Identification of a robust biomarker LAPTM4A for glioma based on comprehensive computational biology and experimental verification.

BACKGROUND: Glioma, a highly invasive and deadly form of human neoplasm, presents a pressing need for the exploration of potential therapeutic targets. While the lysosomal protein transmembrane 4A (LATPM4A) has been identified as a risk factor in pancreatic cancer patients, its role in glioma remains unexplored. METHODS: The analysis of differentially expressed genes (DEG) was conducted from The Cancer Genome Atlas (TCGA) glioma dataset and the Genotype Tissue Expression (GTEx) dataset. Through weighted gene co-expression network analysis (WGCNA), the key glioma-related genes were identified. Among these, by using Kaplan-Meier (KM) analysis and univariate/multivariate COX methods, LAPTM4A emerged as the most influential gene. Moreover, the bioinformatics methods and experimental verification were employed to analyze its relationships with diagnosis, clinical parameters, epithelial-mesenchymal transition (EMT), metastasis, immune cell infiltration, immunotherapy, drug sensitivity, and ceRNA network. RESULTS: Our findings revealed that LAPTM4A was up-regulated in gliomas and was associated with clinicopathological features, leading to poor prognosis. Furthermore, functional enrichment analysis demonstrated that LATPM4A played a role in the immune system and cancer progression. In vitro experiments indicated that LAPTM4A may influence metastasis through the EMT pathway in glioma. Additionally, we found that LAPTM4A was associated with the tumor microenvironment (TME) and immunotherapy. Notably, drug sensitivity analysis revealed that patients with high LAPTM4A expression were sensitive to doxorubicin, which contributed to a reduction in LAPTM4A expression. Finally, we uncovered the FGD5-AS1-hsa-miR-103a-3p-LAPTM4A axis as a facilitator of glioma progression. CONCLUSIONS: In conclusion, our study identifies LATPM4A as a promising biomarker for prognosis and immune characteristics in glioma.

What the SARS-CoV-2 Pandemic Has Taught Us About Immunosuppression, Vaccinations, and Immune Dysregulation: The Rheumatology Experience.

PURPOSE OF REVIEW: This review reflects on the impact of the COVID-19 pandemic on the field of rheumatology, emphasizing resulting insights related to the risks of viral infections in immunosuppressed patients, vaccine immunogenicity in immunocompromised patients, and immune dysregulation in the setting of viral infection. RECENT FINDINGS: During the pandemic, global patient registries provided real-time insights into the risk factors associated with severe COVID-19 outcomes in rheumatology patients. Updated evidence-based recommendations from the American College of Rheumatology (ACR) guided rheumatology practice during a time of considerable uncertainty. Studies on COVID-19 vaccines in immunocompromised populations enhanced our understanding of specific immunosuppressive therapies on vaccine efficacy. The immune dysregulation seen in severe COVID-19 underscored a role for immunomodulation in this and other severe infections. Furthermore, novel post-infectious conditions, namely multisystem inflammatory syndrome in children (MIS-C) and Long COVID, reshaped our understanding of post-viral syndromes and revealed novel pathological mechanisms. Lessons from the COVID-19 pandemic demonstrate the power of collaborative research. The scientific revelations from this dreadful time will, nonetheless, benefit the practice of rheumatology for years to come.

LAMP3 is a potent uterine corpus endometrial carcinoma prognostic biomarker associated with immune behavior.

