bluuebunny/crossref_metadata_2025 huggingface dataset:
Booster dose of COVID-19 mRNA vaccine does not increase risks of myocarditis and pericarditis compared with primary vaccination: New insights from the vaccine adverse event reporting system
Authors: Chen Congqin , Fu Fang , Ding Lingqing , Fang Jie , Xiao Jie
Published: September 2022

Background

Despite the likely association between coronavirus 2019 (COVID-19) mRNA vaccines and cases of myocarditis/pericarditis, the benefit–risk assessment by the Centers for Disease Control (CDC) still showed a favorable balance for the primary series of COVID-19 mRNA vaccinations. Since August 2021, a full-scale booster vaccination in certain recipients has been recommended. Great concerns about whether the COVID-19 mRNA booster vaccination could increase the risks of myocarditis/pericarditis have been raised since then. The present study aimed to compare the incidence rates and risks of myocarditis/pericarditis between booster and primary vaccination programs.

Methods

The CDC COVID Data Tracker and the Vaccines Adverse Event Reporting System (VAERS) were queried between December 11, 2020 and March 15, 2022. Incidence rates were calculated by cases of myocarditis/pericarditis divided by the number of vaccinated people or the total doses of COVID-19 mRNA vaccines. Disproportionality patterns for myocarditis/pericarditis of different COVID-19 mRNA vaccinations were accessed based on the reporting odds and proportional reporting ratios (ROR and PRR, respectively).

Results

A total of 2,588 reports of myocarditis/pericarditis were identified after administration of primary-series COVID-19 mRNA vaccination and 269 after the booster dose program during the study period. The incidence of myocarditis/pericarditis following booster COVID-19 mRNA vaccination was lower than that of primary series. The results showed significantly high reporting of myocarditis/pericarditis following the administration of primary COVID-19 mRNA vaccination, whereas the disproportional level was lower in the booster-dose vaccination.

Conclusion

This study found that the booster dose of COVID-19 mRNA vaccination when compared with primary series course did not lead to an increase in the risks of myocarditis/pericarditis.
Antibody-mediated cell depletion therapies in multiple sclerosis
Authors: Mariottini Alice , Muraro Paolo A. , Lünemann Jan D.
Published: September 2022

Development of disease-modifying therapies including monoclonal antibody (mAb)-based therapeutics for the treatment of multiple sclerosis (MS) has been extremely successful over the past decades. Most of the mAb-based therapies approved for MS deplete immune cell subsets and act through activation of cellular Fc-gamma receptors expressed by cytotoxic lymphocytes and phagocytes, resulting in antibody-dependent cellular cytotoxicity or by initiation of complement-mediated cytotoxicity. The therapeutic goal is to eliminate pathogenic immune cell components and to potentially foster the reconstitution of a new and healthy immune system. Ab-mediated immune cell depletion therapies include the CD52-targeting mAb alemtuzumab, CD20-specific therapeutics, and new Ab-based treatments which are currently being developed and tested in clinical trials. Here, we review recent developments in effector mechanisms and clinical applications of Ab-based cell depletion therapies, compare their immunological and clinical effects with the prototypic immune reconstitution treatment strategy, autologous hematopoietic stem cell transplantation, and discuss their potential to restore immunological tolerance and to achieve durable remission in people with MS.
Inhibitory targeting cGAS-STING-TBK1 axis: Emerging strategies for autoimmune diseases therapy
Authors: Zhang Min , Zou Yan , Zhou Xujun , Zhou Jinming
Published: September 2022

The cGAS-STING signaling plays an integral role in the host immune response, and the abnormal activation of cGAS-STING is highly related to various autoimmune diseases. Therefore, targeting the cGAS-STING-TBK1 axis has become a promising strategy in therapy of autoimmune diseases. Herein, we summarized the key pathways mediated by the cGAS-STING-TBK1 axis and various cGAS-STING-TBK1 related autoimmune diseases, as well as the recent development of cGAS, STING, or TBK1 selective inhibitors and their potential application in therapy of cGAS-STING-TBK1 related autoimmune diseases. Overall, the review highlights that inhibiting cGAS-STING-TBK1 signaling is an attractive strategy for autoimmune disease therapy.
Circulating immune-complexes of IgG/IgM bound to B2-glycoprotein-I associated with complement consumption and thrombocytopenia in antiphospholipid syndrome
Authors: Naranjo Laura , Stojanovich Ljudmila , Djokovic Aleksandra , Andreoli Laura , Tincani Angela , Maślińska Maria , Sciascia Savino , Infantino Maria , Garcinuño Sara , Kostyra-Grabczak Kinga , Manfredi Mariangela , Regola Francesca , Stanisavljevic Natasa , Milanovic Milomir , Saponjski Jovica , Roccatello Dario , Cecchi Irene , Radin Massimo , Benucci Maurizio , Pleguezuelo Daniel , Serrano Manuel , Shoenfeld Yehuda , Serrano Antonio
Published: September 2022

Background

Antiphospholipid syndrome (APS) is a multisystemic autoimmune disorder characterized by thrombotic events and/or gestational morbidity in patients with antiphospholipid antibodies (aPL). In a previous single center study, APS-related clinical manifestations that were not included in the classification criteria (livedo reticularis, thrombocytopenia, leukopenia) were associated with the presence of circulating immune-complexes (CIC) formed by beta-2-glycoprotein-I (B2GP1) and anti-B2GP1 antibodies (B2-CIC). We have performed a multicenter study on APS features associated with the presence of B2-CIC.

Methods

A multicenter, cross-sectional and observational study was conducted on 303 patients recruited from six European hospitals who fulfilled APS classification criteria: 165 patients had primary APS and 138 APS associated with other systemic autoimmune diseases (mainly systemic lupus erythematosus, N=112). Prevalence of B2-CIC (IgG/IgM isotypes) and its association with clinical manifestations and biomarkers related to the disease activity were evaluated.

