bluuebunny/crossref_metadata_2025 huggingface dataset:
Construction and validation of a novel and superior protein risk model for prognosis prediction in esophageal cancer
Authors: Liu Yang , Wang Miaomiao , Lu Yang , Zhang Shuyan , Kang Lin , Zheng Guona , Ren Yanan , Guo Xiaowan , Zhao Huanfen , Hao Han
Published: November 2022

Esophageal cancer (EC) is recognized as one of the most common malignant tumors in the word. Based on the biological process of EC occurrence and development, exploring molecular biomarkers can provide a good guidance for predicting the risk, prognosis and treatment response of EC. Proteomics has been widely used as a technology that identifies, analyzes and quantitatively acquires the composition of all proteins in the target tissues. Proteomics characterization applied to construct a prognostic signature will help to explore effective biomarkers and discover new therapeutic targets for EC. This study showed that we established a 8 proteins risk model composed of ASNS, b-Catenin_pT41_S45, ARAF_pS299, SFRP1, Vinculin, MERIT40, BAK and Atg4B via multivariate Cox regression analysis of the proteome data in the Cancer Genome Atlas (TCGA) to predict the prognosis power of EC patients. The risk model had the best discrimination ability and could distinguish patients in the high- and low-risk groups by principal component analysis (PCA) analysis, and the high-risk patients had a poor survival status compared with the low-risk patients. It was confirmed as one independent and superior prognostic predictor by the receiver operating characteristic (ROC) curve and nomogram. K-M survival analysis was performed to investigate the relationship between the 8 proteins expressions and the overall survival. GSEA analysis showed KEGG and GO pathways enriched in the risk model, such as metabolic and cancer-related pathways. The high-risk group presented upregulation of dendritic cells resting, macrophages M2 and NK cells activated, downregulation of plasma cells, and multiple activated immune checkpoints. Most of the potential therapeutic drugs were more appropriate treatment for the low-risk patients. Through adequate analysis and verification, this 8 proteins risk model could act as a great prognostic evaluation for EC patients and provide new insight into the diagnosis and treatment of EC.
ClNAC84 interacts with ClMIP to regulate the cell cycle and reduce the size of Chrysanthemum lavandulifolium organs
Authors: Gao Ri , Wang Haibin , Qi Xiangyu , Zhu Lu , Yang Xiaodong , Chen Sumei , Jiang Jiafu , Wang Zhenxing , Chen Fadi
Published: November 2022

The NAC transcription factor is plant-specific proteins and one of the largest families of transcription factors in plants. NAC proteins are involved in various aspects of plant growth and development, but little is known about how NAC proteins regulate the cell cycle. Here, we characterized ClNAC84 from C. lavandulifolium (an NAC transcription factor). ClNAC84 overexpression in C. lavandulifolium resulted in a semi-dwarf phenotype with shorter plant height, smaller leaf size, and smaller flower size than wild-type plants. The number of cells in the S phase during the cell cycle was less in ClNAC84-overexpression transgenic C. lavandulifolium than in wild-type C. lavandulifolium. This indicates that ClNAC84 overexpression can induce cell cycle arrest at the S and G2 phases. To elucidate the ClNAC84 regulatory network, ClMIP protein was shown to interact with ClNAC84 in vitro and in vivo. ClMIP overexpression in C. lavandulifolium also resulted in dwarfism and decreased cell numbers, and the expression level of ClKRP5 was higher in transgenic C. lavandulifolium than in wild-type plants. We also found that ClMIP can bind to the promoter of ClKRP5. Our data indicate that the interaction between ClNAC84 and ClMIP may promote ClKRP5 expression and inhibit S and G2 phases of the cell cycling.
Morphine suppresses peripheral responses and transforms brain myeloid gene expression to favor neuropathogenesis in SIV infection
Authors: Fox Howard S. , Niu Meng , Morsey Brenda M. , Lamberty Benjamin G. , Emanuel Katy , Periyasamy Palsamy , Callen Shannon , Acharya Arpan , Kubik Gregory , Eudy James , Guda Chittibabu , Dyavar Shetty Ravi , Fletcher Courtney V. , Byrareddy Siddappa N. , Buch Shilpa
Published: November 2022

The twin pandemics of opioid abuse and HIV infection can have devastating effects on physiological systems, including on the brain. Our previous work found that morphine increased the viral reservoir in the brains of treated SIV-infected macaques. In this study, we investigated the interaction of morphine and SIV to identify novel host-specific targets using a multimodal approach. We probed systemic parameters and performed single-cell examination of the targets for infection in the brain, microglia and macrophages. Morphine treatment created an immunosuppressive environment, blunting initial responses to infection, which persisted during antiretroviral treatment. Antiretroviral drug concentrations and penetration into the cerebrospinal fluid and brain were unchanged by morphine treatment. Interestingly, the transcriptional signature of both microglia and brain macrophages was transformed to one of a neurodegenerative phenotype. Notably, the expression of osteopontin, a pleiotropic cytokine, was significantly elevated in microglia. This was especially notable in the white matter, which is also dually affected by HIV and opioids. Increased osteopontin expression was linked to numerous HIV neuropathogenic mechanisms, including those that can maintain a viral reservoir. The opioid morphine is detrimental to SIV/HIV infection, especially in the brain.
Development and validation of immunogenic cell death-related signature for predicting the prognosis and immune landscape of uveal melanoma
Authors: Hu Yuanyuan , Cai Jiayang , Ye Meng , Mou Qianxue , Zhao Bowen , Sun Qian , Lou Xiaotong , Zhang Hong , Zhao Yin
Published: November 2022

Introduction

Uveal melanoma (UM) is the most common primary intraocular malignant tumor in adults, and the main treatment for UM is currently surgery and plaque brachytherapy. UM is highly susceptible to metastasis, which eventually occurs in nearly half of all patients; once metastasis occurs, patients have a poor prognosis and the condition is difficult to treat. Therefore, the identification of new and effective UM biomarkers is vital for the application of therapeutic strategies. Immunogenic cell death (ICD) is a type of regulatory cell death that activates adaptive immune responses and generates long-term immunological memory. ICD can promote antitumor immunity, which may be a potential immunotherapeutic strategy for UM.