BACKGROUND: Uterine corpus endometrial carcinoma (UCEC) is one of the most common gynecological malignancies and its incidence and mortality continue apace. Lysosome-associated membrane protein 3 (LAMP3) is the third member of the LAMP family and its overexpression has been described to be involved in the progression of breast, ovarian and cervical cancers, but there has been an absence of research focusing on its role in UCEC. METHODS: WGCNA, TIMER, LinkedOmics, GSEA, Cytoscape, Kaplan-Meier plotter, GDC, GeneMANIA, cBioPortal, PDB, RNAinter, miRNet were applied in this research. RESULTS: Our study uncovers that LAMP3 possesses higher expression levels in UCEC compared to normal tissues, and this differential expression profile is tightly aligned with clinical and pathological features, and patients demonstrating high LAMP3 expression tend to have a shorter survival expectancy. The high expression of LAMP3 is modulated by the designated ceRNA network. LAMP3 is engaged in UCEC progression by functioning in a variety of biological roles of relevance to immunity. Furthermore, we predicted several prospering drugs based on drug sensitivity. Finally, we also constructed possible docking patterns of LAMP3 with ABCA3, RAB9A, and SGTB. CONCLUSIONS: LAMP3 is a formidable biomarker for UCEC and could be a prospective candidate for the diagnosis, treatment and prognostic assessment of UCEC.

Fibroblast activation protein drives tumor metastasis via a protease-independent role in invadopodia stabilization.

During metastasis, tumor cells invade through the basement membrane and intravasate into blood vessels and then extravasate into distant organs to establish metastases. Here, we report a critical role of a transmembrane serine protease fibroblast activation protein (FAP) in tumor metastasis. Expression of FAP and TWIST1, a metastasis driver, is significantly correlated in several types of human carcinomas, and FAP is required for TWIST1-induced breast cancer metastasis to the lung. Mechanistically, FAP is localized at invadopodia and required for invadopodia-mediated extracellular matrix degradation independent of its proteolytic activity. Live cell imaging shows that association of invadopodia precursors with FAP at the cell membrane promotes the stabilization and growth of invadopodia precursors into mature invadopodia. Together, our study identified FAP as a functional target of TWIST1 in driving tumor metastasis via promoting invadopodia-mediated matrix degradation and uncovered a proteolytic activity-independent role of FAP in stabilizing invadopodia precursors for maturation.

Identified RP2 as a prognostic biomarker for glioma, facilitating glioma pathogenesis mainly via regulating tumor immunity.

Glioma is the most common primary intracranial tumor in the central nervous system, with a high degree of malignancy and poor prognosis, easy to recur, difficult to cure. The mutation of Retinitis Pigmentosa 2 (RP2) can cause retinitis pigmentosa, it is a prognostic factor of osteosarcoma, however, its role in glioma remains unclear. Based on the data from TCGA and GTEx, we identified RP2 as the most related gene for glioma by WGCNA, and used a series of bioinformatics analyses including LinkedOmics, GSCA, CTD, and so on, to explore the expression of RP2 in glioma and the biological functions it is involved in. The results showed that RP2 was highly expressed in glioma, and its overexpression could lead to poor prognosis. In addition, the results of enrichment analysis showed that RP2 was highly correlated with cell proliferation and immune response. And then, we found significant enrichment of Macrophages among immune cells. Furthermore, our experiments have confirmed that Macrophages can promote the development of glioma by secreting or influencing the secretion of some cytokines. Moreover, we investigated the influence of RP2 on the immunotherapy of glioma and the role of m6A modification in the influence of RP2 on glioma. Ultimately, we determined that RP2 is an independent prognostic factor that is mainly closely related to immune for glioma.

Impacts of crosslinking conditions on Pickering emulsions stabilized by genipin-crosslinked chitosan-caseinophosphopeptides nanocomplexes.

Polysaccharide-polypeptide nanocomplexes are promising colloidal Pickering stabilizers. The resulting Pickering emulsions, however, are susceptible to pH and ionic strength changes. This phenomenon was also observed in our recently developed Pickering emulsions stabilized by the chitosan (CS)-caseinophosphopeptides (CPPs) nanocomplexes. To improve the stability of these Pickering emulsions, we herein crosslinked the CS-CPPs nanocomplexes with a natural crosslinker genipin. The genipin-crosslinked CS-CPPs nanocomplexes (GCNs) were used to prepare Pickering emulsions. The impacts of genipin concentration, crosslinking temperature, and duration on the characteristics of GCNs and the GCNs-stabilized Pickering emulsions (GPEs) were systemically investigated. GCNs showed crosslinking strength-dependent variations in their physical properties. Crosslinking at a weak or strong condition weakened the emulsification ability of GCNs at low concentrations. A strong crosslinking condition also compromised the capacity of GCNs to stabilize a high fraction of oil. GPEs were oil-in-water type and gel-like. GCNs crosslinked at a lower temperature and for a shorter crosslinking duration stabilized stronger gel-like GPEs. Moreover, GPEs had high pH and ionic strength stabilities. This work provided a feasible way to enhance the stability and regulate the physical properties of Pickering emulsions stabilized by polysaccharide-polypeptide nanocomplexes.

