Utilizing machine learning algorithms for predicting risk factors for bone metastasis from right-sided colon carcinoma after complete mesocolic excision: a 10-year retrospective multicenter study.

BACKGROUND: Bone metastasis (BM) occurs when colon cancer cells disseminate from the primary tumor site to the skeletal system via the bloodstream or lymphatic system. The emergence of such bone metastases typically heralds a significantly poor prognosis for the patient. This study's primary aim is to develop a machine learning model to identify patients at elevated risk of bone metastasis among those with right-sided colon cancer undergoing complete mesocolonectomy (CME). PATIENTS AND METHODS: The study cohort comprised 1,151 individuals diagnosed with right-sided colon cancer, with a subset of 73 patients presenting with bone metastases originating from the colon. We used univariate and multivariate regression analyses as well as four machine learning algorithms to screen variables for 38 characteristic variables such as patient demographic characteristics and surgical information. The study employed four distinct machine learning algorithms, namely, extreme gradient boosting (XGBoost), random forest (RF), support vector machine (SVM), and k-nearest neighbor algorithm (KNN), to develop the predictive model. Additionally, the model was assessed using receiver operating characteristic (ROC) curves, calibration curves, and decision curve analysis (DCA), while Shapley additive explanation (SHAP) was utilized to visualize and analyze the model. RESULTS: The XGBoost algorithm performed the best performance among the four prediction models. In the training set, the XGBoost algorithm had an area under curve (AUC) value of 0.973 (0.953-0.994), an accuracy of 0.925 (0.913-0.936), a sensitivity of 0.921 (0.902-0.940), and a specificity of 0.908 (0.894-0.922). In the validation set, the XGBoost algorithm had an AUC value of 0.922 (0.833-0.995), an accuracy of 0.908 (0.889-0.926), a sensitivity of 0.924 (0.873-0.975), and a specificity of 0.883 (0.810-0.956). Furthermore, the AUC value of 0.83 for the external validation set suggests that the XGBoost prediction model possesses strong extrapolation capabilities. The results of SHAP analysis identified alkaline phosphatase (ALP) levels, tumor size, invasion depth, lymph node metastasis, lung metastasis, and postoperative neutrophil-to-lymphocyte ratio (NLR) levels as significant risk factors for BM from right-sided colon cancer subsequent to CME. CONCLUSION: The prediction model for BM from right-sided colon cancer developed using the XGBoost machine learning algorithm in this study is both highly precise and clinically valuable.

Improvement of MASLD and MASH by suppression of hepatic N-acetyltransferase 10.

OBJECTIVE: Metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH) are characterized by excessive triglyceride accumulation in the liver. However, due to an incomplete understanding of its pathogenesis, more efforts are needed to identify specific and effective treatments. N4-acetylcytidine (ac4C) is a newly discovered RNA modification to regulate mRNA. N-acetyltransferase 10 (NAT10) has not been fully explored in MASLD and MASH. METHODS: The clinical relevance of NAT10 was evaluated based on its expression in various mouse and human models of MASLD and MASH. Acetylated RNA immunoprecipitation sequencing and mRNA stability assays were used to explore the role of NAT10 in regulating ac4C modification and expression of target genes. Genetically engineered mice were employed to investigate the role of NAT10 in MASLD and MASH progression. RESULTS: Hepatic NAT10 expression was significantly increased in multiple mice and humans of MASLD and MASH. Genetic knockout of NAT10 protected mice from diet-induced hepatic steatosis and steatohepatitis, whereas overexpression of NAT10 exacerbated high-fat-diet-induced liver steatosis. Mechanistically, NAT10 binds to Srebp-1c mRNA, promoting its stability and expression, thereby upregulating lipogenic enzymes. Treatment with Remodelin, a NAT10-specific inhibitor, effectively ameliorates liver steatosis and dyslipidemia in a preclinical mouse model. CONCLUSIONS: Our findings indicate that NAT10 could regulate lipid metabolism in MASLD and MASH by stabilizing Srebp-1c mRNA and upregulating lipogenic enzymes. This study highlights the role of NAT10 and RNA acetylation in the pathogenesis of MASLD and MASH. Thus, our findings suggest a promising new therapeutic approach, such as the use of NAT10 inhibitor, for treating metabolic liver disease.

