: We searched the following electronic bibliographic databases: PubMed, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), and Web of Science. Eligible studies provided information to calculate the frequencies of anti-NF155 antibody and anti-CNTN1 antibody, the sensitivity and specificity of anti-NF155 antibody, and the incidence of improvement and deterioration among anti-NF155 antibody seropositive CIDP patients. Heterogeneity was assessed using Q and I2 statistics.

Results: The pooled frequency of anti-NF155 autoantibody across 14 studies was 7% [95% confidence interval (CI): 0.05–0.10] with high heterogeneity; the overall pooled sensitivity and specificity of anti-NF155 antibody for the diagnosis of a specific subgroup of CIDP patients were 0.45 (95% CI: 0.29–0.63) and 0.93 (95% CI: 0.86–0.97), respectively.

Conclusions: For diagnosing of a specific subset of CIDP characterized by poor response to intravenous immunoglobulin (IVIg), we found a moderate sensitivity and a high specificity. The anti-NF155 antibody test should be used as a confirmatory test rather than a screening test.

Systematic Review Registration: PROSPERO, identifier: CRD42020203385 and CRD42020190789.
Immediate Analgesic Effect of Acupuncture in Patients With Primary Dysmenorrhea: A fMRI Study
Authors: Wang Yanan , Xu Jing , Zhang Qing , Zhang Qi , Yang Ya , Wei Wei , Guo Xiaoli , Liang Fanrong , Yu Siyi , Yang Jie
Published: May 2021

Primary dysmenorrhea (PDM) is a common gynecological disease characterized by lower abdominal pain. Acupuncture is considered a good alternative therapy for PDM. However, the central mechanism of the analgesic effect of acupuncture is largely unknown. In this study, eligible patients were randomized into the real and sham acupuncture groups using a computer-generated, permuted block randomization method. The study cohort comprised 34 patients: 19 in the real acupuncture group and 15 in the sham acupuncture group. The clinical characteristics of the patients during their menstrual period were collected, and imaging scans were performed during the first 3 days of the patients’ menstrual period. We analyzed task and resting functional magnetic resonance imaging (fMRI) data to investigate the potential central mechanism of the immediate effect of acupuncture intervention on the intensity of PDM pain. The task fMRI study found that the rostral anterior cingulate cortex (rACC) and right supplemental motor area were activated during real acupuncture. Using the resting-state functional connectivity (FC) method, we found a post- versus pre-treatment change in the FC of the rACC and left precentral gyrus in the comparison of real acupuncture versus sham acupuncture. In addition, the FC of the rACC–left precentral gyrus at baseline was negatively correlated with short-term analgesia, while the change in the FC of the rACC–left precentral gyrus was positively correlated with short-term analgesia after acupuncture treatment. These findings support the importance of rACC–left precentral gyrus resting-state FC in the modulation of the intensity of PDM pain through acupuncture, which may shed light on the central mechanism of acupuncture in the treatment of PDM.
Alzheimer’s Disease and microRNA-132: A Widespread Pathological Factor and Potential Therapeutic Target
Authors: Zhang Meng , Bian Zhigang
Published: May 2021

Alzheimer’s disease (AD) is a common neurodegenerative disease in the elderly and is the most common type of dementia. AD is mostly gradual onset, and involves slow, progressive mental decline, accompanied by personality changes; the incidence of AD gradually increases with age. The etiology of AD is unknown, although it is currently believed to be related to abnormal deposition of amyloid β-protein (Aβ) in the brain, hyperphosphorylation of microtubule-associated protein tau, and the release of various cytokines, complements, activators and chemokines by cells. MicroRNAs (miRNAs) are a class of highly conserved non-coding RNAs that regulate gene expression at the post-transcriptional level, and manipulate the functions of intracellular proteins and physiological processes. Emerging studies have shown that miRNA plays an important role in regulating AD-related genes. MiR-132 is known as “NeurimmiR” due to its involvement in numerous neurophysiological and pathological processes. Accumulating pre-clinical results suggest that miR-132 may be involved in the progression of Aβ and tau pathology. Moreover, clinical studies have indicated that decreased circulating miR-132 levels could be used a potential diagnostic biomarker in AD. Here, we review the pathogenic role of miR-132 activity in AD, and the potential of targeting miR-132 for developing future therapeutic strategies.
Affective Neurofeedback Under Naturalistic Conditions: A Mini-Review of Current Achievements and Open Challenges
Authors: Trambaiolli Lucas R. , Tiwari Abhishek , Falk Tiago H.
Published: May 2021