Methods

The data of UM from the Cancer Genome Atlas (TCGA) was used as a training set and the data from Gene Expression Omnibus (GEO) was used as a validation set. To determine the expression pattern of ICD-related genes in UM, survival analysis and difference analysis was conducted. The ICD-related risk signature was constructed by employing the least absolute shrinkage and selection operator (LASSO) Cox regression. Subsequently, immune profile and somatic mutation analysis were performed. In addition, cell experiments were performed to verify the role of immunogenic cell death-related genes in UM.

Results

In this study, we analyzed the relationship between ICD-related gene expression and UM patient prognosis, somatic mutations, and the tumor immune microenvironment. Importantly, we constructed a 5-gene ICD-related risk signature and confirmed it as a novel prognostic biomarker in UM patients. We found that the high-risk group had more immune cell infiltration and a worse prognosis than the low-risk group. In cellular experiments, we confirmed the high expression of FOXP3 inMUM2B andOCM-1A cell lines and that knockdown of FOXP3 markedly inhibited the proliferation of UM tumor cells.

Discussion

ICD-related genes play a critical role in the tumor immune microenvironment. Our results may contribute to the development of effective immunotherapies.
Multiple sclerosis and obesity: The role of adipokines
Authors: Correale Jorge , Marrodan Mariano
Published: November 2022

Multiple Sclerosis (MS), a chronic inflammatory disease of the central nervous system that leads to demyelination and neurodegeneration has been associated with various environmental and lifestyle factors. Population-based studies have provided evidence showing the prevalence of MS is increasing worldwide. Because a similar trend has been observed for obesity and metabolic syndrome, interest has grown in possible underlying biological mechanisms shared by both conditions. Adipokines, a family of soluble factors produced by adipose tissue that participate in a wide range of biological functions, contribute to a low state of chronic inflammation observed in obesity, and influence immune function, metabolism, and nutritional state. In this review, we aim to describe epidemiological and biological factors common to MS and obesity, as well as provide an update on current knowledge of how different pro- and anti-inflammatory adipokines participate as immune response mediators in MS, as well as in the animal model for MS, namely, experimental autoimmune encephalomyelitis (EAE). Multiple Sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) leading to demyelination, and neurodegeneration. Although its pathogenesis is not yet fully understood, there is considerable evidence to suggest MS arises from complex interactions between individual genetic susceptibility and external environmental factors. In recent decades, population-based studies have provided evidence indicating the prevalence of MS is increasing worldwide, in parallel with the rise in obesity and metabolic syndrome. This synchronous increment in the incidence of both MS and obesity has led to a search for potential biological mechanisms linking both conditions. Notably, a large number of studies have established significant correlation between obesity and higher prevalence, or worse prognosis, of several immune-mediated conditions. Fat tissue has been found to produce a variety of soluble factors named adipokines. These mediators, secreted by both adipocytes as well as diverse immune cells, participate in a wide range of biological functions, further strengthening the concept of a link between immune function, metabolism, and nutritional state. Because obesity causes overproduction of pro-inflammatory adipokines (namely leptin, resistin and visfatin) and reduction of anti-inflammatory adipokines (adiponectin and apelin), adipose tissue dysregulation would appear to contribute to a state of chronic, low-grade inflammation favoring the development of disease. In this review, we present a summary of current knowledge related to the pathological effects of different adipokines, prevalent in obese MS patients.
Integrated multi-omics analysis identifies CD73 as a prognostic biomarker and immunotherapy response predictor in head and neck squamous cell carcinoma
Authors: Shen Ao , Ye Yafen , Chen Fan , Xu Yunyun , Zhang Zhen , Zhao Qi , Zeng Zhao-lei
Published: November 2022

Background

Advances in tumor immunotherapy have been developed for patients with advanced recurrent or metastatic (R/M) HNSCC. However, the response of most HNSCC patients to immune checkpoint inhibitors (ICI) remains unsatisfactory. CD73 is a promising target for tumor immunotherapy, but its role in HNSCC remains insufficient. In this study, we aim to explore the function of CD73 in HNSCC.

Methods

Transcriptomic and clinical data of TCGA-HNSC were downloaded from UCSC Xena for analysis of CD73 mRNA expression and prognosis. Immunohistochemical assay were performed to validate the expression of CD73 in tumor tissues and its relationship with CD8+ T cells. GSEA analysis was performed with the “clusterProfiler” R package. Immune infiltration analysis was calculated with ESTIMATE, CIBERSORT and MCP-counter algorithms. Single-cell transcriptomic data was originated from GSE103322. Cell clustering, annotation and CD73 expression were from the TISCH database. Correlation data between CD73 and tumor signatures were obtained from the CancerSEA database. Somatic mutation data were obtained from TCGA-HNSC and analyzed by “maftools” R package. Immune efficacy prediction was performed using TIDE algorithm and validated with the IMvigor210 cohort.