Weakening the Space Charge Layer Effect Through Tethered Anion Electrolyte and Piezoelectric Effect Toward Ultra-Stable Zinc Anode.

The space charge layer (SCL) dilemma, caused by mobile anion concentration gradient and the rapid consumption of cations, is the fundamental reason for the generation of zinc dendrites, especially under high-rate discharge conditions. To address the issue, a physical (PbTiO3)/chemical (AMPS-Zn) barrier is designed to construct stable zinc ion flow and disrupt the gradient of anion concentration by coupling the ferroelectric effect with tethered anion electrolyte. The ferroelectric materials PbTiO3 with extreme-high piezoelectric constant can spontaneously generate an internal electric field to accelerate the movement of zinc ions, and the polyanionic polymer AMPS-Zn can repel mobile anions and disrupt the anions concentration gradient by tethering anions. Through numerical simulations and analyses, it is discovered that a high Zn2+ transference number can effectively weaken the SCL, thus suppressing the occurrence of zinc dendrites and parasitic side reactions. Consequently, an asymmetric cell using the PbTiO3@Zn demonstrates a reversible plating/stripping performance for 2900 h, and an asymmetric cell reaches a state-of-the-art runtime of 3450 h with a high average Coulombic efficiency of 99.98%. Furthermore, the PbTiO3@Zn/I2 battery demonstrated an impressive capacity retention rate of 84.0% over 65000 cycles by employing a slender Zn anode.

Genomic and immune heterogeneity of multiple synchronous lung adenocarcinoma at different developmental stages.

Multiple synchronous lung cancers (MSLCs) constitute a unique subtype of lung cancer. To explore the genomic and immune heterogeneity across different pathological stages of MSLCs, we analyse 16 MSLCs from 8 patients using single-cell RNA-seq, single-cell TCR sequencing, and bulk whole-exome sequencing. Our investigation indicates clonally independent tumours with convergent evolution driven by shared driver mutations. However, tumours from the same individual exhibit few shared mutations, indicating independent origins. During the transition from pre-invasive to invasive adenocarcinoma, we observe a shift in T cell phenotypes characterized by increased Treg cells and exhausted CD8+ T cells, accompanied by diminished cytotoxicity. Additionally, invasive adenocarcinomas exhibit greater neoantigen abundance and a more diverse TCR repertoire, indicating heightened heterogeneity. In summary, despite having a common genetic background and environmental exposure, our study emphasizes the individuality of MSLCs at different stages, highlighting their unique genomic and immune characteristics.

Targeting APT2 improves MAVS palmitoylation and antiviral innate immunity.

Innate immunity serves as the primary defense against viral and microbial infections in humans. The precise influence of cellular metabolites, especially fatty acids, on antiviral innate immunity remains largely elusive. Here, through screening a metabolite library, palmitic acid (PA) has been identified as a key modulator of antiviral infections in human cells. Mechanistically, PA induces mitochondrial antiviral signaling protein (MAVS) palmitoylation, aggregation, and subsequent activation, thereby enhancing the innate immune response. The palmitoyl-transferase ZDHHC24 catalyzes MAVS palmitoylation, thereby boosting the TBK1-IRF3-interferon (IFN) pathway, particularly under conditions of PA stimulation or high-fat-diet-fed mouse models, leading to antiviral immune responses. Additionally, APT2 de-palmitoylates MAVS, thus inhibiting antiviral signaling, suggesting that its inhibitors, such as ML349, effectively reverse MAVS activation in response to antiviral infections. These findings underscore the critical role of PA in regulating antiviral innate immunity through MAVS palmitoylation and provide strategies for enhancing PA intake or targeting APT2 for combating viral infections.