Infectious profiles in pediatric anti-N-methyl-d-aspartate receptor encephalitis.

Anti-N-methyl-d-aspartate receptor autoimmune encephalitis (NMDAR AE) is an antibody-mediated neurological disorder that may be caused by post-herpes simplex virus-1 meningoencephalitis (HSV ME) and ovarian teratomas, although most pediatric cases are idiopathic. We sought to evaluate if other infections precede NMDAR AE by conducting a single-center, retrospective, case-control study of 86 pediatric cases presenting to Texas Children's Hospital between 2006 and 2022. HSV ME (HSV-1 and HSV-2) was a significantly more common preceding infection in the experimental group compared to control patients with idiopathic intracranial hypertension, while there was no difference in remote HSV infection between the two groups. Recent Epstein-Barr virus infection was evident in 8/42 (19%) tested experimental patients in comparison to 1/25 (4%) tested control patients which provided evidence for a genuine measure of effect but was not statistically significant due to small sample size (p = 0.07). The other 25 infectious etiologies were not different among the two groups and not all variables were clinically indicated or obtained in every subject, highlighting the need for future standardized, multi-institutional studies on underlying infectious precursors of autoimmune encephalitis.

FARSB serves as a novel hypomethylated and immune cell infiltration related prognostic biomarker in hepatocellular carcinoma.

PURPOSE: Hepatocellular carcinoma (HCC) is a prevalent tumor with high morbidity, and an unfavourable prognosis. FARSB is an aminoacyl tRNA synthase, and plays a key role in protein synthesis in cells. Furthermore, previous reports have indicated that FARSB is overexpressed in gastric tumor tissues and is associated with a poor prognosis and tumorigenesis. However, the function of FARSB in HCC has not been studied. RESULTS: The results showed that FARSB mRNA and protein levels were upregulated in HCC and were closely related to many clinicopathological characteristics. Besides, according to multivariate Cox analysis, high FARSB expression was linked with a shorter survival time in HCC and may be an independent prognostic factor. In addition, the FARSB promoter methylation level was negatively associated with the expression of FARSB. Furthermore, enrichment analysis showed that FARSB was related to the cell cycle. And TIMER analysis revealed that the FARSB expression was closely linked to tumor purity and immune cell infiltration. The TCGA and ICGC data analysis suggested that FARSB expression is greatly related to m6A modifier related genes. Potential FARSB-related ceRNA regulatory networks were also constructed. What's more, based on the FARSB-protein interaction network, molecular docking models of FARSB and RPLP1 were constructed. Finally, drug susceptibility testing revealed that FARSB was susceptible to 38 different drugs or small molecules. CONCLUSIONS: FARSB can serve as a prognostic biomarker for HCC and provide clues about immune infiltration, and m6A modification.