Results

Compared with normal tissues, both mRNA and protein expressions of CD73 were elevated in tumor tissues (P = 9.7×10-10, P = 7.6×10-5, respectively). Kaplan-Meier analysis revealed that patients with high expression of CD73 had worse overall survival (log-rank P = 0.0094), and CD73 could be used as a diagnostic factor for HNSCC (AUC = 0.778). Both bulk RNA-seq and single-cell RNA-seq analysis showed that high CD73 expression can promote EMT and metastasis, samples with high CD73 expression had reduced CD8+ T cells. Furthermore, it was found that CD73-high group was more prone to have mutations in TP53, HRAS and CDKN2A, and were negatively correlated with TMB (P = 0.0055) and MSI (P = 0.00034). Mutational signature analysis found that CD73 was associated with APOBEC signature. Immunotherapy efficacy analysis showed that CD73-high group was less sensitive to immune efficacy.

Conclusions

Our results demonstrate that CD73 has an inhibitory effect on the tumor microenvironment, and is more likely to be unresponsive to ICI therapy. Collectively, targeting CD73 may provide new insights for tumor targeted therapy and/or immunotherapy.
Gata3ZsG and Gata3ZsG-fl: Novel murine Gata3 reporter alleles for identifying and studying Th2 cells and ILC2s in vivo
Authors: Gurram Rama K. , Wei Danping , Yu Qiao , Kamenyeva Olena , Chung Hyunwoo , Zheng Mingzhu , Butcher Matthew J. , Kabat Juraj , Liu Chengyu , Khillan Jaspal S. , Zhu Jinfang
Published: November 2022

T helper-2 (Th2) cells and type 2 innate lymphoid cells (ILC2s) play crucial roles during type 2 immune responses; the transcription factor GATA3 is essential for the differentiation and functions of these cell types. It has been demonstrated that GATA3 is critical for maintaining Th2 and ILC2 phenotype in vitro; GATA3 not only positively regulates type 2 lymphocyte-associated genes, it also negatively regulates many genes associated with other lineages. However, such functions cannot be easily verified in vivo because the expression of the markers for identifying Th2 and ILC2s depends on GATA3. Thus, whether Th2 cells and ILC2s disappear after Gata3 deletion or these Gata3-deleted “Th2 cells” or “ILC2s” acquire an alternative lineage fate is unknown. In this study, we generated novel GATA3 reporter mouse strains carrying the Gata3ZsG or Gata3ZsG-fl allele. This was achieved by inserting a ZsGreen-T2A cassette at the translation initiation site of either the wild type Gata3 allele or the modified Gata3 allele which carries two loxP sites flanking the exon 4. ZsGreen faithfully reflected the endogenous GATA3 protein expression in Th2 cells and ILC2s both in vitro and in vivo. These reporter mice also allowed us to visualize Th2 cells and ILC2s in vivo. An inducible Gata3 deletion system was created by crossing Gata3ZsG-fl/fl mice with a tamoxifen-inducible Cre. Continuous expression of ZsGreen even after the Gata3 exon 4 deletion was noted, which allows us to isolate and monitor GATA3-deficient “Th2” cells and “ILC2s” during in vivo immune responses. Our results not only indicated that functional GATA3 is dispensable for regulating its own expression in mature type 2 lymphocytes, but also revealed that GATA3-deficient “ILC2s” might be much more stable in vivo than in vitro. Overall, the generation of these novel GATA3 reporters will provide valuable research tools to the scientific community in investigating type 2 immune responses in vivo.
CAR T-cells for colorectal cancer immunotherapy: Ready to go?
Authors: Ghazi Bouchra , El Ghanmi Adil , Kandoussi Sarah , Ghouzlani Amina , Badou Abdallah
Published: November 2022

Chimeric antigen receptor (CAR) T-cells represent a new genetically engineered cell-based immunotherapy tool against cancer. The use of CAR T-cells has revolutionized the therapeutic approach for hematological malignancies. Unfortunately, there is a long way to go before this treatment can be developed for solid tumors, including colorectal cancer. CAR T-cell therapy for colorectal cancer is still in its early stages, and clinical data are scarce. Major limitations of this therapy include high toxicity, relapses, and an impermeable tumor microenvironment for CAR T-cell therapy in colorectal cancer. In this review, we summarize current knowledge, highlight challenges, and discuss perspectives regarding CAR T-cell therapy in colorectal cancer.
Response of microbiota to exogenous inoculation improved the enzymatic activities of medium-temperature Daqu
Authors: Pan Qianglin , Huang Jun , Zhang Suyi , Qin Hui , Wang Xiaojun , Mu Yu , Tang Huifang , Zhou Rongqing
Published: November 2022

To explore the potential mechanism of improving enzymatic activities in medium-temperature Daqu (MTD) by inoculation functional isolates, we inoculated a single strain of Bacillus licheniformis, and the microbiota composed of Bacillus velezensis and Bacillus subtilis in MTD to investigate the association between the response of the functional microbiota and the enzymatic activity. The results showed that the bacterial community of MTD might be more sensitive to bioturbation than the fungal community, and the indigenous microbiota responded to the single strain more than to the microbiota. Moreover, the differential microorganisms mainly included Lactobacillales, Bacillales, and Saccharomycetales between the conventional and fortified samples. Notably, the composition of functional microbiota related to liquefying activity (LA) and saccharifying activity (SA) were significantly different, changing from Lactobacillus and Rhizomucor to Bacillus, Weissella, and Hyphopichia. That might be closely related to the effect of the bioturbation on LA (31.33%) and SA (43.54%) associated microorganisms was more tellingly. Furthermore, the relative abundance changes of bioturbation-sensitive modules in the co-occurrence network might also lead to the difference in enzymatic activities. Therefore, the LA and SA of MTD were improved by bioturbation significantly. These results provide diverse insights into the exogenous functional isolates to regulate the MTD microbiota and improve enzymatic activities.
3D spatial organization and improved antibiotic treatment of a Pseudomonas aeruginosa–Staphylococcus aureus wound biofilm by nanoparticle enzyme delivery
Authors: Rubio-Canalejas Alba , Baelo Aida , Herbera Sara , Blanco-Cabra Núria , Vukomanovic Marija , Torrents Eduard
Published: November 2022