Characterization of driver mutations identifies gene signatures predictive of prognosis and treatment sensitivity in multiple myeloma.

In multiple myeloma (MM), while frequent mutations in driver genes are crucial for disease progression, they traditionally offer limited insights into patient prognosis. This study aims to enhance prognostic understanding in MM by analyzing pathway dysregulations in key cancer driver genes, thereby identifying actionable gene signatures. We conducted a detailed quantification of mutations and pathway dysregulations in 10 frequently mutated cancer driver genes in MM to characterize their comprehensive mutational impacts on the whole transcriptome. This was followed by a systematic survival analysis to identify significant gene signatures with enhanced prognostic value. Our systematic analysis highlighted 2 significant signatures, TP53 and LRP1B, which notably outperformed mere mutation status in prognostic predictions. These gene signatures remained prognostically valuable even when accounting for clinical factors, including cytogenetic abnormalities, the International Staging System (ISS), and its revised version (R-ISS). The LRP1B signature effectively distinguished high-risk patients within low/intermediate-risk categories and correlated with significant changes in the tumor immune microenvironment. Additionally, the LRP1B signature showed a strong association with proteasome inhibitor pathways, notably predicting patient responses to bortezomib and the progression from monoclonal gammopathy of unknown significance to MM. Through a rigorous analysis, this study underscores the potential of specific gene signatures in revolutionizing the prognostic landscape of MM, providing novel clinical insights that could influence future translational oncology research.

Identification of Disulfidptosis-Related Genes in Ischemic Stroke by Combining Single-Cell Sequencing, Machine Learning Algorithms, and In Vitro Experiments.

BACKGROUND: Ischemic stroke (IS) is a severe neurological disorder with a pathogenesis that remains incompletely understood. Recently, a novel form of cell death known as disulfidptosis has garnered significant attention in the field of ischemic stroke research. This study aims to investigate the mechanistic roles of disulfidptosis-related genes (DRGs) in the context of IS and to examine their correlation with immunopathological features. METHODS: To enhance our understanding of the mechanistic underpinnings of disulfidptosis in IS, we initially retrieved the expression profile of peripheral blood from human IS patients from the GEO database. We then utilized a suite of machine learning algorithms, including LASSO, random forest, and SVM-RFE, to identify and validate pivotal genes. Furthermore, we developed a predictive nomogram model, integrating multifactorial logistic regression analysis and calibration curves, to evaluate the risk of IS. For the analysis of single-cell sequencing data, we employed a range of analytical tools, such as "Monocle" and "CellChat," to assess the status of immune cell infiltration and to characterize intercellular communication networks. Additionally, we utilized an oxygen-glucose deprivation (OGD) model to investigate the effects of SLC7A11 overexpression on microglial polarization. RESULTS: This study successfully identified key genes associated with disulfidptosis and developed a reliable nomogram model using machine learning algorithms to predict the risk of ischemic stroke. Examination of single-cell sequencing data showed a robust correlation between disulfidptosis levels and the infiltration of immune cells. Furthermore, "CellChat" analysis elucidated the intricate characteristics of intercellular communication networks. Notably, the TNF signaling pathway was found to be intimately linked with the disulfidptosis signature in ischemic stroke. In an intriguing finding, the OGD model demonstrated that SLC7A11 expression suppresses M1 polarization while promoting M2 polarization in microglia. CONCLUSION: The significance of our findings lies in their potential to shed light on the pathogenesis of ischemic stroke, particularly by underscoring the pivotal role of disulfidptosis-related genes (DRGs). These insights could pave the way for novel therapeutic strategies targeting DRGs to mitigate the impact of ischemic stroke.

Evaluating TRAIL and IP-10 alterations in vaccinated pregnant women after COVID-19 diagnosis and their correlation with neutralizing antibodies.