Results

B2-CIC prevalence in APS patients was 39.3%. B2-CIC-positive patients with thrombotic APS presented a higher incidence of thrombocytopenia (OR: 2.32, p=0.007), heart valve thickening and dysfunction (OR: 9.06, p=0.015) and triple aPL positivity (OR: 1.83, p=0.027), as well as lower levels of C3, C4 and platelets (p-values: <0.001, <0.001 and 0.001) compared to B2-CIC-negative patients. B2-CIC of IgM isotype were significantly more prevalent in gestational than thrombotic APS.

Conclusions

Patients with thrombotic events and positive for B2-CIC had lower platelet count and complement levels than those who were negative, suggesting a greater degree of platelet activation.
Integrated single-cell RNA-seq analysis identifies immune heterogeneity associated with KRAS/TP53 mutation status and tumor-sideness in colorectal cancers
Authors: Liu Xiaoyu , Xu Xu , Wu Zhuozhuo , Shan Qungang , Wang Ziyin , Wu Zhiyuan , Ding Xiaoyi , Huang Wei , Wang Zhongmin
Published: September 2022

Background

The main objective of this study was to analyze the effects of KRAS/TP53 mutation status and tumor sideness on the immune microenvironment of colorectal cancer using integrated scRNA-seq data.

Methods

A total of 78 scRNA-seq datasets, comprising 42 treatment-naive colorectal tumors, 13 tumor adjacent tissues and 23 normal mucosa tissues were included. Standardized Seurat procedures were applied to identify cellular components with canonical cell marks. The batch-effect was assessed and corrected using harmony algorithm. The scMetabolism algorithm was used for single-cell metabolic analysis. The results and clinical significance were further validated using immunofluorescent-staining and TCGA-COAD datasets. Immune-infiltration scores of bulk-RNA-seq data were estimated using ssGSEA. The presto-wilcoxauc algorithm was used to identify differentially enriched genes or pathways across different subgroups. Two-sided p-value less than 0.05 was considered statistically significant.

Results

We refined the landscape of functional immune cell subtypes, especially T cells and myeloid cells, across normal mucosa, tumor adjacent and tumor tissue. The existence and function of two states of exhausted CD8+ T (Tex) subtypes in colorectal cancer, and FOLR2+ LYVE1+ macrophages indicating unfavorable prognosis in colorectal cancer were identified and validated. The diverse tumor mutation status reshaped the immune cell function and immune checkpoint ligands/receptors (ICLs/ICRs) expression pattern. Importantly, the KRAS/TP53 dual mutations significantly reduced the major energy metabolic functions in immune cells, and promoted the cell-to-cell communications towards immunosuppression in colorectal cancers. The results revealed LAG3, CD24-SIGLEC10 and HBEGF-CD9 pathways as potential therapeutic targets for dual mutant colorectal cancers.

Conclusions

We revealed that the immune microenvironment underwent a gradual remodeling with an enrichment of immunosuppressive myeloid cells from normal mucosa to tumor regions in colorectal cancers. Moreover, we revealed the metabolic heterogeneity of tumor-infiltrating immune cells and suggested that the KRAS/TP53 dual mutation may impair antitumor immunity by reducing T and myeloid cell energy metabolism and reshaping cellular interactions toward immunosuppression.
Immunoprofiling of monocytes in STAT1 gain-of-function chronic mucocutaneous candidiasis
Authors: Bloomfield Marketa , Zentsova Irena , Milota Tomas , Sediva Anna , Parackova Zuzana
Published: September 2022

Patients with STAT1 gain-of-function (GOF) mutations suffer from an inborn error of immunity hallmarked by chronic mucocutaneous candidiasis (CMC). The pathogenesis behind this complex and heterogeneous disease is still incompletely understood. Beyond the well-recognized Th17 failure, linked to the STAT1/STAT3 dysbalance-driven abrogation of antifungal defense, only little is known about the consequences of augmented STAT1 signaling in other cells, including, interestingly, the innate immune cells. STAT1-mediated signaling was previously shown to be increased in STAT1 GOF CD14+ monocytes. Therefore, we hypothesized that monocytes might represent important co-orchestrators of antifungal defense failure, as well as various immunodysregulatory phenomena seen in patients with STAT1 GOF CMC, including autoimmunity. In this article, we demonstrate that human STAT1 GOF monocytes are characterized by proinflammatory phenotypes and a strong inflammatory skew of their secretory cytokine profile. Moreover, they exhibit diminished CD16 expression, and reduction of classical (CD14++C16-) and expansion of intermediate (CD14++16+) subpopulations. Amongst the functional aberrations, a selectively enhanced responsiveness to TLR7/8 stimulation, but not to other TLR ligands, was noted, which might represent a contributing mechanism in the pathogenesis of STAT1 GOF-associated autoimmunity. Importantly, some of these features extend to STAT1 GOF monocyte-derived dendritic cells and to STAT1 GOF peripheral myeloid dendritic cells, suggesting that the alterations observed in monocytes are, in fact, intrinsic due to STAT1 mutation, and not mere bystanders of chronic inflammatory environment. Lastly, we observe that the proinflammatory bias of STAT1 GOF monocytes may be ameliorated with JAK inhibition. Taken together, we show that monocytes likely play an active role in both the microbial susceptibility and autoimmunity in STAT1 GOF CMC.
CXCL13 is elevated in inflammatory bowel disease in mice and humans and is implicated in disease pathogenesis
Authors: Liu Ting , Liu Yu , Liu Chen-xi , Jiang Yong-mei
Published: September 2022