Chronic wounds infected by Pseudomonas aeruginosa and Staphylococcus aureus are a relevant health problem worldwide because these pathogens grow embedded in a network of polysaccharides, proteins, lipids, and extracellular DNA, named biofilm, that hinders the transport of antibiotics and increases their antimicrobial tolerance. It is necessary to investigate therapies that improve the penetrability and efficacy of antibiotics. In this context, our main objectives were to study the relationship between P. aeruginosa and S. aureus and how their relationship can affect the antimicrobial treatment and investigate whether functionalized silver nanoparticles can improve the antibiotic therapy. We used an optimized in vitro wound model that mimics an in vivo wound to co-culture P. aeruginosa and S. aureus biofilm. The in vitro wound biofilm was treated with antimicrobial combinatory therapies composed of antibiotics (gentamycin and ciprofloxacin) and biofilm-dispersing free or silver nanoparticles functionalized with enzymes (α-amylase, cellulase, DNase I, or proteinase K) to study their antibiofilm efficacy. The interaction and colocalization of P. aeruginosa and S. aureus in a wound-like biofilm were examined and detailed characterized by confocal and electronic microscopy. We demonstrated that antibiotic monotherapy is inefficient as it differentially affects the two bacterial species in the mixed biofilm, driving P. aeruginosa to overcome S. aureus when using ciprofloxacin and the contrary when using gentamicin. In contrast, dual-antibiotic therapy efficiently reduces both species while maintaining a balanced population. In addition, DNase I nanoparticle treatment had a potent antibiofilm effect, decreasing P. aeruginosa and S. aureus viability to 0.017 and 7.7%, respectively, in combined antibiotics. The results showed that using nanoparticles functionalized with DNase I enhanced the antimicrobial treatment, decreasing the bacterial viability more than using the antibiotics alone. The enzymes α-amylase and cellulase showed some antibiofilm effect but were less effective compared to the DNase I treatment. Proteinase K showed insignificant antibiofilm effect. Finally, we proposed a three-dimensional colocalization model consisting of S. aureus aggregates within the biofilm structure, which could be associated with the low efficacy of antibiofilm treatments on bacteria. Thus, designing a clinical treatment that combines antibiofilm enzymes and antibiotics may be essential to eliminating chronic wound infections.
Association of retinal thickness and microvasculature with cognitive performance and brain volumes in elderly adults
Authors: Wang Ruilin , Kwapong William Robert , Tao Wendan , Cao Le , Ye Chen , Liu Junfeng , Zhang Shuting , Wu Bo
Published: November 2022

Background

Retinal structural and microvascular changes can be visualized and have been linked with cognitive decline and brain changes in cerebral age-related disorders. We investigated the association between retinal structural and microvascular changes with cognitive performance and brain volumes in elderly adults.

Materials and methods

All participants underwent magnetic resonance imaging (MRI), and a battery of neuropsychological examinations. Macula retinal thicknesses (retinal nerve fiber layer, mRNFL, and ganglion cell-inner plexiform layer, GCIPL) were imaged and measured with swept-source optical coherence tomography (SS-OCT) while Optical Coherence Tomography Angiography (OCTA) imaged and measured the superficial vascular complex (SVC) and deep vascular complex (DVC) of the retina.

Results

Out of the 135 participants, 91 (67.41%) were females and none had dementia. After adjusting for risk factors, Shape Trail Test (STT)-A correlated with SVC (P < 0.001), DVC (P = 0.015) and mRNFL (P = 0.013) while STT-B correlated with SVC (P = 0.020) and GCIPL (P = 0.015). mRNFL thickness correlated with Montreal Cognitive Assessment (MoCA) (P = 0.007) and Stroop A (P = 0.030). After adjusting for risk factors and total intracranial volume, SVC correlated with hippocampal volume (P < 0.001). Hippocampal volume correlated (P < 0.05) with most cognitive measures. Stroop B (P < 0.001) and Stroop C (P = 0.020) correlated with white matter volume while Stroop measures and STT-A correlated with gray matter volume (P < 0.05).

Conclusion

Our findings suggest that the retinal structure and microvasculature can be useful pointers for cognitive performance, giving a choice for early discovery of decline in cognition and potential early treatment.
Ferroptosis-related biomarkers for Alzheimer’s disease: Identification by bioinformatic analysis in hippocampus
Authors: Wang Binyang , Fu Chenyang , Wei Yuanyuan , Xu Bonan , Yang Rongxing , Li Chuanxiong , Qiu Meihua , Yin Yong , Qin Dongdong
Published: November 2022

Background

Globally, Alzheimer’s Disease (AD) accounts for the majority of dementia, making it a public health concern. AD treatment is limited due to the limited understanding of its pathogenesis. Recently, more and more evidence shows that ferroptosis lead to cell death in the brain, especially in the regions of the brain related to dementia.

Materials and methods

Three microarray datasets (GSE5281, GSE9770, GSE28146) related to AD were downloaded from Gene Expression Omnibus (GEO) datasets. Ferroptosis-related genes were extracted from FerrDb database. Data sets were separated into two groups. GSE5281 and GSE9770 were used to identify ferroptosis-related genes, and GSE28146 was used to verify results. During these processes, protein–protein interaction (PPI), the Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were conducted. Finally, the differentiated values of ferroptosis-related genes were determined by receiver operator characteristic (ROC) monofactor analysis to judge their potential quality as biomarkers.