Background: This study evaluates tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and interferon-γ-induced protein-10 (IP-10) in pregnant women with COVID-19 and their newborns, exploring the effects of antiviral treatments and vaccine-induced neutralizing antibody (Nab) inhibition on these key viral infection biomarkers. Methods: We studied 61 pregnant women with past COVID-19 and either three (n=56) or four (n=5) doses of vaccination, and 46 without COVID-19 but vaccinated. We analyzed them and their newborns' blood for TRAIL, IP-10, and Nab levels using enzyme-linked immunosorbent assays (ELISA), correlating these with other clinical factors. Results: Our study found lower TRAIL but higher IP-10 levels in maternal blood than neonatal cord blood, irrespective of past COVID-19 diagnosis. Cases diagnosed with COVID-19 < 4 weeks previously had higher maternal blood TRAIL levels (16.49 vs. 40.81 pg/mL, p=0.0064) and IP-10 (154.68 vs. 225.81 pg/mL, p=0.0170) than those never diagnosed. Antiviral medication lowered TRAIL and IP-10 in maternal blood without affecting Nab inhibition (TRAIL: 19.24 vs. 54.53 pg/mL, p=0.028; IP-10: 158.36 vs. 255.47 pg/mL, p=0.0089). TRAIL and IP-10 levels were similar with three or four vaccine doses, but four doses increased Nab inhibition (p=0.0363). Previously COVID-19 exposed pregnant women had higher Nab inhibition (p < 0.0001). No obvious correlation was found among TRAIL, IP-10, and Nab inhibition level. Conclusions: Our study suggests that lower maternal TRAIL and higher IP-10 levels compared to neonatal cord blood coupled with a rise in both markers following COVID-19 diagnosis that could be reduced by antivirals indicates a correlation to infection severity. Higher vaccine doses enhance Nab inhibition, irrespective of antiviral medication use and independent of TRAIL or IP-10 levels, highlighting the significance and safety of adequate vaccination and antiviral use post-diagnosis in pregnant women.

The prognostic effect of infiltrating immune cells is shaped by proximal M2 macrophages in lung adenocarcinoma.

The spatial arrangement of immune cells within the tumor microenvironment (TME) and their interactions play critical roles in the initiation and development of cancer. Several advanced technologies such as imaging mass cytometry (IMC) providing the immunological landscape of the TME with single-cell resolution. In this study, we develop a new method to quantify the spatial proximity between different cell types based on single-cell spatial data. Using this method on IMC data from 416 lung adenocarcinoma patients, we show that the proximity between different cell types is more correlated with patient prognosis compared to the traditional features such immune cell density and fractions. Consistent with previous reports, our results validate that proximity of T helper (Th) and B cells to cancer cells is associated with survival benefits. More importantly, we discover that the proximity of M2 macrophages to multiple immune cells is associated with poor prognosis. When Th/B cells are stratified into M2-distal and M2-proximal, the abundance of the former but not the latter category of Th/B cells is correlated with enhanced patient survival. Additionally, the abundance of M2-distal and M2-proximal cytotoxic T cells (Tc) is respectively associated with good and poor prognosis. Our results indicate that the prognostic effect of Th, Tc, and B cells in the tumor microenvironment is modulated by the nearby M2 macrophages. The proposed new method proposed can be readily applied to all single-cell spatial data for revealing functional impact of immune cell interactions.

Targeting ALDOA to modulate tumorigenesis and energy metabolism in retinoblastoma.

This study aims to elucidate the pivotal role of aldolase A (ALDOA) in retinoblastoma (RB) and evaluate the potential of the ALDOA inhibitor itaconate in impeding RB progression. Utilizing single-cell RNA sequencing, ALDOA consistently exhibits overexpression across diverse cell types, particularly in cone precursor cells, retinoma-like cells, and retinoblastoma-like cells. This heightened expression is validated in RB tissues and cell lines. ALDOA knockdown significantly diminishes RB cell viability, impedes colony formation, and induces notable metabolic alterations. RNA-seq analysis identifies SUSD2, ARHGAP27, and CLK2 as downstream genes associated with ALDOA. The application of itaconate demonstrates efficacy in inhibiting RB cell proliferation, validated through in vitro and in vivo models. This study emphasizes ALDOA as a promising target for innovative RB therapies, with potential implications for altering tumor energy metabolism.

