IndGOterm: a qualitative method for the identification of individually dysregulated GO terms in cancer.

Individual pathway analysis can dissect heterogeneities among different cancer patients and provide efficient guidelines for individualized therapy. However, the existence of the batch effect brings extensive limitations for the application of many individual methods for pathway analysis. Previously, researchers proposed that methods based on within-sample relative expression ordering (REO) of the genes are notably insensitive to 'batch effects'. In this article, we focus on the Gene Ontology (GO) database and propose an individual qualitative GO term analysis method (IndGOterm) based on the REO of genes. Compared with some current widely used single-sample enrichment analysis methods, such as ssGSEA and GSVA, IndGOterm has a predominance of ignoring the batch effects caused by diverse technologies. Through the survival and drug responses analysis, we found IndGOterm could capture more terms connected to cancer than other single-sample enrichment analysis methods. Furthermore, through the application of IndGOterm, we found some terms that present different dysregulation models that manifest heterogenetic in homologous patients. Collectively, these results attested that IndGOterm could capture useful information from patients and be a useful tool to reveal the intrinsic characteristic of cancer. An open-source R statistical analysis package 'IndGOterm' is available at https://github.com/robert19960424/IndGOterm.

Immunotherapies for the Effective Treatment of Primary Autoimmune Cerebellar Ataxia: a Case Series.

Primary autoimmune cerebellar ataxia (PACA) is an idiopathic sporadic cerebellar ataxia that is thought to be immune-mediated but lacks biomarkers or a known cause. Here, we report two cases of immune-mediated cerebellar ataxia that responded favorably to immunotherapy, in which tissue-based indirect immunofluorescence test for serum or cerebrospinal fluid (CSF) samples yielded positive results. Case 1 was a 78-year-old man who presented with subacute progressive gait ataxia with truncal instability and dysarthria in response to steroids. Case 2 was a 62-year-old man who presented with relapses and remissions of acute progressive cerebellar ataxia occurring 1-2 times per year. Despite a favorable response to steroid treatment, he relapsed repeatedly in the absence of long-term immunosuppression. In the case of "idiopathic" cerebellar ataxia, immune-mediated causes should be investigated, and immunotherapy may have therapeutic effects.

Whole transcriptome sequencing and integrated network analysis elucidates the effects of 3,8-Di-O-methylellagic acid 2-O-glucoside derived from Sanguisorba offcinalis L., a novel differentiation inducer on erythroleukemia cells.

Acute erythroid leukemia (AEL) is a rare and aggressive hematologic malignancy with no specific treatment. Sanguisorba officinalis L. (S. officinalis), a well-known traditional Chinese medicine, possesses potent anticancer activity. However, the active components of S. officinalis against AEL and the associated molecular mechanisms remain unknown. In this study, we predicted the anti-AML effect of S. officinalis based on network pharmacology. Through the identification of active components of S. officinalis, we found that 3,8-Di-O-methylellagic acid 2-O-glucoside (DMAG) not only significantly inhibited the proliferation of erythroleukemic cell line HEL, but also induced their differentiation to megakaryocytes. Furthermore, we demonstrated that DMAG could prolong the survival of AEL mice model. Whole-transcriptome sequencing was performed to elucidate the underlying molecular mechanisms associated with anti-AEL effect of DMAG. The results showed that the total of 68 miRNAs, 595 lncRNAs, 4030 mRNAs and 35 circRNAs were significantly differentially expressed during DMAG induced proliferation inhibition and differentiation of HEL cells. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses revealed that the differentially expressed miRNAs, lncRNAs, mRNAs and circRNAs were mainly involved in metabolic, HIF-1, MAPK, Notch pathway and apoptosis. The co-expression networks showed that miR-23a-5p, miR-92a-1-5p, miR-146b and miR-760 regulatory networks were crucial for megakaryocyte differentiation induced by DMAG. In conclusion, our results suggest that DMAG, derived from S. officinalis might be a potent differentiation inducer of AEL cells and provide important information on the underlying mechanisms associated with its anti-AEL activity.