CXCL13 is a chemokine that is widely involved in the pathogenesis of autoimmune diseases, tumors and inflammatory diseases. In this study, we investigate the role of CXCL13 in the pathogenesis of inflammatory bowel disease using both clinical specimens and animal models. We found that the serum CXCL13 concentration in IBD patients was significantly higher than that in healthy controls, and correlated with that of CRP, neutrophils counts and hemoglobin. The increase of CXCL13 in IBD patients might be related to the significant decrease of circulating CD4+CXCR5+ T cells, the increase of CD19+CD5+ B cells and the enhancement of humoral immunity. In mice colitis model, we also found elevated levels of CXCL13 in colon tissue. Cxcl13-/- knockout mice exhibited a mild, self-limiting form of disease. Additionally, CXCL13 deficiency restricted CD4+CXCR5+ T cells migration in mesenteric lymph nodes, resulting locally regulatory B cells increased in colon. In conclusion, our findings raise the possibility that CXCL13 plays a critical role in the pathogenesis of IBD. We believe that our findings will contribute to the understanding of the etiology, and that antagonizing or inhibiting CXCL13 may work as a potential adjunctive therapy strategy for patients with IBD.
Manipulation of tissue factor-mediated basal PAR-2 signalling on macrophages determines sensitivity for IFNγ responsiveness and significantly modifies the phenotype of murine DTH
Authors: Wilkinson Hannah , Leonard Hugh , Robson Michael G. , Smith Richard , Tam ElLi , McVey John H. , Kirckhofer Daniel , Chen Daxin , Dorling Anthony
Published: September 2022

Background

Tissue factor (TF) generates proteases that can signal through PAR-1 and PAR-2. We have previously demonstrated PAR-1 signalling primes innate myeloid cells to be exquisitely sensitive to interferon-gamma (IFNγ). In this work we explored how TF mediated PAR-2 signalling modulated responsiveness to IFNγ and investigated the interplay between PAR-1/-2 signalling on macrophages.

Methodology

We characterised how TF through PAR-2 influenced IFNγ sensitivity in vitro using PCR and flow cytometry. and how it influenced oxazolone-induced delayed type hypersensitivity (DTH) responses in vivo. We investigated how basal signalling through PAR-2 influenced PAR-1 signalling using a combination of TF-inhibitors and PAR-1 &-2 agonists and antagonists. Finally, we investigated whether this system could be targeted therapeutically using 3-mercaptopropionyl-F-Cha-Cha-RKPNDK (3-MP), which has actions on both PAR-1 and -2.

Results

TF delivered a basal signal through PAR-2 that upregulated SOCS3 expression and blunted M1 polarisation after IFNγ stimulation, opposing the priming achieved by signalling through PAR-1. PAR-1 and -2 agonists or antagonists could be used in combination to modify this basal signal in vitro and in vivo. 3-MP, by virtue of its PAR-2 agonist properties was superior to agents with only PAR-1 antagonist properties at reducing M1 polarisation induced by IFNγ and suppressing DTH. Tethering a myristoyl electrostatic switch almost completely abolished the DTH response.

Conclusions

TF-mediated signalling through PARs-1 and -2 act in a homeostatic way to determine how myeloid cells respond to IFNγ. 3-MP, an agent that simultaneously inhibits PAR-1 whilst delivering a PAR-2 signal, can almost completely abolish immune responses dependent on M1 polarisation, particularly if potency is enhanced by targeting to cell membranes; this has potential therapeutic potential in multiple diseases.
Pre-clinical development of a vaccine for human lymphatic filariasis
Authors: Melendez Valeria , Turner Cheri , Khatri Vishal , Davis Jenn , Chauhan Nikhil , Nagalati Sudhakar Divya Sree , Cabullos Richard , Carter Darrick , Gray Sean A. , Kalyanasundaram Ramaswamy
Published: September 2022

This study was conducted to optimize a fusion protein vaccine for translational development as a vaccine against the human tropical parasitic infection, lymphatic filariasis (LF). The vaccine candidate, His-tagged rBmHAXT was developed previously in our laboratory and was tested in various animal models including mouse, gerbils and Rhesus macaque where it exhibited significant levels of vaccine-induced protection. However, for commercial manufacturing and for regulatory approval for human use, there was a need to modify the vaccine antigen and its production and analytical release methods. Therefore, the major focus of this study was to develop a process for manufacturing an affinity tag-free rBmHAXT and evaluate its immunogenicity, potency and protective efficacy in both inbred and outbred mouse models, as well as in outbred gerbil models. Our results demonstrate that the tag-free rBmHAXT vaccine produced with a process suitable for cGMP production had protective properties equivalent to the original His-tagged rBmHAXT.
Inter-individual variability of early life stages of a model marine invertebrate with a bi-phasic life cycle is shaped by contrasting oceanographic conditions
Authors: Leal Miguel Costa , Rey Felisa , Ferreira Guilherme Duarte , Domingues M. Rosário , Calado Ricardo
Published: September 2022

Inter-individual variability plays a key role in species resilience. This, however, is difficult to assess in marine invertebrates with complex life cycles due to the inherent difficulty of sampling individuals in oceanic environments throughout their ontogeny. This study monitored the effect of contrasting oceanographic conditions, namely downwelling and upwelling, on the inter-variability of embryos and megalopae (the final larval stage) of the model brachyuran crab Carcinus maenas. We assessed i) the heterogeneity of energetic reserves, biomass, elemental composition, and isotopic niche in these early life stages, and ii) the effect of oceanographic conditions (up- and downwelling) on inter-individual variability. Indeed, organisms developing during downwelling consistently exhibited a higher heterogeneity than those developing during upwelling. While this finding suggests a higher resilience during downwelling, the overall condition of individuals was better during upwelling (i.e., higher C:N), irrespective of the developmental stage. Altogether, our data suggests that trophic history experienced under contrasting oceanographic conditions shape the plasticity of C. maenas populations and cascades over different life stages.
Structural and functional characterization of Cas2 of CRISPR-Cas subtype I-C lacking the CRISPR component
Authors: Anand Vineet , Prabhakaran Harshini Sheeja , Gogoi Prerana , Kanaujia Shankar Prasad , Kumar Manish
Published: September 2022