Comprehensive analysis reveals TSEN54 as a robust prognosis biomarker and promising immune-related therapeutic target for hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma represents the most common primary malignancy of all liver cancer types and its prognosis is usually unsatisfactory. TSEN54 encodes a protein constituting a subunit of the tRNA splicing endonuclease heterotetramer. Previous researches concentrated on the contribution of TSEN54 in pontocerebellar hypoplasia, but no studies have yet reported its role in HCC. METHODS: TIMER, HCCDB, GEPIA, HPA, UALCAN, MEXPRESS, SMART, TargetScan, RNAinter, miRNet, starBase, Kaplan-Meier Plotter, cBioPortal, LinkedOmics, GSEA, TISCH, TISIDB, GeneMANIA, PDB, GSCALite were applied in this research. RESULTS: We identified the upregulation of TSEN54 expression in HCC and related it to multiple clinicopathological features. Hypomethylation of TSEN54 was closely associated with its high expression. HCC sufferers who held high TSEN54 expression typically had shorter survival expectations. Enrichment analysis showed the involvement of TSEN54 in the cell cycle and metabolic processes. Afterward, we observed that TSEN54 expression level had a positive relationship to the infiltration level of multiple immune cells and the expression of several chemokines. We additionally identified that TSEN54 was related to the expression level of several immune checkpoints and TSEN54 was linked to several m6A-related regulators. CONCLUSIONS: TSEN54 is a prognostic marker of HCC. TSEN54 could become a prospective candidate for HCC diagnosis and therapy.

Microglia C-lectin/selectin' neurons to eat.

ß-glucosylceramide (ß-GlcCer) accumulates in Gaucher disease, but how ß-GlcCer, a Mincle ligand, causes characteristic neuroinflammation and neuronopathy is poorly understood. In this issue of Immunity, Shimizu et al. reveal that Mincle-dependent activation of microglia led to phagocytosis of neurons and neurologic symptoms.

Therapeutic strategies for human poxvirus infections: Monkeypox (mpox), smallpox, molluscipox, and orf.

Therapeutic and vaccine development for human poxvirus infections (e.g., monkeypox (mpox) virus, variola virus, molluscum contagiosum virus, orf virus) has been largely deserted, especially after the eradication of smallpox by 1980. Human mpox is a self-limited disease confined to Central and West Africa for decades. However, since April 2022, mpox has quickly emerged as a multi-country outbreak, urgently calling for effective antiviral agents and vaccines to control mpox. Here, this review highlights possible therapeutic options (e.g., tecovirimat, brincidofovir, cidofovir) and other strategies (e.g., vaccines, intravenous vaccinia immune globulin) for the management of human poxvirus infections worldwide.

Comprehensive analysis of prognostic value, relationship to cell cycle, immune infiltration and m6A modification of ZSCAN20 in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a common tumor across the globe with a high mortality rate. ZSCAN20 is a ZNF transcription factor, a key determinant of gene expression. Nonetheless, the mechanism of ZSCAN20 as a potential clinical biomarker and therapeutic target for HCC is not understood. Here, TIMER, TCGA, ICGC databases and immunohistochemical (IHC) and Western Blot found ZSCAN20 mRNA and protein levels were upregulated. Additionally, Kaplan-Meier Plotter, GEPIA and TCGA databases showed high ZSCAN20 expression was related to the short survival time of HCC patients. Multivariate Cox analysis exposed that ZSCAN20 can act as an independent prognostic factor. We observed methylation level of ZSCAN20 was associated with the clinicopathological characteristics and prognosis of HCC patients through UALCAN. Furthermore, enrichment examination exposed functional association between ZSCAN20 and cell cycle, immune infiltration. Functional experiments showed that interference with ZSCAN20 significantly reduced the invasion, migration and proliferation abilities of HCC cells. An immune infiltration analysis showed that ZSCAN20 was associated with immune cells, particularly T cells. The expression of ZSCAN20 was correlated with poor prognosis in the Regulatory T-cell. And Real-Time RT-PCR analysis found interference with ZSCAN20 significantly reduced the expression of some chemokines. Finally, the TCGA and ICGC data analysis suggested that the ZSCAN20 expression was greatly related to m6A modifier related genes. In conclusion, ZSCAN20 can serve as a prognostic biomarker for HCC and provide clues about cell cycle, immune infiltration, and m6A modification.

MND1 functions as a potential prognostic biomarker associated with cell cycle and immune infiltration in kidney renal clear cell carcinoma.