IL-22: A key inflammatory mediator as a biomarker and potential therapeutic target for lung cancer.

Lung cancer, one of the most prevalent cancers worldwide, stands as the primary cause of cancer-related deaths. As is well-known, the utmost crucial risk factor contributing to lung cancer is smoking. In recent years, remarkable progress has been made in treating lung cancer, particularly non-small cell lung cancer (NSCLC). Nevertheless, the absence of effective and accurate biomarkers for diagnosing and treating lung cancer remains a pressing issue. Interleukin 22 (IL-22) is a member of the IL-10 cytokine family. It exerts biological functions (including induction of proliferation and anti-apoptotic signaling pathways, enhancement of tissue regeneration and immunity defense) by binding to heterodimeric receptors containing type 1 receptor chain (R1) and type 2 receptor chain (R2). IL-22 has been identified as a pro-cancer factor since dysregulation of the IL-22-IL-22R system has been implicated in the development of different cancers, including lung, breast, gastric, pancreatic, and colon cancers. In this review, we discuss the differential expression, regulatory role, and potential clinical significance of IL-22 in lung cancer, while shedding light on innovative approaches for the future.

[18F]AlF-PSMA-11 PET in diagnosing prostate cancer: a head-to-head comparison with [68Ga]Ga-PSMA-11 PET and an exploration of dual-phase scanning.

PURPOSE: To evaluate the physiological distribution and tumour detection ability of [18F]AlF-PSMA-11 positron emission tomography (PET) dual-phase scans in patients with prostate cancer (PCa). METHODS: As a retrospective study, clinical and PET data of PCa patients who underwent dual-phase [18F]AlF-PSMA-11 PET of routine scan (45-50 min) and delayed scan (120 min) from November 2020 to June 2021 were collected, and physiological and pathological regions of interest were quantified to determine the time-dependent maximum standardized uptake value (SUVmax) of [18F]AlF-PSMA-11. Part of the above subjects who underwent [68Ga]Ga-PSMA-11 PET in the following 6 months were included in a head-to-head comparison. The difference with a p-value < 0.05 was defined as statistical significance. Diagnosis accuracy of primary and metastatic lesions was measured referring to the surgical findings, pathology, and follow-up imaging. RESULTS: [68Ga]Ga-PSMA-11 and [18F]AlF-PSMA-11 were of the comparable uptake in glands in head, but the latter was of a significant lower distribution in liver and spleen. For the 25 patients initially diagnosed with prostate cancer and 3 patients with biochemical recurrence after radical surgery, the SUVmax of the primary lesions, lacrimal glands, parotid glands and submandibular glands was higher at 120 min compared to that at 45-50 min, but not a significant difference. SUVmax of the liver, spleen and bladder decreased significantly at 120 min, but the bladder SUVmax remained higher than that of primary lesions. SUVmax of the kidneys and centrum was the same in dual-phase scans. For the 31 primary lesions detected in [18F]AlF-PSMA-11 PET, both the SUVmax of the two phases kept the positive correlation with PSA, Gleason score and initial risk stratification. For the 39 distant metastatic lesions, 94.87% accuracy of routine scan and 100% accuracy of delayed scan were acquired, and 7.14% patients (2/28) benefited from the dual-phase [18F]AlF-PSMA-11 scans that revealed novel information on metastatic lesions compared to the routine scan. CONCLUSION: [18F]AlF-PSMA-11 PET expanded the time window and further decreased metabolic background of [68Ga]Ga-PSMA-11 PET. The dual-phase scan of [18F]AlF-PSMA-11 PET can benefit prostate cancer diagnosis via providing more PSMA-specific information.