Affective neurofeedback training allows for the self-regulation of the putative circuits of emotion regulation. This approach has recently been studied as a possible additional treatment for psychiatric disorders, presenting positive effects in symptoms and behaviors. After neurofeedback training, a critical aspect is the transference of the learned self-regulation strategies to outside the laboratory and how to continue reinforcing these strategies in non-controlled environments. In this mini-review, we discuss the current achievements of affective neurofeedback under naturalistic setups. For this, we first provide a brief overview of the state-of-the-art for affective neurofeedback protocols. We then discuss virtual reality as a transitional step toward the final goal of “in-the-wild” protocols and current advances using mobile neurotechnology. Finally, we provide a discussion of open challenges for affective neurofeedback protocols in-the-wild, including topics such as convenience and reliability, environmental effects in attention and workload, among others.
GluN2D NMDA Receptors Gate Fear Extinction Learning and Interneuron Plasticity
Authors: Dubois Christophe J. , Liu Siqiong June
Published: May 2021

The cerebellum is critically involved in the formation of associative fear memory and in subsequent extinction learning. Fear conditioning is associated with a long-term potentiation at both excitatory and inhibitory synapses onto Purkinje cells. We therefore tested whether fear conditioning unmasks novel forms of synaptic plasticity, which enable subsequent extinction learning to reset cerebellar circuitry. We found that fear learning enhanced GABA release from molecular layer interneurons and this was reversed after fear extinction learning. Importantly an extinction-like stimulation of parallel fibers after fear learning is sufficient to induce a lasting decrease in inhibitory transmission (I-LTDstim) in the cerebellar cortex, a form of plasticity that is absent in naïve animals. While NMDA (N-methyl-D-aspartate) receptors are required for the formation and extinction of associative memory, the role of GluN2D, one of the four major NMDA receptor subunits, in learning and memory has not been determined. We found that fear conditioning elevates spontaneous GABA release in GluN2D KO as shown in WT mice. Deletion of GluN2D, however, abolished the I-LTDstim induced by parallel fiber stimulation after learning. At the behavioral level, genetic deletion of GluN2D subunits did not affect associative learning and memory retention, but impaired subsequent fear extinction learning. D-cycloserine, a partial NMDA receptor (NMDAR) agonist, failed to rescue extinction learning in mutant mice. Our results identify GluN2D as a critical NMDAR subunit for extinction learning and reveal a form of GluN2D-dependent metaplasticity that is associated with extinction in the cerebellum.
Is Contrast-Enhanced Ultrasound Superior to Computed Tomography for Differential Diagnosis of Gallbladder Polyps? A Cross-Sectional Study
Authors: Yuan Zhiqing , Liu Xuesong , Li Qiwei , Zhang Yunhe , Zhao Ling , Li Fenghua , Chen Tao
Published: May 2021

Objective

To compare the clinical value of contrast-enhanced ultrasonography (CEUS) versus computed tomography (CT) for distinguishing neoplastic and non-neoplastic gallbladder polyps. Given whether laparoscopic cholecystectomy is needed, differential diagnosis of neoplastic and non-neoplastic gallbladder polyps is more important than benign and malignant polyps.

Methods

A total of 89 consecutive patients with polypoid lesions of the gallbladder > 10 mm in size without local invasion or distant metastasis during primary screening were enrolled in this prospective and comparative study. All patients who met the inclusion criteria underwent CEUS and CT examinations prior to surgical resection. The enhancement patterns and microvascular imaging types were analyzed on CEUS. The maximum diameter and CT value of the lesions were also recorded and subjected to a comparative analysis. The clinical value of the two diagnostic methods is compared.