Kidney renal clear cell carcinoma (KIRC) is a common and invasive subtype of renal tumors, which has poor prognosis and high mortality. MND1 is a meiosis specific protein that participates in the progress of diverse cancers. Nonetheless, its function in KIRC was unclear. Here, TIMER, TCGA, GEO databases and IHC found MND1 expression is upregulated in KIRC, leading to poor overall survival, and MND1 can serve as an independent prognostic factor. Moreover, enrichment analysis revealed the functional relationship between MND1 and cell cycle, immune infiltration. EdU and transwell assays confirmed that MND1 knockdown surely prohibited the proliferation, migration, and invasion of KIRC cells. Additionally, immune analysis showed that MND1 displayed a strong correlation with various immune cells. Interference with MND1 significantly reduces the expression of chemokines. TCGA and GEO databases indicated that MND1 expression is significantly related to two m6A modification related gene (METTL14, IGF2BP3). Finally, the drug sensitivity analysis revealed 7 potentially sensitive drugs for KIRC patients with high MND1 expression. In conclusion, MND1 can be used as a prognostic biomarker for KIRC and provides clues regarding cell cycle, immune infiltrates and m6A. Sensitive drugs may be an effective treatment strategy for KIRC patients with high expression of MND1.

SARS-CoV-2 Infection Is Not Associated With Pediatric Appendicitis.

Although case reports have suggested an association between severe acute respiratory distress syndrome coronavirus 2 and appendicitis, we found that the overall incidence of appendicitis was stable throughout the pandemic at our tertiary pediatric hospital. Furthermore, we did not find evidence of CoV2 infection in 9 appendicitis tissues. Therefore, we conclude that severe acute respiratory distress syndrome coronavirus 2 infection of the appendix is not a common etiologic cause of pediatric appendicitis.

Enhancing Intestinal Permeability of Theaflavin-3,3'-digallate by Chitosan-Caseinophosphopeptides Nanocomplexes.

Low intestinal permeability is an unfavorable feature that limits the bioavailability of many hydrophilic polyphenols. In this study, chitosan (CS) was used to complex with caseinophosphopeptides (CPPs), aiming to improve the intestinal permeability of theaflavin-3,3'-digallate (TF-3), a characteristic polyphenol in black tea with poor intestinal permeability. Complexation between CS and CPPs was systemically investigated by turbidimetric titration under various conditions, revealing that electrostatic interaction was the dominant force. The sizes, PDIs, and ζ potentials of CS-CPP nanocomplexes varied with their compositions. The optimized CS-CPP nanocomplex was subsequently used to encapsulate TF-3, which showed high encapsulation efficiency and low cytotoxicity. Microstructural studies showed strong intermolecular associations between CS, CPPs, and TF-3. Encapsulation of TF-3 maintained the globular unit structure of CS-CPP nanocomplexes, but high concentrations of TF-3 resulted in aggregation. Importantly, as proved using the Caco-2 monolayer model, the intestinal permeability of TF-3 was significantly enhanced by the CS-CPP nanocomplexes.

Programmable Electrodeposition of Janus Alginate/Poly-L-Lysine/Alginate (APA) Microcapsules for High-Resolution Cell Patterning and Compartmentalization.

Encapsulation of live cells in protective, semipermeable microcapsules is one of the kernel techniques for in vitro tissue regeneration, cell therapies, and pharmaceutical screening. Advanced fabrication techniques for cell encapsulation have been developed to meet different requirements. Existing cell encapsulation techniques place substantial constraints on the spatial patterning of live cells as well as on the compartmentalization of heterotypic cells. Alginate-Poly-L-lysine-alginate (APA) microcapsules that use sodium alginate as the polyanion and poly-L-lysine (PLL) as the polycation have been extensively employed for cell microencapsulation due to their excellent biocompatibility and biodegradability. This study proposes a novel method for developing programmable Janus APA microcapsules with variable shapes and sizes by using electrodeposition. By the versatile design of the microelectrode device, sequential electrodeposition is triggered to electro-address the cells at specific locations immobilized within a Janus APA microcapsule. The osteogenesis is evaluated by resembling cell compartmentalized and vascularized osteoblast-laden constructs. This technique allows precise spatial patterning of heterotypic cells inside the APA microcapsule, enabling the observation of cellular growth, interactions, and differentiation in a well-controlled chemical and mechanical microenvironment.