Avicularin Attenuated Lead-Induced Ferroptosis, Neuroinflammation, and Memory Impairment in Mice.

Lead (Pb) is a common environmental neurotoxicant that results in abnormal neurobehavior and impaired memory. Avicularin (AVL), the main dietary flavonoid found in several plants and fruits, exhibits neuroprotective and hepatoprotective properties. In the present study, the effects of AVL on Pb-induced neurotoxicity were evaluated using ICR mice to investigate the molecular mechanisms behind its protective effects. Our study has demonstrated that AVL treatment significantly ameliorated memory impairment induced by lead (Pb). Furthermore, AVL mitigated Pb-triggered neuroinflammation, ferroptosis, and oxidative stress. The inhibition of Pb-induced oxidative stress in the brain by AVL was evidenced by the reduction in malondialdehyde (MDA) levels and the enhancement of glutathione (GSH) and glutathione peroxidase (GPx) activities. Additionally, in the context of lead-induced neurotoxicity, AVL mitigated ferroptosis by increasing the expression of GPX4 and reducing ferrous iron levels (Fe2+). AVL increased the activities of glycogenolysis rate-limiting enzymes HK, PK, and PYG. Additionally, AVL downregulated TNF-α and IL-1ß expression while concurrently enhancing the activations of AMPK, Nrf2, HO-1, NQO1, PSD-95, SNAP-25, CaMKII, and CREB in the brains of mice. The findings from this study suggest that AVL mitigates the memory impairment induced by Pb, which is associated with the AMPK/Nrf2 pathway and ferroptosis.

Exploring the prognostic value of BRMS1 + microglia based on single-cell anoikis regulator patterns in the immunologic microenvironment of GBM.

BACKGROUND: Anoikis is a specialized form of programmed cell death induced by the loss of cell adhesion to the extracellular matrix (ECM). Acquisition of anoikis resistance is a significant marker for cancer cell invasion, metastasis, therapy resistance, and recurrence. Although current research has identified multiple factors that regulate anoikis resistance, the pathological mechanisms of anoikis-mediated tumor microenvironment (TME) in glioblastoma (GBM) remain largely unexplored. METHODS: Utilizing single-cell RNA sequencing (scRNA-seq) data and employing non-negative matrix factorization (NMF), we identified and characterized TME cell clusters with distinct anoikis-associated gene signatures. Prognostic and therapeutic response analyses were conducted using TCGA and CGGA datasets to assess the clinical significance of different TME cell clusters. The spatial relationship between BRMS1 + microglia and tumor cells was inferred from spatial transcriptome RNA sequencing (stRNA-seq) data. To simulate the tumor immune microenvironment, co-culture experiments were performed with microglia (HMC3) and GBM cells (U118/U251), and microglia were transfected with a BRMS1 overexpression lentivirus. Western blot or ELISA were used to detect BRMS1, M2 macrophage-specific markers, PI3K/AKT signaling proteins, and apoptosis-related proteins. The proliferation and apoptosis capabilities of tumor cells were evaluated using CCK-8, colony formation, and apoptosis assays, while the invasive and migratory abilities of tumor cells were assessed using Transwell assays. RESULTS: NMF-based analysis successfully identified CD8 + T cell and microglia cell clusters with distinct gene signature characteristics. Trajectory analysis, cell communication, and gene regulatory network analyses collectively indicated that anoikis-mediated TME cell clusters can influence tumor cell development through various mechanisms. Notably, BRMS1 + AP-Mic exhibited an M2 macrophage phenotype and had significant cell communication with malignant cells. Moreover, high expression of BRMS1 + AP-Mic in TCGA and CGGA datasets was associated with poorer survival outcomes, indicating its detrimental impact on immunotherapy. Upregulation of BRMS1 in microglia may lead to M2 macrophage polarization, activate the PI3K/AKT signaling pathway through SPP1/CD44-mediated cell interactions, inhibit tumor cell apoptosis, and promote tumor proliferation and invasion. CONCLUSION: This pioneering study used NMF-based analysis to reveal the important predictive value of anoikis-regulated TME in GBM for prognosis and immunotherapeutic response. BRMS1 + microglial cells provide a new perspective for a deeper understanding of the immunosuppressive microenvironment of GBM and could serve as a potential therapeutic target in the future.