Results

Twenty-four ferroptosis-related genes were obtained. Using STRING (https://cn.string-db.org/) and Cytoscape with CytoHubba, the top 10 genes (RB1, AGPAT3, SESN2, KLHL24, ALOX15B, CA9, GDF15, DPP4, PRDX1, UBC, FTH1, ASNS, GOT1, PGD, ATG16L1, SLC3A2, DDIT3, RPL8, VDAC2, GLS2, MTOR, HSF1, AKR1C3, NCF2) were identified as target genes. GO analysis revealed that response to carboxylic acid catabolic process, organic acid catabolic process, alpha-amino acid biosynthetic process and cellular amino acid biosynthetic process were the most highly enriched terms. KEGG analysis showed that these overlapped genes were enriched in p53 signaling pathways, longevity regulating pathway, mTOR signaling pathway, type 2 diabetes mellitus and ferroptosis. Box plots and violine plots were created and verified to confirm the significance of identified target genes. Moreover, ROC monofactor analysis was performed to determine the diagnostic value of identified genes. Two genes (ASNS, SESN2) were subsequently obtained. For the tow genes, STRING was used to obtain the five related genes and determined enriched GO terms and KEGG pathways for those genes.

Conclusion

Our results suggest that ASNS and SENS2 may serve as potential diagnostic biomarkers for AD and provide additional evidence regarding the essential role of ferroptosis in AD.
Bayesian continual learning via spiking neural networks
Authors: Skatchkovsky Nicolas , Jang Hyeryung , Simeone Osvaldo
Published: November 2022

Among the main features of biological intelligence are energy efficiency, capacity for continual adaptation, and risk management via uncertainty quantification. Neuromorphic engineering has been thus far mostly driven by the goal of implementing energy-efficient machines that take inspiration from the time-based computing paradigm of biological brains. In this paper, we take steps toward the design of neuromorphic systems that are capable of adaptation to changing learning tasks, while producing well-calibrated uncertainty quantification estimates. To this end, we derive online learning rules for spiking neural networks (SNNs) within a Bayesian continual learning framework. In it, each synaptic weight is represented by parameters that quantify the current epistemic uncertainty resulting from prior knowledge and observed data. The proposed online rules update the distribution parameters in a streaming fashion as data are observed. We instantiate the proposed approach for both real-valued and binary synaptic weights. Experimental results using Intel's Lava platform show the merits of Bayesian over frequentist learning in terms of capacity for adaptation and uncertainty quantification.
Risk of falls, vestibular multimodal processing, and multisensory integration decline in the elderly–Predictive role of the functional head impulse test
Authors: Politi Leandro , Salerni Lorenzo , Bubbico Luciano , Ferretti Fabio , Carucci Mario , Rubegni Giovanni , Mandalà Marco
Published: November 2022

Age-related degeneration of the vestibular system, also known as presbyastasis, leads to unstable gait and higher risk of falls. These conditions affect lifestyle and may have non-negligible social repercussions due to fear-related states of anxiety and depression. In order to develop a model for predicting risk of falls, we assessed vestibulo-ocular function by video and functional Head Impulse Tests (vHIT and fHIT) and their possible correlations with Tinetti Balance Test score. Thirty-one patients over 65 years of age admitted with trauma due to falls were recruited. Vestibular evaluation (complete otoneurological assessment, vHIT, fHIT), cognitive tests (Mini Mental State Examination), anxiety and depression evaluation and Tinetti Balance Test were performed. The possibility of a correlation between the head impulse tests (vHIT, fHIT) and the Tinetti Balance Test was investigated by logistic regression analysis (Nagelkerke r2 and Wald test). A linear correlation was found between the Tinetti Balance Test score and fHIT, whereas no correlation was found for vHIT. Functional HIT is an effective test for predicting the risk of falls in elderly patients.
Ultrastructural destruction of neurovascular unit in experimental cervical spondylotic myelopathy
Authors: Li Guang-Sheng , Wang Xu-Xiang , Tan Ron-Bang , Wang Kang-Heng , Hu Xiao-song , Hu Yong
Published: November 2022

Background and purpose

The pathogenesis of cervical spondylotic myelopathy (CSM) remains unclear. This study aimed to explore the ultrastructural pathology of neurovascular unit (NVU) during natural development of CSM.

Methods

A total of 24 rats were randomly allocated to the control group and the CSM group. Basso–Beattie–Bresnahan (BBB) scoring and somatosensory evoked potentials (SEP) were used as functional assessments. Hematoxylin–eosin (HE), toluidine blue (TB), and Luxol fast blue (LFB) stains were used for general structure observation. Transmission electron microscopy (TEM) was applied for investigating ultrastructural characteristics.

Results

The evident compression caused significant neurological dysfunction, which was confirmed by the decrease in BBB score and SEP amplitude, as well as the prolongation of SEP latency (P < 0.05). The histopathological findings verified a significant decrease in the amount of Nissl body and myelin area and an increase in vacuolation compared with the control group (P < 0.05). The TEM results revealed ultrastructural destruction of NVU in several forms, including: neuronal degeneration and apoptosis; disruption of axonal cytoskeleton (neurofilaments) and myelin sheath and dystrophy of axonal terminal with dysfunction mitochondria; degenerative oligodendrocyte, astrocyte, and microglial cell inclusions with degenerating axon and dystrophic dendrite; swollen microvascular endothelium and loss of tight junction integrity; corroded basement membrane and collapsed microvascular wall; and proliferated pericyte and perivascular astrocytic endfeet. In the CSM group, reduction was observed in the amount of mitochondria with normal appearance and the number of cristae per mitochondria (P < 0.05), while no substantial drop of synaptic vesicle number was seen (P > 0.05). Significant narrowing of microvascular lumen size was also observed, accompanied by growth in the vascular wall area, endothelial area, basement membrane thickness, astrocytic endfeet area, and pericyte coverage area (rate) (P < 0.05).