Current understandings and clinical translation of nanomedicines for breast cancer therapy.

Breast cancer is one of the most frequently diagnosed cancers that is threatening women's life. Current clinical treatment regimens for breast cancer often involve neoadjuvant and adjuvant systemic therapies, which somewhat are associated with unfavorable features. Also, the heterogeneous nature of breast cancers requires precision medicine that cannot be fulfilled by a single type of systemically administered drug. Taking advantage of the nanocarriers, nanomedicines emerge as promising therapeutic agents for breast cancer that could resolve the defects of drugs and achieve precise drug delivery to almost all sites of primary and metastatic breast tumors (e.g. tumor vasculature, tumor stroma components, breast cancer cells, and some immune cells). Seven nanomedicines as represented by Doxil® have been approved for breast cancer clinical treatment so far. More nanomedicines including both non-targeting and active targeting nanomedicines are being evaluated in the clinical trials. However, we have to realize that the translation of nanomedicines, particularly the active targeting nanomedicines is not as successful as people have expected. This review provides a comprehensive landscape of the nanomedicines for breast cancer treatment, from laboratory investigations to clinical applications. We also highlight the key advances in the understanding of the biological fate and the targeting strategies of breast cancer nanomedicine and the implications to clinical translation.

Fabrication and in vitro digestion behavior of Pickering emulsions stabilized by chitosan-caseinophosphopeptides nanocomplexes.

The nanocomplexes assembled from chitosan (CS) and caseinophosphopeptides (CPPs) were utilized to stabilize Pickering emulsions with medium-chain triglyceride (MCT) as the oil phase. The CS-CPPs nanocomplexes composed of CS:CPPs = 1:1, 2:1, 4:1 were prepared and their physical properties including particle size, contact angle, and surface tension were characterized. The concentration ranges of these nanocomplexes that can stabilize Picking emulsion decreased in the following sequence, CS:CPPs = 1:1 (C1P1) > 2:1 (C2P1) > 4:1 (C4P1). The fraction of oil that can be stabilized by these three kinds of nanocomplexes at 0.15 wt% concentration was similar, and increasing the concentration of nanocomplexes can stabilize a higher fraction of MCT. The fluorescence microscopy image indicated that the Pickering emulsions were oil-in-water type emulsions. These emulsions were stable against ionic strength (0-0.3 M NaCl) changes after 24 h storage but low pH (pH 2) could affect their stabilities. These CS-CPPs nanocomplexes stabilized Pickering emulsions showed gel-like behavior. In vitro lipolysis studies revealed that coverage of the CS-CPPs nanocomplexes at the oil-water interface could reduce the rate and extent of MCT digestion, manifesting that they may potentially be used as fat replacers in foods to reduce oil absorption.

Associations between caseinophosphopeptides and theaflavin-3,3'-digallate and their impact on cellular antioxidant activity.

Caseinophosphopeptides (CPPs) are a group of bioactive polypeptides hydrolyzed from caseins. Theaflavin-3,3'-digallate (TF-3) is a characteristic biofunctional polyphenol in black tea. In the present study, the interactions between CPPs and TF-3 were systematically investigated with fluorescence quenching, quartz crystal microbalance with dissipation monitoring (QCM-D), circular dichroism (CD), and small-angle X-ray scattering (SAXS). Both fluorescence quenching and QCM-D studies demonstrated that TF-3 interacted with CPPs primarily through hydrogen bonding. Other forces were also involved. The addition of TF-3 did not change the secondary structures and the radius of gyration of CPPs, but it induced the aggregation of CPPs. The size of the aggregates increased with the concentration of TF-3. The impact of the association between TF-3 and CPPs on the antioxidant activity of TF-3 was studied by the cellular antioxidant activity (CAA) assay, which revealed that the cellular antioxidant activity of TF-3 was enhanced after binding to CPPs.