Case report: Cytokine and miRNA profiling in multisystem inflammatory syndrome in children.

Multisystem inflammatory syndrome in children (MIS-C) is an imperative pediatric inflammatory condition closely linked to COVID-19, which garners substantial attention since the onset of the pandemic. Like Kawasaki illness, this condition is characterized by an overactive immune response, leading to symptoms including pyrexia, cardiac and renal complications. To elucidate the pathogenesis of MIS-C and identify potential biomarkers, we conducted an extensive examination of specific cytokines (IL-6, IL-1ß, IL-6R, IL-10, and TNF-α) and microRNA (miRNA) expression profiles at various intervals (ranging from 3 to 20 days) in the peripheral blood sample of a severely affected MIS-C patient. Our investigation revealed a gradual decline in circulating levels of IL-6, IL-1ß, IL-10, and TNF-α following intravenous immune globulin (IVIG) therapy. Notably, IL-6 exhibited a significant reduction from 74.30 to 1.49 pg./mL, while IL-6R levels remained consistently stable throughout the disease course. Furthermore, we observed an inverse correlation between the expression of hsa-miR-596 and hsa-miR-224-5p and the aforementioned cytokines. Our findings underscore a robust association between blood cytokine and miRNA concentrations and the severity of MIS-C. These insights enhance our understanding of the genetic regulatory mechanisms implicated in MIS-C pathogenesis, offering potential avenues for early biomarker detection and therapy monitoring through miRNA analysis.

Genome-wide identification of pan-cancer common and cancer-specific alternative splicing events in 9 types of cancer.

Alternative splicing (AS) has significant clinical relevance with cancers and is a potential source of neoepitopes. In this study, RNA-seq data of 94 solid tumor and matched adjacent normal tissues from 47 clinical patients covering nine cancer types were comprehensively analyzed using SUVA developed by ourselves. The results identified highly conserved pan-cancer differential alternative splicing (DAS) events and cancer-specific DAS events in a series of tumor samples, which in turn revealed the heterogeneity of AS post-transcriptional regulation across different cancers. The co-disturbed network between spliceosome factors (SFs) and common cancer-associated DAS was further constructed, suggesting the potential possibility of the regulation of differentially expressed SFs on DAS. Finally, the common cancer-associated DAS events were fully validated using the TCGA dataset, confirming the significant correlation between cancer-associated DAS and prognosis. Briefly, our study elucidates new insights into conservatived and specific DAS in cancer, providing valuable resources for cancer therapeutic targets.

Advances in the Clinical Application of High-throughput Proteomics.

High-throughput proteomics has become an exciting field and a potential frontier of modern medicine since the early 2000s. While significant progress has been made in the technical aspects of the field, translating proteomics to clinical applications has been challenging. This review summarizes recent advances in clinical applications of high-throughput proteomics and discusses the associated challenges, advantages, and future directions. We focus on research progress and clinical applications of high-throughput proteomics in breast cancer, bladder cancer, laryngeal squamous cell carcinoma, gastric cancer, colorectal cancer, and coronavirus disease 2019. The future application of high-throughput proteomics will face challenges such as varying protein properties, limitations of statistical modeling, technical and logistical difficulties in data deposition, integration, and harmonization, as well as regulatory requirements for clinical validation and considerations. However, there are several noteworthy advantages of high-throughput proteomics, including the identification of novel global protein networks, the discovery of new proteins, and the synergistic incorporation with other omic data. We look forward to participating in and embracing future advances in high-throughput proteomics, such as proteomics-based single-cell biology and its clinical applications, individualized proteomics, pathology informatics, digital pathology, and deep learning models for high-throughput proteomics. Several new proteomic technologies are noteworthy, including data-independent acquisition mass spectrometry, nanopore-based proteomics, 4-D proteomics, and secondary ion mass spectrometry. In summary, we believe high-throughput proteomics will drastically shift the paradigm of translational research, clinical practice, and public health in the near future.