Results

Of the 89 patients, there were 58 (65.2%) cases of non-neoplastic polyps and 31 (34.8%) cases of neoplastic polyps. The average diameter of neoplastic polyps was significantly higher than that of non-neoplastic polyps (P<0.001). The detection rate using CEUS was 100%. The proportion of perceived non-neoplastic polyps in the nonenhanced and arterial phases were 48.3% and 77.6%, respectively, which were significantly lower than those of neoplastic polyps (93.5%, P<0.001 and 100.0%, P<0.001, respectively). However, in the venous and delayed phases, all cholesterol polyps and neoplastic polyps were perceived. CT showed that non-neoplastic polyps exhibited delayed enhancement. On CEUS 29.0% neoplastic polyps showed a perfusion defect, whereas 6.9% non-neoplastic polyps showed a perfusion defect (P=0.005). The microvascular architecture of the lesions on CEUS was categorized into 4 types: spotty, linear, branched, and spinous, and there were significant differences between the two groups (P<0.001). The sensitivities and specificities were 87.10% and 68.97% for CEUS and 83.87% and 77.59% for CT, respectively (P=0.406).

Conclusions

CEUS and CT are useful for differential diagnosis of neoplastic and nonneoplastic polypoid lesions of the gallbladder. Diagnostic efficacy was comparable between CEUS and CT. Thus, CEUS is preferred over CT in the differential diagnosis of neoplastic and non-neoplastic gallbladder polyps due to its comparable diagnostic efficacy and lack of radiation dose.
Predicting Treatment Response to Neoadjuvant Chemoradiotherapy in Rectal Mucinous Adenocarcinoma Using an MRI-Based Radiomics Nomogram
Authors: Li Zhihui , Li Shuai , Zang Shuqin , Ma Xiaolu , Chen Fangying , Xia Yuwei , Chen Liuping , Shen Fu , Lu Yong , Lu Jianping
Published: May 2021

Objective

To build and validate an MRI-based radiomics nomogram to predict the therapeutic response to neoadjuvant chemoradiotherapy (nCRT) in rectal mucinous adenocarcinoma (RMAC).

Methods

Totally, 92 individuals with pathologically confirmed RMAC administered surgical resection upon nCRT in two different centers were assessed retrospectively (training set, n = 52, validation set, n = 40). Rectal MRI was performed pre-nCRT. Radiomics parameters were obtained from high-resolution T2-weighted images and selected to construct a radiomics signature. Then, radiomics nomogram construction integrated patient variables and the radiomics signature. The resulting radiomics nomogram was utilized to assess the tumor regression grade (TRG). Diagnostic performance was determined by generating receiver operating characteristic (ROC) curves and decision curve analysis (DCA).

Results

Six optimal features related to TRG were obtained to construct a radiomics signature. The nomogram combining the radiomics signature with age and mucin deposit outperformed the radiomics signature alone in the training (AUC, 0.950 vs 0.843, p < 0.05) and validation (AUC, 0.868 vs 0.719, p < 0.05) cohorts. DCA demonstrated a clinical utility for the radiomics nomogram model.

Conclusions

The established quantitative MRI-based radiomics nomogram is effective in predicting treatment response to neoadjuvant therapy in patients with RMAC.
Early Exanthema Upon Vemurafenib Plus Cobimetinib Is Associated With a Favorable Treatment Outcome in Metastatic Melanoma: A Retrospective Multicenter DeCOG Study
Authors: Kähler Katharina C. , Gutzmer Ralf , Meier Friedegrund , Zimmer Lisa , Heppt Markus , Gesierich Anja , Thoms Kai-Martin , Utikal Jochen , Hassel Jessica C. , Loquai Carmen , Pföhler Claudia , Heinzerling Lucie , Kaatz Martin , Göppner Daniela , Pflugfelder Annette , Bohne Ann-Sophie , Satzger Imke , Reinhardt Lydia , Placke Jan-Malte , Schadendorf Dirk , Ugurel Selma
Published: May 2021

Background

The combination of BRAF and MEK inhibitors has become standard of care in the treatment of metastatic BRAF V600-mutated melanoma. Clinical factors for an early prediction of tumor response are rare. The present study investigated the association between the development of an early exanthema induced by vemurafenib or vemurafenib plus cobimetinib and therapy outcome.