Conclusion

Altogether, the findings of this study demonstrated ultrastructural destruction of NVU in an experimental CSM model with dorsal–lateral compression, revealing one of the crucial pathophysiological mechanisms of CSM.
Inhibition of microRNA-200c preserves astrocyte sirtuin-1 and mitofusin-2, and protects against hippocampal neurodegeneration following global cerebral ischemia in mice
Authors: Griffiths Brian , Xu Lijun , Sun Xiaoyun , Greer Majesty , Murray Isabella , Stary Creed
Published: November 2022

Memory impairment remains a leading disability in survivors of global cerebral ischemia, occurring secondary to delayed neurodegeneration of hippocampal cornu ammonis-1 (CA1) neurons. MicroRNA-200c (miR-200c) is induced following ischemic stress and we have previously demonstrated that pre-treatment with anti-miR-200c is protective against embolic stroke in mice. In the present study we assessed the role of miR-200c on CA1 neurodegeneration, sirtuin-1 (SIRT1), and mitochondrial dynamic protein expression in a mouse model of transient global cerebral ischemia and in vitro in primary mouse astrocyte cultures after simulated ischemia. Mice were subjected to 10 min bilateral common carotid artery occlusion plus hypotension with 5% isoflurane. After 2 h recovery mice were treated with intravenous injection of either anti-miR-200c or mismatch control. Memory function was assessed by Barnes maze at post-injury days 3 and 7. Mice were sacrificed at post-injury day 7 for assessment of brain cell-type specific expression of miR-200c, SIRT1, and the mitochondrial fusion proteins mitofusin-2 (MFN2) and OPA1 via complexed fluorescent in situ hybridization and fluorescent immunohistochemistry. Global cerebral ischemia induced significant loss of CA1 neurons, impaired memory performance and decreased expression of CA1 SIRT1, MFN2, and OPA1. Post-injury treatment with anti-miR-200c significantly improved survival, prevented CA1 neuronal loss, improved post-injury performance in Barnes maze, and was associated with increased post-injury expression of CA1 SIRT1 and MFN2 in astrocytes. In vitro, primary mouse astrocyte cultures pre-treated with miR-200c inhibitor prior to oxygen/glucose deprivation preserved expression of SIRT1 and MFN2, and decreased reactive oxygen species generation, whereas pre-treatment with miR-200c mimic had opposite effects that could be reversed by co-treatment with SIRT1 activator. These results suggest that miR-200c regulates astrocyte mitochondrial homeostasis via targeting SIRT1, and that CA1 astrocyte mitochondria and SIRT1 represent potential post-injury therapeutic targets to preserve cognitive function in survivors of global cerebral ischemia.
Neuroprotection of cannabidiol in epileptic rats: Gut microbiome and metabolome sequencing
Authors: Gong Xiaoxiang , Liu Lingjuan , Li Xingfang , Xiong Jie , Xu Jie , Mao Dingan , Liu Liqun
Published: November 2022

Aims

Epilepsy is a neurological disease occurring worldwide. Alterations in the gut microbial composition may be involved in the development of Epilepsy. The study aimed to investigate the effects of cannabidiol (CBD) on gut microbiota and the metabolic profile of epileptic rats.

Materials and methods and results

A temporal lobe epilepsy rat model was established using Li-pilocarpine. CBD increased the incubation period and reduced the epileptic state in rats. Compared to epileptic rats, the M1/M2 ratio of microglia in the CBD group was significantly decreased. The expression of IL-1β, IL-6, and TNF-α in the CBD group decreased, while IL-10, IL-4, and TGF-β1 increased. 16S rDNA sequencing revealed that the ANOSIM index differed significantly between the groups. At the genus level, Helicobacter, Prevotellaceae_UCG-001, and Ruminococcaceae_UCG-005 were significantly reduced in the model group. CBD intervention attenuated the intervention effects of Li-pilocarpine. Roseburia, Eubacterium_xylanophilum_group, and Ruminococcus_2 were strongly positively correlated with proinflammatory cytokine levels. CBD reversed dysregulated metabolites, including glycerophosphocholine and 4-ethylbenzoic acid.

Conclusion

CBD could alleviate the dysbiosis of gut microbiota and metabolic disorders of epileptic rats. CBD attenuated Epilepsy in rats might be related to gut microbial abundance and metabolite levels.