Thymoma-associated autoimmune encephalitis: Analysis of factors determining prognosis.

INTRODUCTION: Autoimmune encephalitis (AE) is a heterogeneous group of inflammatory central nervous system disorders caused by a misdirected immune response against self-antigens expressed in the central nervous system. The thymus is a central organ in the immune system and thymic tumors are thought to be possible initiators of many neurological disorders. Recently, there is growing evidence that thymomas are associated with autoimmune encephalitis. AIMS: Our study initially explored the characteristics of patients with autoimmune encephalitis combined with thymoma. METHODS: We used patient data from January 1, 2011 to October 1, 2021 from the PubMed, Web of Science, Ovid, and CNKI platforms to analyze overall demographics, frequency of symptoms and associations, and treatment prognosis outcomes. RESULTS: A total of 68 patients were included. There were 39 female cases (57.4%). The mean age was 50 years (IQR 40-66 years). All had acute and subacute onset. The clinical manifestations were mostly cognitive changes (70.6%), mental disorders (57.4%), and epilepsy (50.0%). The most common neuronal antibody was alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA). Magnetic resonance imaging (MRI) abnormalities were present in 81.0% of patients, mostly in the hippocampus, temporal lobe, and some in cortical and subcortical areas. Abnormalities in the electroencephalogram (EEG) in 69.8% of patients. Treatment involved immunotherapy and thymoma treatment, with 79.7% of patients improving after treatment. While 20.3% of patients had a poor prognosis. Further, 14.8% of patients relapsed. Mental disorders, autonomic dysfunction, sleep disturbances, anti-Ma2, and thymoma untreated were more frequent in patients with poor prognosis. CONCLUSION: Thymoma-associated autoimmune encephalitis is a unique disease entity. Long-term follow-up of chest CT findings is recommended for patients with autoimmune encephalitis.

Peripheral blood CD19 positive B lymphocytes increase after ischemic stroke and correlate with carotid atherosclerosis.

Introduction: Atherosclerosis is the primary pathological basis of ischemic stroke, and dyslipidemia is one of its major etiological factors. Acute ischemic stroke patients exhibit imbalances in lymphocyte subpopulations, yet the correlation between these dynamic changes in lymphocyte subpopulations and lipid metabolism disorders, as well as carotid atherosclerosis in stroke patients remains poorly understood. Methods: We retrospectively analyzed the demographic data, risk factors of cerebrovascular disease, laboratory examination (lymphocyte subsets, lipid indexes, etc.), clinical features and c;/]-sity from December 2017 to September 2019 and non-stroke patients with dizziness/vertigo during the same period. Results: The results showed that peripheral B lymphocyte proportions are elevated in acute ischemic stroke patients compared with those of the control group (13.6 ± 5.3 vs. 11.7 ± 4.4%, p = 0.006). Higher B lymphocyte proportions are associated with concurrent dyslipidemia, increased levels of vascular risk factors including triglycerides (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and very-low-density lipoprotein cholesterol (VLDL-C), as well as decreased levels of the protective factor high-density lipoprotein cholesterol (HDL-C). Elevated B lymphocyte proportions are independently correlated with carotid atherosclerosis in stroke patients. Discussion: We found CD19 positive B Lymphocytes increase after ischemic stroke and correlate with Carotid Atherosclerosis. Lymphocyte subpopulations should be highlighted in stroke patients.

Overlapping Epstein-Barr virus encephalitis and autoimmune glial fibrillary acidic protein astrocytopathy.

We describe three cases of overlapping Epstein-Barr virus (EBV) Encephalitis and Autoimmune Glial Fibrillary Acidic Protein Astrocytopathy (GFAP-A). The three cases all presented with initial symptoms of fever, headache, coma, and posture tremor of the upper limbs, then followed by limb weakness and dysuria. All of the three cases were on ventilators. Case 1 and 2 improved dramatically after intravenous methylprednisoloneand immunoglobulin treatment. However, case 3 presented dyspneic, and died from gastrointestinal hemorrhage. The GFAP-A triggered by EBV intracranial infection could initially masquerade as EBV encephalitis only, and the detection of GFAP antibody is essential for differentiation.