Methods

This multicenter retrospective study included patients with BRAF V600-mutated irresectable AJCC-v8 stage IIIC/D to IV metastatic melanoma who received treatment with vemurafenib (VEM) or vemurafenib plus cobimetinib (COBIVEM). The development of an early exanthema within six weeks after therapy start and its grading according to CTCAEv4.0 criteria was correlated to therapy outcome in terms of best overall response, progression-free (PFS), and overall survival (OS).

Results

A total of 422 patients from 16 centers were included (VEM, n=299; COBIVEM, n=123). 20.4% of VEM and 43.1% of COBIVEM patients developed an early exanthema. In the VEM cohort, objective responders (CR/PR) more frequently presented with an early exanthema than non-responders (SD/PD); 59.0% versus 38.7%; p=0.0027. However, median PFS and OS did not differ between VEM patients with or without an early exanthema (PFS, 6.9 versus 6.0 months, p=0.65; OS, 11.0 versus 12.4 months, p=0.69). In the COBIVEM cohort, 66.0% of objective responders had an early exanthema compared to 54.3% of non-responders (p=0.031). Median survival times were significantly longer for patients who developed an early exanthema compared to patients who did not (PFS, 9.7 versus 5.6 months, p=0.013; OS, not reached versus 11.6 months, p=0.0061). COBIVEM patients with a mild early exanthema (CTCAEv4.0 grade 1-2) had a superior survival outcome as compared to COBIVEM patients with a severe (CTCAEv4.0 grade 3-4) or non early exanthema, respectively (p=0.047). This might be caused by the fact that 23.6% of patients with severe exanthema underwent a dose reduction or discontinuation of COBIVEM compared to only 8.9% of patients with mild exanthema.

Conclusions

The development of an early exanthema within 6 weeks after treatment start indicates a favorable therapy outcome upon vemurafenib plus cobimetinib. Patients presenting with an early exanthema should therefore be treated with adequate supportive measures to provide that patients can stay on treatment.
Central Nervous System Hemangioblastoma in a Pediatric Patient Associated With Von Hippel-Lindau Disease: A Case Report and Literature Review
Authors: Yang Bo , Li Zhenyu , Wang Yubo , Zhang Chaoling , Zhang Zhen , Zhang Xianfeng
Published: May 2021

Background

Hemangioblastoma is a benign tumor of the central nervous system and may appear as a component of von Hippel-Lindau (VHL) disease. At present, approximately 40 cases of optic nerve HGBs have been reported in the literature. VHL disease is a rare autosomal-dominant inherited cancer syndrome with different phenotypes caused by variants in the VHL gene. Herein, the authors describe a case of a pediatric patient with VHL disease and with optic nerve HGB, a rare phenotypic expression. The purpose of this study was to explore the genotype-phenotype, clinical features, treatment and follow-up of VHL-associated hemangioblastomas in pediatric patients.

Case Description

A 12-year-old boy presented with vision loss, headache and dizziness at our hospital. Magnetic resonance imaging (MRI) revealed a large (19.8 mm*18.5 mm*23.5 mm) irregular mass located in the suprasellar region. The mass was successfully removed after craniotomy and microsurgical treatment. The pathological diagnosis was left optic nerve HGB. Genetic analyses showed p.Pro86Leu (c. 257C>T) heterozygous missense mutations in the VHL gene.