Significance and impact of study

The study may provide a reliable scientific clue to explore the regulatory pathway of CBD in alleviating Epilepsy.
Origin of static magnetic field induced quality improvement in sea bass (Lateolabrax japonicus) during cold storage: Microbial growth inhibition and protein structure stabilization
Authors: Tong Li , Tang Haiqing , Chen Jingyi , Sang Shangyuan , Liang Ruiping , Zhang Zhepeng , Ou Changrong
Published: November 2022

To explore the potential application of static magnetic field (SMF) treatment in marine fish preservation, the sea bass (Lateolabrax japonicus) was exposed to SMF (5 mT) and its quality changes during cold storage were evaluated by total viable counts, water holding capacity, pH, color, and textural properties. Characteristics of the protein in the presence of SMF were investigated by measuring total sulfhydryl (SH) content, Ca2+-ATPase activity, secondary structure, and muscle microstructure. SMF treatment exhibited positive effects on fish quality, showing favorable performance on the most quality indicators, especially a significant reduction in the Microbial Counts. Furthermore, higher total SH content and Ca2+-ATPase activity were observed in SMF-treated samples, demonstrating that the oxidation and denaturation of myofibrillar protein (MP) were delayed due to SMF treatment. The transformation of α-helix to random coil was prevented in SMF-treated samples, indicating that the secondary structure of MP was stabilized by SMF treatment. The above changes in protein structures were accompanied by changes in muscle microstructure. More intact and compact structures were observed in SMF-treated samples, characterized by well-defined boundaries between myofibers. Therefore, our findings suggest that under the conditions of this article, SMF treatment could maintain the quality of fish mainly by inhibiting the growth of microorganisms and enhancing the stability of protein structures, and could be a promising auxiliary technology for preservation of aquatic products.
Delineation of molecular characteristics in pediatric PFA ependymoma involving rare osseous and pulmonary metastases: A case report and literature review
Authors: Zhou Mading , Wang Leiming , Sun Peng , Liu Yutong , Chen Ge , Zeng Gao
Published: November 2022

Ependymoma is the third most common pediatric primary brain tumor, with its most aggressive subtype being posterior fossa group A (PFA). Extraneural metastasis of pediatric PFA ependymoma is rare. Herein, we present a case of a 9-year-old girl with PFA ependymoma characterized by a lack of trimethylation of histone H3 at lysine 27 and elevated chromosome X open reading frame 67 expression. Despite multiple surgeries and radiotherapies, the patient had a rapid recurrence and developed osseous and pulmonary metastases, which may be attributed to the homozygous deletion of cyclin-dependent kinase (CDK) inhibitor 2A/B and CDK12 mutation. Importantly, the CDK12 mutation observed in the patient may be indicative of the need for further work-up to consider chemotherapy rather than administering poly (adenosine diphosphate-ribose) polymerase inhibitors. Taken together, this is the first report of pediatric PFA ependymoma with extraneural metastases, wherein we clarified the diagnostic procedures of this newly identified PFA ependymoma and provided new cues to study the invasiveness of this disease and treatment selection for such patients.
Localized light chain amyloidosis: A self-limited plasmacytic B-cell lymphoproliferative disorder
Authors: Martínez José C. , Lichtman Eben I.
Published: November 2022

Immunoglobulin light chain amyloidosis can be either systemic or localized. Although these conditions share a similar name, they are strikingly different. Localized light chain amyloidosis has been challenging to characterize due to its lower incidence and highly heterogeneous clinical presentation. Here, we review the emerging literature, emphasizing recent reports on large cohorts of patients with localized amyloidosis, and provide insights into this condition’s pathology and natural history. We find that patients with localized amyloidosis have an excellent prognosis with overall survival similar to that of the general population. Furthermore, the risk of progression to systemic disease is low and likely represents initial mischaracterization as localized disease. Therefore, we argue for the incorporation of more sensitive techniques to rule out systemic disease at diagnosis. Despite increasing mechanistic understanding of this condition, much remains to be discovered regarding the cellular clonal evolution and the molecular processes that give rise to localized amyloid formation. While localized surgical resection of symptomatic disease is typically the treatment of choice, the presentation of this disease across the spectrum of plasmacytic B-cell lymphoproliferative disorders, and the frequent lack of an identifiable neoplastic clone, can make therapy selection a challenge in the uncommon situation that systemic chemotherapy is required.
Case report: Undifferentiated sarcoma with multiple tumors involved in Lynch syndrome: Unexpected favorable outcome to sintilimab combined with chemotherapy
Authors: Liu Jiaying , Chang Xiaona , Xiao Guixiang , Zhong Jingmin , Huang Bo , Zhang Jiwei , Gao Beibei , Peng Gang , Nie Xiu
Published: November 2022

Background

Patients with Lynch syndrome are at an increased risk of developing simultaneous or metachronous tumors, while sarcomas have been occasionally reported. Sarcomas are generally not considered part of the common Lynch syndrome tumor spectrum. However, more and more studies and case reports suggested that sarcoma could be a rare clinical manifestation of Lynch syndrome, leading to new treatment strategies for sarcoma.

Case summary

We report the case of a 74-year-old male patient with Lynch syndrome who had rectal mucinous adenocarcinoma and prostate adenocarcinoma and then developed undifferentiated sarcoma of the left neck two years later. Mismatch repair deficiency (dMMR) was confirmed by immunohistochemical staining for the mismatch repair proteins MSH2, MSH6, MLH1 and PMS2. The result of polymerase chain reaction (PCR) microsatellite instability (MSI) testing of sarcoma showed high-level microsatellite instability (MSI-H). Additionally, a pathogenic germline mutation in MSH2 (c.2459-12A>G) was detected by next-generation sequencing (NGS). Taking into account HE morphology, immunohistochemical phenotype, MSI status, NGS result, medical history and germline MSH2 gene mutation, the pathological diagnosis of left neck biopsy tissue was Lynch syndrome related undifferentiated sarcoma with epithelioid morphology. The patient has been receiving immunotherapy (sintilimab) combined with chemotherapy (tegafur, gimeracil and oteracil potassium capsules) and currently has stable disease. We also reviewed the literature to understand the association between sarcoma and Lynch syndrome.