A conditional knockout rat resource of mitochondrial protein-coding genes via a DdCBE-induced premature stop codon.

Hundreds of pathogenic variants of mitochondrial DNA (mtDNA) have been reported to cause mitochondrial diseases, which still lack effective treatments. It is a huge challenge to install these mutations one by one. We repurposed the DddA-derived cytosine base editor to incorporate a premature stop codon in the mtProtein-coding genes to ablate mitochondrial proteins encoded in the mtDNA (mtProteins) instead of installing pathogenic variants and generated a library of both cell and rat resources with mtProtein depletion. In vitro, we depleted 12 of 13 mtProtein-coding genes with high efficiency and specificity, resulting in decreased mtProtein levels and impaired oxidative phosphorylation. Moreover, we generated six conditional knockout rat strains to ablate mtProteins using Cre/loxP system. Mitochondrially encoded ATP synthase membrane subunit 8 and NADH:ubiquinone oxidoreductase core subunit 1 were specifically depleted in heart cells or neurons, resulting in heart failure or abnormal brain development. Our work provides cell and rat resources for studying the function of mtProtein-coding genes and therapeutic strategies.

StemSC: a cross-dataset human stemness index for single-cell samples.

BACKGROUND: Stemness is defined as the potential of cells for self-renewal and differentiation. Many transcriptome-based methods for stemness evaluation have been proposed. However, all these methods showed low negative correlations with differentiation time and can't leverage the existing experimentally validated stem cells to recognize the stem-like cells. METHODS: Here, we constructed a stemness index for single-cell samples (StemSC) based on relative expression orderings (REO) of gene pairs. Firstly, we identified the stemness-related genes by selecting the genes significantly related to differentiation time. Then, we used 13 RNA-seq datasets from both the bulk and single-cell embryonic stem cell (ESC) samples to construct the reference REOs. Finally, the StemSC value of a given sample was calculated as the percentage of gene pairs with the same REOs as the ESC samples. RESULTS: We validated the StemSC by its higher negative correlations with differentiation time in eight normal datasets and its higher positive correlations with tumor dedifferentiation in three colorectal cancer datasets and four glioma datasets. Besides, the robust of StemSC to batch effect enabled us to leverage the existing experimentally validated cancer stem cells to recognize the stem-like cells in other independent tumor datasets. And the recognized stem-like tumor cells had fewer interactions with anti-tumor immune cells. Further survival analysis showed the immunotherapy-treated patients with high stemness had worse survival than those with low stemness. CONCLUSIONS: StemSC is a better stemness index to calculate the stemness across datasets, which can help researchers explore the effect of stemness on other biological processes.

Integrated multi-omics analysis reveals miR-20a as a regulator for metabolic colorectal cancer.

Single-driver molecular events specific to the metabolic colorectal cancer (CRC) have not been clearly elucidated. Herein, we identified 12 functional miRNAs linked to activated metabolism by integrating multi-omics features in metabolic CRC. These miRNAs exhibited significantly enriched CRC driver miRNAs, significant impacts on CRC cell growth and significantly correlated metabolites. Importantly, miR-20a is minimally expressed in normal colorectal tissues but highly expressed in metabolic CRC, suggesting the potential therapeutic target. Bioinformatics analyses further revealed miR-20a as the most powerful determinant that regulates a cascade of dysregulated events, including Wnt signaling pathway, core enzymes involved in FA metabolism program and triacylglycerol abundances. In vitro assays demonstrated that elevated miR-20a up-regulated FA synthesis enzymes via Wnt/ß-catenin signaling, and finally promoted proliferative and migration of metabolic CRC cells. Overall, our study revealed that miR-20a promoted progression of metabolic CRC by regulating FA metabolism and served as a potential target for preventing tumor metastasis.

The Key Role of Magnetic Resonance Imaging in the Detection of Neurodegenerative Diseases-Associated Biomarkers: A Review.