Paper-Based procalcitonin and Interleukin-6 test strip with Spectrum-Based optical reader for enterovirus severity differentiation in children.

Infectious diseases significantly impact global health, necessitating prompt diagnosis to mitigate life-threatening sepsis risk. Identifying patients at risk of severe neurological complications from enterovirus infections is challenging due to nonspecific initial presentations. Point-of-care testing (POCT) has emerged as a transformative tool, with low-cost lateral-flow colorimetric assays showing promise in deployable POCT devices. We developed a PCT/IL-6 rapid diagnostic system integrating lateral flow assay (LFA) test strips and a portable optical spectrum reader, allowing simultaneous semi-quantitative measurement of serum PCT and IL-6 within 30 min at the point of care. The system demonstrated a strong correlation with traditional ELISA and effectively differentiated severe pediatric enterovirus cases using serum samples. IL-6 showed superior discriminatory ability over PCT in identifying patients with severe neurological complications. This novel diagnostic platform holds great potential for early sepsis recognition and infectious disease management, especially in resource-limited settings.

Prognostic stratification in DLBCL patients with aberrant MYC gene.

Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease characterized by a subset of patients who exhibit treatment resistance and poor prognoses. Genomic assays have been widely employed to identify high-risk individuals characterized by rearrangements in the MYC, BCL2 and BCL6 genes. These patients typically undergo more aggressive therapeutic treatments; however, there remains a significant variation in their treatment outcomes. This study introduces an MYC signature score (MYCSS) derived from gene expression profiles, specifically designed to evaluate MYC overactivation in DLBCL patients. MYCSS was validated across several independent cohorts to assess its ability to stratify patients based on MYC-related genetic and molecular aberrations, enhancing the accuracy of prognostic evaluations compared to conventional MYC biomarkers. Our results indicate that MYCSS significantly refines prognostic accuracy beyond that of conventional MYC biomarkers focused on genetic aberrations. More importantly, we found that nearly 50% of patients identified as high risk by traditional MYC metrics actually share similar survival prospects with those having no MYC aberrations. These patients may benefit from standard GCB-based therapies rather than more aggressive treatments. MYCSS provides a robust signature that identifies high-risk patients, aiding in the precision treatment of DLBCL, and minimizing the potential for overtreatment.

Intermittent lysis on a single paper-based device to extract exosomal nucleic acid biomarkers from biological samples for downstream analysis.

As the role of exosomes in physiological and pathological processes has been properly perceived, harvesting them and their internal components is critical for subsequent applications. This study is a debut of intermittent lysis, which has been integrated into a simple and easy-to-operate procedure on a single paper-based device to extract exosomal nucleic acid biomarkers for downstream analysis. Exosomes from biological samples were captured by anti-CD63-modified papers before being intermittently lysed by high-temperature, short-time treatment with double-distilled water to release their internal components. Exosomal nucleic acids were finally adsorbed by sol-gel silica for downstream analysis. Empirical trials not only revealed that sporadically dropping 95 °C ddH2O onto the anti-CD63-modified papers every 5 min for 6 times optimized the exosomal nucleic acids extracted by the anti-CD63 paper but also verified that the whole deployed procedure is applicable for point-of-care testing (POCT) in low-resource areas and for both in vitro (culture media) and in vivo (plasma and chronic lesion) samples. Importantly, downstream analysis of exosomal miR-21 extracted by the paper-based procedure integrated with this novel technique discovered that the content of exosomal miR-21 in chronic lesions related to their stages and the levels of exosomal carcinoembryonic antigen originated from colorectal cancer cells correlated to their exosomal miR-21.