The genome of pathogenic Leptospira interrogans serovars (Copenhageni and Lai) are predicted to have CRISPR-Cas of subtypes I-B and I-C. Cas2, one of the core Cas proteins, has a crucial role in adaptive defense against foreign nucleic acids. However, subtype I-C lacks the CRISPR element at its loci essential for RNA-mediated adaptive immunity against foreign nucleic acids. The reason for sustaining the expense of cas genes are unknown in the absence of a CRISPR array. Thus, Cas2C was chosen as a representative Cas protein from two well-studied serovars of Leptospira to address whether it is functional. In this study, the recombinant Cas2C of Leptospira serovars Copenhageni (rLinCas2C, 12 kDa) and Lai (rLinCas2C_Lai, 8.6 kDa) were overexpressed and purified. Due to natural frameshift mutation in the cas2c gene of serovar Lai, rLinCas2C_Lai was overexpressed and purified as a partially translated protein. Nevertheless, the recombinant Cas2C from each serovar exhibited metal-dependent DNase and metal-independent RNase activities. The crystal structure of rLinCas2C obtained at the resolution of 2.60 Å revealed the protein is in apostate conformation and contains N- (1–71 amino acids) and C-terminal (72–90 amino acids) regions, with the former possessing a ferredoxin fold. Substitution of the conserved residues (Tyr7, Asp8, Arg33, and Phe39) with alanine and deletion of Loop L2 resulted in compromised DNase activity. On the other hand, a moderate reduction in RNase activity was evident only in selective rLinCas2C mutants. Overall, in the absence of an array, the observed catalytic activity of Cas2C may be required for biological processes distinct from the CRISPR-Cas-associated function.
Natural frequencies of neural activities and cognitions may serve as precise targets of rhythmic interventions to the aging brain
Authors: Qiao Jingwen , Wang Yifeng , Wang Shouyan
Published: September 2022

Rhythmic neural activities are critical to the efficiency of regulatory procedures in brain functions. However, brain functions usually decline in aging as accompanied by frequency shift and temporal dedifferentiation of neural activities. Considering the strong oscillations and long-lasting after-effects induced by rhythmic brain stimulations, we suggest that non-invasive rhythmic brain stimulation technique may help restore the natural frequencies of neural activities in aging to that in younger and healthy brains. Although with tremendous work to do, this technique offers great opportunities for the restoration of normal brain functions in aging, or even in those suffering from neurodegenerative diseases and neuropsychiatric disorders.
Calcium/calmodulin-dependent protein kinase II associates with the K+ channel isoform Kv4.3 in adult rat optic nerve
Authors: Ogata Genki , Partida Gloria J. , Fasoli Anna , Ishida Andrew T.
Published: September 2022

Spikes are said to exhibit “memory” in that they can be altered by spikes that precede them. In retinal ganglion cell axons, for example, rapid spiking can slow the propagation of subsequent spikes. This increases inter-spike interval and, thus, low-pass filters instantaneous spike frequency. Similarly, a K+ ion channel blocker (4-aminopyridine, 4AP) increases the time-to-peak of compound action potentials recorded from optic nerve, and we recently found that reducing autophosphorylation of calcium/calmodulin-dependent protein kinase II (CaMKII) does too. These results would be expected if CaMKII modulates spike propagation by regulating 4AP-sensitive K+ channels. As steps toward identifying a possible substrate, we test whether (i) 4AP alters optic nerve spike shape in ways consistent with reducing K+ current, (ii) 4AP alters spike propagation consistent with effects of reducing CaMKII activation, (iii) antibodies directed against 4AP-sensitive and CaMKII-regulated K+ channels bind to optic nerve axons, and (iv) optic nerve CaMKII co-immunoprecipitates with 4AP-sensitive K+ channels. We find that, in adult rat optic nerve, (i) 4AP selectively slows spike repolarization, (ii) 4AP slows spike propagation, (iii) immunogen-blockable staining is achieved with anti-Kv4.3 antibodies but not with antibodies directed against Kv1.4 or Kv4.2, and (iv) CaMKII associates with Kv4.3. Kv4.3 may thus be a substrate that underlies activity-dependent spike regulation in adult visual system pathways.
Morning blue light treatment improves sleep complaints, symptom severity, and retention of fear extinction memory in post-traumatic stress disorder
Authors: Vanuk John R. , Pace-Schott Edward F. , Bullock Ayla , Esbit Simon , Dailey Natalie S. , Killgore William D. S.
Published: September 2022