Conclusion

This is the first reported pediatric case of VHL-associated optic nerve HGB. The genotype-phenotype correlation of VHL disease may provide new evidences for predicting tumor penetrance and survival. Gross tumor resection combined with stereotactic radiosurgery might be the most beneficial treatment.
CT-Based Radiomics Signature With Machine Learning Predicts MYCN Amplification in Pediatric Abdominal Neuroblastoma
Authors: Chen Xin , Wang Haoru , Huang Kaiping , Liu Huan , Ding Hao , Zhang Li , Zhang Ting , Yu Wenqing , He Ling
Published: May 2021

Purpose

MYCN amplification plays a critical role in defining high-risk subgroup of patients with neuroblastoma. We aimed to develop and validate the CT-based machine learning models for predicting MYCN amplification in pediatric abdominal neuroblastoma.

Methods

A total of 172 patients with MYCN amplified (n = 47) and non-amplified (n = 125) were enrolled. The cohort was randomly stratified sampling into training and testing groups. Clinicopathological parameters and radiographic features were selected to construct the clinical predictive model. The regions of interest (ROIs) were segmented on three-phrase CT images to extract first-, second- and higher-order radiomics features. The ICCs, mRMR and LASSO methods were used for dimensionality reduction. The selected features from the training group were used to establish radiomics models using Logistic regression, Support Vector Machine (SVM), Bayes and Random Forest methods. The performance of four different radiomics models was evaluated according to the area under the receiver operator characteristic (ROC) curve (AUC), and then compared by Delong test. The nomogram incorporated of clinicopathological parameters, radiographic features and radiomics signature was developed through multivariate logistic regression. Finally, the predictive performance of the clinical model, radiomics models, and nomogram was evaluated in both training and testing groups.

Results

In total, 1,218 radiomics features were extracted from the ROIs on three-phrase CT images, and then 14 optimal features, including one original first-order feature and eight wavelet-transformed features and five LoG-transformed features, were identified and selected to construct the radiomics models. In the training group, the AUC of the Logistic, SVM, Bayes and Random Forest model was 0.940, 0.940, 0.780 and 0.927, respectively, and the corresponding AUC in the testing group was 0.909, 0.909, 0.729, 0.851, respectively. There was no significant difference among the Logistic, SVM and Random Forest model, but all better than the Bayes model (p <0.005). The predictive performance of the Logistic radiomics model based on three-phrase is similar to nomogram, but both better than the clinical model and radiomics model based on single venous phase.

Conclusion

The CT-based radiomics signature is able to predict MYCN amplification of pediatric abdominal NB with high accuracy based on SVM, Logistic and Random Forest classifiers, while Bayes classifier yields lower predictive performance. When combined with clinical and radiographic qualitative features, the clinics-radiomics nomogram can improve the performance of predicting MYCN amplification.
CHOP Regulates Endoplasmic Reticulum Stress-Mediated Hepatoxicity Induced by Monocrotaline
Authors: Guo Yazhou , Yang Chen , Guo Rong , Huang Ruijie , Su Yongxia , Wang Shuai , Kong Yezi , Wang Jianguo , Tan Chengjian , Mo Chonghui , Wu Chenchen , Zhao Baoyu
Published: May 2021

Monocrotaline (MCT), a pyrrolizidine alkaloid, is the major toxin in Crotalaria, which causes cell apoptosis in humans and animals. It has been reported that the liver is a vulnerable target of MCT. However, the exact molecular mechanism of the interaction between endoplasmic reticulum (ER) stress and liver injury induced by MCT is still unclear. In this study, the cytotoxicity of MCT on primary rat hepatocytes was analyzed by a CCK-8 assay and Annexin V-FITC/PI assay. Protein expression was detected by western blotting and immunofluorescence staining. As a result, MCT significantly decreased the cell viability and mediated the apoptosis of primary rat hepatocytes. Meanwhile, MCT could also induce ER stress in hepatocytes, indicated by the expression of ER stress-related proteins, including GRP78, p-IRE1α, ATF6, p-eIF2α, ATF4, and CHOP. Pretreatment with 4-PBA, an inhibitor of ER stress, or knockdown of CHOP by siRNA could partly enhance cell viability and relieve the apoptosis. Our findings indicate that ER stress is involved in the hepatotoxicity induced by MCT, and CHOP plays an important role in this process.