Neurodegenerative diseases (NDs), including chronic disease such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and multiple sclerosis, and acute diseases like traumatic brain injury and ischemic stroke are characterized by progressive degeneration, brain tissue damage and loss of neurons, accompanied by behavioral and cognitive dysfunctions. So far, there are no complete cures for NDs; thus, early and timely diagnoses are essential and beneficial to patients' treatment. Magnetic resonance imaging (MRI) has become one of the advanced medical imaging techniques widely used in the clinical examination of NDs due to its non-invasive diagnostic value. In this review, research published in English in current decade from PubMed electronic database on the use of MRI to detect specific biomarkers of NDs was collected, summarized, and discussed, which provides valuable suggestions for the early diagnosis, prevention, and treatment of NDs in the clinic.

A Cancer-Specific Qualitative Method for Estimating the Proportion of Tumor-Infiltrating Immune Cells.

Tumor-infiltrating immune cells are important components in the tumor microenvironment (TME) and different types of these cells exert different effects on tumor development and progression; these effects depend upon the type of cancer involved. Several methods have been developed for estimating the proportion of immune cells using bulk transcriptome data. However, there is a distinct lack of methods that are capable of predicting the immune contexture in specific types of cancer. Furthermore, the existing methods are based on absolute gene expression and are susceptible to experimental batch effects, thus resulting in incomparability across different datasets. In this study, we considered two common neoplasms as examples (colorectal cancer [CRC] and melanoma) and introduced the Tumor-infiltrating Immune Cell Proportion Estimator (TICPE), a cancer-specific qualitative method for estimating the proportion of tumor-infiltrating immune cells. The TICPE was based on the relative expression orderings (REOs) of gene pairs within a sample and is notably insensitive to batch effects. Performance evaluation using public expression data with mRNA mixtures, single-cell RNA-Seq (scRNA-Seq) data, immunohistochemistry data, and simulated bulk RNA-seq samples, indicated that the TICPE can estimate the proportion of immune cells with levels of accuracy that are clearly superior to other methods. Furthermore, we showed that the TICPE could effectively detect prognostic signals in patients with tumors and changes in the fractions of immune cells during immunotherapy in melanoma. In conclusion, our work presented a unique novel method, TICPE, to estimate the proportion of immune cells in specific cancer types and explore the effect of the infiltration of immune cells on the efficacy of immunotherapy and the prognosis of cancer. The source code for TICPE is available at https://github.com/huitingxiao/TICPE.

Qualitative Ras pathway signature for cetuximab therapy reveals resistant mechanism in colorectal cancer.

Cetuximab therapy, which heavily relies on the activation of Ras pathway, has been used in KRAS, NRAS, BRAF, and PIK3CA wild-type colorectal cancer (CRC) (Ras-normal). However, the response rate only reached 60%, due to false-negative mutation detection and mutation-like transcriptome features in wild-type patients. Herein, by integrating RNA-seq, microarray, and mutation data, we developed a Ras pathway signature by characterizing KRAS/NRAS/BRAF/PIK3CA mutations to identify the hidden nonresponders from the Ras-normal patients by mutation detection. Using public and in-house data of CRC patients treated with cetuximab, discovery of the signature could identify cetuximab-resistant samples from the Ras-normal samples. Cetuximab resistance-related genes, such as PTEN, were significantly and frequently mutated in the identified Ras-activated samples, whereas two cetuximab sensitivity-related genes, APC and TP53, showed comutation and significantly higher mutation frequencies in the remaining Ras-normal samples. Furthermore, all the NF1- and BCL2L1-mutated samples were identified as Ras-activated from the Ras-normal samples by the Ras pathway signature with significantly under-regulated expression. Genes co-expressed with the two genes were both involved in Ras signaling pathway, the out-of-control of which could be attributed by the genes' loss-of-function mutations. To improve the treatment of cetuximab in CRC, NF1 and BCL2L1 could be used as complementary detection technique to those applied in clinical. In conclusion, the proposed Ras pathway signature could identify the hidden CRC patients resistant to cetuximab therapy and help to reveal resistance mechanisms.