Disrupted sleep is a major feature in numerous clinical disorders and is related to decrements in affective memory processing. The prevalence of sleep disruption in post-traumatic stress disorder (PTSD) is suggested to be a key feature that exacerbates the impaired ability to recall extinction memories during experimental fear conditioning. We hypothesized that an intervention employing blue-wavelength light therapy (BLT) to regulate sleep and stabilize circadian rhythms in patients with PTSD (i.e., via regulated morning exposure) would be associated with PTSD symptom improvement, decreased sleep-related complaints, as well as improved consolidation and retention of extinction memories relative to a fear conditioning/extinction paradigm. Eighty-two individuals with PTSD underwent a well-validated fear conditioning/extinction protocol with subsequent assignment to receive morning BLUE (BLT) or placebo AMBER (ALT) light therapy daily for 30-min over 6-weeks. Participants returned after the intervention for post-treatment extinction recall, comprised of exposure to the previously conditioned stimuli, with the difference in skin conductance response between the “extinguished” and the “never-extinguished” stimuli at follow-up. Participants also viewed previously conditioned stimuli in a novel context during a functional magnetic resonance imaging (fMRI) scan. BLUE light therapy was associated with improvements relative to correlated decreases between PTSD symptoms and sleep-related complaints. Participants receiving BLT also sustained retention of the extinction memory, while those in the placebo amber light treatment group showed impairment, characterized by the restoration of the extinguished fear response after 6-weeks. Participants in the ALT also demonstrated greater reactivity in the left insula when viewing the previously extinguished fear-conditioned stimuli in a novel context. Daily BLUE-wavelength morning light exposure was associated with greater retention of extinction learning in patients with PTSD when compared to ALT, as supported by both autonomic and neurobiological reactivity. We speculate that improved sleep facilitated by a stabilized circadian rhythm, after fear-learning, led to greater consolidation of the fear extinction memory, decreased PTSD symptom presentation, and associated decreases in sleep-related complaints. Prominent exposure treatments for PTSD incorporate principles of fear extinction, and our findings suggest that blue light treatment may facilitate treatment gains by promoting the consolidation of extinction memories via improved sleep.
Tryptophan metabolites in depression: Modulation by gut microbiota
Authors: Lukić Iva , Ivković Sanja , Mitić Miloš , Adžić Miroslav
Published: September 2022

Clinical depression is a multifactorial disorder and one of the leading causes of disability worldwide. The alterations in tryptophan metabolism such as changes in the levels of serotonin, kynurenine, and kynurenine acid have been implicated in the etiology of depression for more than 50 years. In recent years, accumulated evidence has revealed that gut microbial communities, besides being essential players in various aspects of host physiology and brain functioning are also implicated in the etiology of depression, particularly through modulation of tryptophan metabolism. Therefore, the aim of this review is to summarize the evidence of the role of gut bacteria in disturbed tryptophan metabolism in depression. We summed up the effects of microbiota on serotonin, kynurenine, and indole pathway of tryptophan conversion relevant for understanding the pathogenesis of depressive behavior. Moreover, we reviewed data regarding the therapeutic effects of probiotics, particularly through the regulation of tryptophan metabolites. Taken together, these findings can open new possibilities for further improvement of treatments for depression based on the microbiota-mediated modulation of the tryptophan pathway.
The viral and inflammation hypothesis of epileptic seizures based on bioinformatic study of circulating miRNAs and peripheral whole-blood mRNAs of adult epilepsy patients
Authors: Wu Jiahuan , Meng Ying , Xu Fei , Wu Qian , Wang Cheng
Published: September 2022

Background

The study aimed to investigate the genome-wide biological significance of the circulating miRNAs markers found in peripheral whole blood of adult epileptic seizures patients by integrating analysis using bioinformatics approaches.

Methods

The Gene Expression Omnibus (GEO) dataset was accessed to retrieve epilepsy-related circulating miRNA profile data (GSE114847) including 89 subjects (n = 40 epileptic and n = 49 healthy control), peripheral whole-blood mRNA expression data (GSE143772) including 64 subjects (n = 32 epileptic and n = 32 healthy control). To eliminate age disparities in epilepsy pathophysiology only adult epileptic patients were selected. Furthermore, GEO2R was used to identify adult-related mRNAs (AD-mRNAs) against epilepsy as potential biomarkers. Moreover, to predict the potential target genes for these mRNAs, we used mirWalk. Finally, the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were utilized to investigate the biological activities of AD-mRNAs. Importantly, the protein–protein network of these identified AD-mRNAs was constructed. Eventually, the overlapping AD-mRNAs and AD-miRNAs and their functions were explored to shortlist potential AD-epileptic markers.

Result

The current study resulted in the identification of 79 upregulated and 40 downregulated different expression gene (DEGs) in both applied data. These targets were cross-linked and mapped with each other to acquire common adult epilepsy-related overlapped mRNAs (Mo-mRNAs). It was found that there was a total of 36 overlapping genes. These overlapped AD-mRNAs markers were found to be functionally enriched in cell regulating pathways i.e., positive regulation of type 1 interferon signaling pathway and mitochondrial cytochrome C release pathway, respectively.

Conclusion

This research gives a comprehensive depiction of the mRNAs that may be involved in adult epilepsy patients' pathophysiological progressions.
Functional network alterations in young brain tumor patients with radiotherapy-induced memory impairments and vascular injury
Authors: Morrison Melanie A. , Walter Sadie , Mueller Sabine , Felton Erin , Jakary Angela , Stoller Schuyler , Molinaro Annette M. , Braunstein Steve E. , Hess Christopher P. , Lupo Janine M.
Published: September 2022

Background

Cognitive impairment and cerebral microbleeds (CMBs) are long-term side-effects of cranial radiation therapy (RT). Previously we showed that memory function is disrupted in young patients and that the rate of cognitive decline correlates with CMB development. However, vascular injury alone cannot explain RT-induced cognitive decline. Here we use resting-state functional MRI (rsfMRI) to further investigate the complex mechanisms underlying memory impairment after RT.

Methods

Nineteen young patients previously treated with or without focal or whole-brain RT for a brain tumor underwent cognitive testing followed by 7T rsfMRI and susceptibility-weighted imaging for CMB detection. Global brain modularity and efficiency, and rsfMRI signal variability within the dorsal attention, salience, and frontoparietal networks were computed. We evaluated whether MR metrics could distinguish age- and sex-matched controls (N = 19) from patients and differentiate patients based on RT exposure and aggressiveness. We also related MR metrics with memory performance, CMB burden, and risk factors for cognitive decline after RT.