Conclusion

Sarcoma may now be considered a rare clinical manifestation of Lynch syndrome. Attention and awareness about the association between Lynch syndrome and sarcoma need to be increased. Therefore, timely detection of MMR proteins and validation at the gene level for suspicious patients are the keys to avoiding missed or delayed diagnosis and to identifying patients suited for immunotherapy, which may also help to provide appropriate genetic counseling and follow-up management for patients.
PUS1 is a novel biomarker for predicting poor outcomes and triple-negative status in breast cancer
Authors: Fang Zheng , Shen Hong-yu , Xu Qi , Zhou Hong-lei , Li Lei , Yang Si-Yuan , Zhu Zhen , Tang Jin-hai
Published: November 2022

Breast cancer patients’ outcomes have improved dramatically in recent years, but relapses and poor prognosis remain common due to its aggressiveness and heterogeneity. The development of reliable biomarkers is still needed for predicting prognosis and treatment effectiveness. Recently, a growing body of research suggests that pseudouridine synthases contribute to the development of many cancers, but their contribution to breast cancer remains largely unknown. Using an integrative analysis, we selected pseudouridine synthase1(PUS1) as the candidate biomarker. A tissue microarray of 131 breast cancer patients was then utilized to determine the clinical significance and prognostic value of PUS1. RNA sequencing analysis was conducted to identify downstream genes that differ between control and PUS1 knockdown cells. The effect of PUS1 on phenotypes of cells was assessed using cell proliferation, colony formation, and transwell invasion assays. We found that breast tumors overexpressed PUS1 compared with paired normal tissues. PUS1 expression was positively correlated with triple-negative breast cancer (TNBC) status (P= 0.020) and tumor grade (P <0.0001), but not with age (P= 0.736), tumor size (P= 0.608), lymph node (P= 0.742), oestrogen receptor (ER) (P= 0.162), progesterone receptor (PR) (P= 0.901), human epidermal growth factor receptor 2 (HER2) (P= 0.608) or tumor stage (P= 0.411). Comparatively, patients with high PUS1 levels had shorter overall survival time (P=0.0001) and relapse-free survival time (P = 0.0093). A univariate and multivariate survival analysis suggested that the overall survival of patients was independently influenced by the PUS1 score (Univariate Cox P <0.0001, HR=5.176, 95% CI =2.420-11.07; Multivariate Cox P = 0.001, HR = 5.291, 95% CI =1.893-14.78). RNA sequencing data revealed the PUS1 knockdown significantly affects a series of cancer related biological process such as regulation of cell proliferation and cell migration, as well as KEGG pathways including Mitophagy and PI3K-Akt signaling. In vitro, knockdown of PUS1 significantly suppressed the proliferation and colony formation abilities of MDA-MB-231 cells and BT-549 cells. Additionally, the ability of tumor cells to invade was remarkably attenuated in low PUS1 expression groups compared with the corresponding control groups. Our results suggested that PUS1 is a novel biomarker that predicts poor outcomes in patients with breast cancer and may prove to be a promising treatment target.
Canagliflozin, characterized as a HDAC6 inhibitor, inhibits gastric cancer metastasis
Authors: Jiang Dandan , Ma Peizhi
Published: November 2022

Gastric cancer is a common gastrointestinal cancer. Survival outcome for patients with the recurrence or metastasis remains poor due to the lack of effective targeting drugs. The mechanisms of non-histone acetylation modifications are key epigenetic regulations that participate in various biological processes. HDAC6 is mostly located in the cytoplasm to deacetylate non-histone substrates, which has been identified as a critical promoter of many oncogenic pathways in cancers, including gastric cancer. Nevertheless, its inhibitor has not been applied in gastric cancer clinically. In this study, we identified canagliflozin as an active HDAC6-targeted inhibitor from FDA-approved Drug Library by enzymatic assay. The strong affinity of the compounds with HDAC6 was further verified by surface plasmon resonance (SPR) and cellular thermal shift assay (CETSA). In addition, molecular docking showed that canagliflozin could bind to the active pocket of HDAC6 and form interactions with key residues. Further experiments revealed that canagliflozin could effectively inhibit the migration and epithelial-mesenchymal-transition (EMT) of gastric cancer cells in vitro and in vivo. These results reveal a novel finding that canagliflozin has the potential to be an effective agent in inhibiting gastric cancer metastasis.
Case report: Rechallenge with EGFR–TKIs after immunotherapy in EGFR–mutated non–small cell lung cancer with leptomeningeal metastasis
Authors: Qian Chunfa , Zhang Yuhai , Cheng Wanwan , Zhang Qingchao , Li Mengzhen , Fang Shencun
Published: November 2022

Rechallenge of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) after PD-1 blockade failure was an effective therapy for non-small cell lung cancer (NSCLC) patients with resistance to EGFR-TKIs. The third-generation TKIs, like osimertinib and furmonertinib, can reach higher concentration in the cerebrospinal fluid (CSF) than other TKIs, and exhibit a beneficial effect in NSCLC patients with leptomeningeal metastases (LM) harboring sensitive EGFR mutation. Here, we report that two-stage IV pulmonary adenocarcinoma patients with LM harboring an EGFR L858R mutation benefit from the third-generation EGFR-TKIs rechallenge after immune checkpoint inhibitor (ICI) and anti-angiogenic agent combination therapy. Complete response (CR) to partial response (PR) of central nervous system (CNS) response was achieved immediately after the administration of furmonertinib and osimertinib. We conducted next-generation sequencing (NGS) and IHC to elucidate the evolution of driver mutations and the immune microenvironment. In conclusion, these two cases might provide a therapeutic strategy for further clinical practice. More research was needed to elucidate the resistance mechanisms and improve current treatment strategies in EGFR-mutated patients with LM.