Results

Compared to controls, patients exhibited widespread hyperconnectivity, similar modularity, and significantly increased efficiency (p < 0.001) and network variability (p < 0.001). The most abnormal values were detected in patients treated with high dose whole-brain RT, having supratentorial tumors, and who did not undergo RT but had hydrocephalus. MR metrics and memory performance were correlated (R = 0.34–0.53), though MR metrics were more strongly related to risk factors for cognitive worsening and CMB burden with evidence of functional recovery.

Conclusions

MR metrics describing brain connectivity and variability represent promising candidate imaging biomarkers for monitoring of long-term cognitive side-effects after RT.
Neuromyelitis optica spectrum disorder in Western China impacts employment and increases financial burden in women
Authors: Han Lin , Hong Peiwei , Wan Yang , Cai Linjun , Shi Ziyan , Wang Jiancheng , Lang YanLin , Zhou Hongyu
Published: September 2022

Background

Neuromyelitis optica spectrum disorder (NMOSD) often leads to disability and exerts a heavy toll on the work and life of affected female patients. This study aimed to analyze the current employment situation and economic burden as well as the risk factors for unemployment in female patients with NMSOD.

Methods

We compared the following unemployment- and employment-related aspects in with NSMOD, which were investigated using questionnaires: the specific impact of NMOSD on work, medical expenses, and factors affecting unemployment.

Results

We enrolled 351 female patients with NMOSD. More than half (54.1%, 190/351) of participants reported that the disease led to unemployment. The unemployment group was significantly older (46.9 ± 12.1 years vs. 39.3 ± 9.4 years, P = 0.000), had a higher annual recurrence rate (ARR) (0.6 [inter quartile range [IQR]:0.4–0.9] vs. 0.5 [IQR: 0.3–0.8], P = 0.141), and a higher severe disability rate (44.2% vs. 11.2%, P = 0.000) than the employment group. Moreover, unemployed patients had lower education levels. The factors influencing unemployment included low education (junior middle-school or below), age, higher ARR, and severe disability (odds ratio [OR] = 6.943, P = 0.000; OR = 1.034, P = 0.010; OR = 1.778, P = 0.038; and OR = 4.972, P = 0.000, respectively). Medication and hospitalization costs constituted the principal economic burdens.

Conclusion

The heavy financial burden, employment difficulties, and high unemployment rate are the most prominent concerns of female patients with NMOSD who require more social support and concern.
Efficacy of idebenone in the Treatment of iRBD into Synucleinopathies (EITRS): rationale, design, and methodology of a randomized, double-blind, multi-center clinical study
Authors: Li Yuanyuan , Wang Chunyi , Luo Ningdi , Chen Fangzheng , Zhou Liche , Niu Mengyue , Kang Wenyan , Liu Jun
Published: September 2022

Background

As the strongest prodromal marker of α-synuclein-specific neurodegeneration, idiopathic REM sleep behavior disorder (iRBD) is becoming a focus of interest in disease-modifying therapy. Idebenone has been widely portrayed as a potent antioxidant targeting mitochondrial dysfunction. Previous study has identified the effect of idebenone on Parkinson's disease with promising outcomes by regulating mitophagy. A novel indication of idebenone should be highlighted in iRBD population.

Methods

The EITRS study is a randomized, double-blind, multi-center clinical study assessing the efficacy and safety of idebenone in the treatment of iRBD into synucleinopathies. One hundred forty-two patients (aged 40–75 years old) with clinically diagnosed iRBD are planned to be recruited with 80% statistical power and randomly assigned to idebenone (30 mg each time, three times a day) or matching placebo orally for 5 years. The assessment of rating scales, blood testing and neuroimaging examinations will be conducted at baseline, the 1st, 3rd and 5th year of follow-up. The primary efficacy endpoint is the 5-year conversion rate in patients with iRBD. The secondary endpoint is the safety and tolerability of idebenone in the treatment of iRBD. The study has been launched in July 2020.

Discussion

This is the first prospective study designed to identify the efficacy and safety of idebenone on the treatment of iRBD into synucleinopathies. The current results are expected to promote the development of evidence-based recommendations for the management of patients with iRBD. Furthermore, we hope to provide insights on a possible disease-modifying approach with robust evidence.

Trial Registration

Clinicaltrials.gov, identifier: NCT 04534023.
Baseline blood pressure does not modify the effect of intravenous thrombolysis in successfully revascularized patients
Authors: Xiaoxi Zhang , Xuan Zhu , Lei Zhang , Zifu Li , Pengfei Xing , Hongjian Shen , Yongxin Zhang , Weilong Hua , Yihan Zhou , Dongwei Dai , Qiang Li , Rui Zhao , Qinghai Huang , Yi Xu , Song Lili , Anderson Craig S. , Jianmin Liu , Yongwei Zhang , Pengfei Yang
Published: September 2022

Background

Studies indicate a trajectory relationship between baseline blood pressure (BP) and outcome in patients with acute ischemic stroke (AIS) eligible for both intravenous thrombolysis (IVT) with alteplase and endovascular treatment (EVT). We determined whether baseline BP modified the effect of IVT in successfully revascularized AIS patients who participated in the Direct Intra-Arterial Thrombectomy to Revascularize AIS Patients With Large Vessel Occlusion Efficiently in Chinese Tertiary Hospitals (DIECT-MT) trial.

Methods

The association of baseline systolic BP, trichotomized as high (141–185 mmHg), middle (121–140 mmHg), and low (91–120 mmHg), and the outcomes of any intracerebral hemorrhage (ICH), symptomatic ICH (sICH), and mortality and functional outcome on the modified Rankin scale at 90 days were explored. Logistic regression models determined the interaction between clinical outcomes and baseline systolic and diastolic BP, and mean arterial pressure (MAP), at 10 mmHg intervals. Data are reported as odds ratios (OR) and 95% CI.

Results

A post-hoc analysis of DIRECT-MT, in 510 of the 656 randomized participants with successful revascularization underwent MT. The overall adjusted common OR of IVT and baseline BP on any ICH, sICH, and 90-day mortality and functional outcome were 0.884 (95%CI 0.613–1.274), 0.643 (95%CI 0.283–1.458), 0.842 (95%CI 0.566–1.252), and 1.286 (95%CI 0.772–2.142), respectively. No significant interaction between baseline blood pressure and intravenous thrombolysis with clinical outcome was observed.

Conclusions

In patients with baseline SBP under 185 mmHg, baseline blood pressure does not alter the risk of hemorrhagic transformation and clinical

outcome in successfully revascularized patients, regardless of intravenous alteplase usage. Future studies are needed to confirm our findings.

Registration

URL: http://www.clinicaltrials.gov, Identifier: NCT03469206.
Breast microbiome associations with breast tumor characteristics and neoadjuvant chemotherapy: A case-control study
Authors: Li Xuejun , Sun Xiaohu , Zhang Ai , Pang Jing , Li Yun , Yan Mengfan , Xu Zhen , Yu Yue , Yang Zhengjun , Chen Xi , Wang Xin , Cao Xu-Chen , Tang Nai-jun
Published: September 2022

Background

Commensal microbiota have been proven to colonize the mammary gland, but whether their composition is altered in patients with breast cancer (BC) remains elusive. This study intends to explore the breast microbiome differences between benign and malignant diseases and to investigate the impact of neoadjuvant chemotherapy (NAC) on the breast microbiota in patients with BC.

Methods

Breast normal adipose tissues (NATs) were collected from 79 patients with BC and 15 controls between July 2019 and November 2021. The BC group consisted of 29 patients who had received NAC and 50 who were non-NAC patients. Participants diagnosed with benign breast disease were recruited as controls. 16S rRNA gene sequencing was used to analyze the bacterial diversity of NATs.

Results

The community structure of the NAT microbiome was significantly different between the BC and control groups. Proteobacteria decreased (47.40% versus 39.74%), whereas Firmicutes increased (15.71% versus 25.33%) in patients with BC when compared with that in control tissues. Nine genera were enriched in BC NATs, and four genera levels increased in the control group. The associations between differential bacterial genera and breast tumor grade were calculated by Spearman’s correlation. The results showed that tumor grade was positively associated with the relative abundance of Streptococcus and negatively related to Vibrio, Pseudoalteromonas, RB41, and Photobacterium. Moreover, menopause was associated with the microbiota composition change of non-NAC BC patients and related to the significant reduction in the abundance level of Pseudoalteromonas, Veillonella, and Alcaligenes. In addition, NAC was related to the beta diversity of patients with BC and associated with the decrease of Clostridium_sensu_stricto_7 and Clostridium_sensu_stricto_2 in postmenopausal patients. Of note, Tax4Fun functional prediction analysis revealed that the metabolic state was more exuberant in the BC group with upregulating of multiple metabolism-related pathways.

Conclusion

Our results offer new insight into the relationship between NAC and breast microbiota and help to better characterize the breast microbial dysbiosis that occurs in patients with BC. Further epidemiological studies with larger sample size and well-designed animal experiments are required to elucidate the role of breast microbiota in the therapeutic outcome of BC.
Comprehensive analysis of ECHDC3 as a potential biomarker and therapeutic target for acute myeloid leukemia: Bioinformatic analysis and experimental verification
Authors: Zhao Yijing , Niu Li-Ting , Hu Li-Juan , Lv Meng
Published: September 2022

Background

Enoyl-CoA hydratase domain containing 3 (ECHDC3) increased in CD34+ progenitor cells of acute myeloid leukemia (AML) cells after chemotherapy. However, the prognostic significance and function of ECHDC3 in AML remain to be clarified.

Methods

In the training cohort, 24 AML (non-acute promyelocytic leukemia, APL) patients were enrolled in Peking University People’s Hospital and tested for ECHDC3 in enriched CD34+ cells at diagnosis. In the validation set, 351 bone marrow RNA-seq data of non-APL AML were obtained by two independent online datasets (TCGA-LAML and BEAT-AML). LASSO regression model was conducted to a new prediction model of ECHDC3-related genes. In addition, the ECHDC3 signature was further explored by GO, KEGG, GSEA, and immuno-infiltration analysis. By RNA interference, the function of ECHDC3 in mitochondrial DNA (mt-DNA) transcriptome and chemoresistance was further explored, and the GSE52919 database re-verified the ECHDC3 chemoresistance feature.

Results

By Kaplan-Meier analysis, patients with ECHDC3high demonstrated inferior overall survival (OS) compared to those with ECHDC3low both in the training (2-year OS, 55.6% vs. 100%, p = 0.011) and validation cohorts (5-year OS, 9.6% vs. 24.3%, p = 0.002). In addition, ECHDC3high predicted inferior OS in the subgroup of patients with ELN 2017 intermediated (int) risk (5-year OS, 9.5% vs. 26.3%, p = 0.039) or FLT3+NPM1− adverse (adv) risk (4-year OS, 6.4% vs. 31.8%, p = 0.003). In multivariate analysis, ECHDC3 was an independent risk factor of inferior OS (HR 1.159, 95% CI 1.013–1.326, p = 0.032). In the prediction model combining ECHDC3 and nine selected genes (RPS6KL1, RELL2, FAM64A, SPATS2L, MEIS3P1, CDCP1, CD276, IL1R2, and OLFML2A) by Lasso regression, patients with high risk showed inferior 5-year OS (9.3% vs. 23.5%, p < 0.001). Bioinformatic analysis suggested that ECHDC3 alters the bone marrow microenvironment by inducing NK, resting mast cell, and monocyte differentiation. Knocking down ECHDC3 in AML cells by RNAi promoted the death of leukemia cells with cytarabine and doxorubicin.

Conclusion

These bioinformatic analyses and experimental verification indicated that high ECHDC3 expression might be a poor prognostic biomarker for non-APL AML, which might be a potential target for reverting chemoresistance.
Regular use of aspirin is associated with a lower cardiovascular risk in prostate cancer patients receiving gonadotropin-releasing hormone therapy
Authors: Chang Wei-Ting , Hong Chon-Seng , Hsieh Kun-Lin , Chen Yi-Chen , Ho Chung−Han , Shih Jhih-Yuan , Kan Wei-Chih , Chen Zhih-Cherng , Lin You-Cheng
Published: September 2022

Gonadotropin-releasing hormone (GnRH) therapy has been known to increase risks of major adverse cardiovascular and cerebrovascular events (MACCEs). Herein, we aim to estimate whether regular use of aspirin attenuates risks of MACCEs in prostate cancer patients receiving GnRHs. Using Taiwanese National Health Insurance Research Database (NHIRD), we identified 7719 patients diagnosed with prostate cancer who were either aspirin-naïve, received irregular or regular aspirin from 2008 to 2015. Through a multivariable logistic regression model, we investigated the impact of aspirin on MACCEs. Compared with nonusers and irregular users, most patients receiving regular aspirin were older and had more comorbidities. The crude incidence of one-year MACCEs was lowest in aspirin nonusers but highest in irregular users of aspirin compared with regular users of aspirin (2.65% vs. 4.41% vs. 2.85%, p=0.0099). After adjusting for age, cancer stage and comorbidities, irregular aspirin users had a higher risk of one-year MACCEs (adjusted OR: 1.33; 95% CI: 0.93-1.90, p=0.1139) than aspirin nonusers, but conversely, there was a trend of reducing the risk of MACCEs among those who received regular aspirin (adjusted OR: 0.79; 95% CI: 0.44-1.42, p=0.4256). In the subgroup analysis, there were age- and cancer stage-independent higher risks of MACCEs in patients who took aspirin irregularly compared to those in patients who did not take aspirin. The risks were attenuated in patients receiving regular aspirin. Collectively, regular use of aspirin presented a trend of reducing risks of MACCEs in prostate cancer patients receiving GnRHs. However, irregular use of aspirin diminished the benefits.
Regulation and roles of FOXK2 in cancer
Authors: Kang Yuanyuan , Zhang Kexin , Sun Lixue , Zhang Ying
Published: September 2022

Forkhead box K2 (FOXK2) is a member of the forkhead box transcription factor family that contains an evolutionarily conserved winged-helix DNA-binding domain. Recently, an increasing number of studies have demonstrated that FOXK2 plays an important role in the transcriptional regulation of cancer. Here, we provide an overview of the mechanisms underlying the regulation of FOXK2 expression and function and discuss the roles of FOXK2 in tumor pathogenesis. Additionally, we evaluated the prognostic value of FOXK2 expression in patients with various cancers. This review presents an overview of the different roles of FOXK2 in tumorigenesis and will help inform the design of experimental studies involving FOXK2. Ultimately, the information presented here will help enhance the therapeutic potential of FOXK2 as a cancer target.
Movement behaviours in paediatric cancer survivors during recovery and school weeks
Authors: Vyhlídal Tomáš , Dygrýn Jan , Pelclová Jana , Chmelík František
Published: September 2022

Purpose

Paediatric cancer survivors (PCS) are a high-risk population, who can suffer from late effects of their treatment, such as metabolic syndrome, cardiovascular conditions, secondary tumours. Optimal movement behaviours (e.g., limited sedentary behaviour [SB] and sufficient physical activity [PA]) can reduce the side effects or avoid late effects of their treatment. The aims of this study were to analyse movement behaviours and meeting the recommendation of 60 minutes of moderate-to-vigorous physical activity (MVPA) a day in Czech PCS, and to compare their movement behaviours during recovery and school weeks in relation to gender, age, and cancer type.

Methods

Twenty-six PCS aged 7-15 years in remission stage took part in the cross-sectional study. Movement behaviours were measured with Actigraph wGT3X+ accelerometers worn 24 hour/day for 20 consecutive days covering recovery week (13 days at recovery camp) and school week (7 days). Based on cancer types, the PCS were categorized into haematological malignancy or solid tumours group.

Results

In the PCS, movement behaviours differed between recovery and school weeks. During recovery week, the PCS showed less SB (451.8 vs. 552.3 min/day, p < 0.001) and spent more time on light PA (350.3 vs. 255.1 min/day, p < 0.001), moderate PA (73.2 vs. 37.4 min/day, p < 0.001), and vigorous PA (10.3 vs. 4.0 min/day p < 0.001) than during school week. The PA recommendation was met by 77% (n = 20) PCS during recovery week, but only by 15% (n = 4) individuals during school week.

Conclusions

The PCS recorded higher levels of PA and lower levels of SB during recovery week than during school week. If provided with appropriate conditions, PCS in the remission stage are able to reach the PA level recommended for the healthy population. Recovery week can be a suitable platform for gaining experience that PCS are able to meet the recommended PA level and could be an integral part of reconditioning and resocialization programmes for PCS after the completion of their treatment.