Downregulation of GPX8 in hepatocellular carcinoma: impact on tumor stemness and migration.

PURPOSE: GPX8, which is found in the endoplasmic reticulum lumen, is a member of the Glutathione Peroxidases (GPXs) family. Its role in hepatocellular carcinoma (HCC) is unknown. METHODS: Immunohistochemical staining was used to detect the protein levels of GPX8 in HCC tissue microarrays. A short hairpin RNA lentivirus was used to knock down GPX8, and the main signaling pathways were investigated using transcriptome sequencing and a phosphorylated kinase array. The sphere formation assays, cloning-formation assays and cell migration assays were used to evaluate the stemness and migration ability of HCC cells. Identifying the GPX8-interacting proteins was accomplished through immunoprecipitation and protein mass spectrometry. RESULTS: The GPX8 protein levels were downregulated in HCC patients. Low expression of GPX8 protein was related to early recurrence and poor prognosis in HCC patients. GPX8 knockdown could enhance the stemness and migration ability of HCC cells. Consistently, Based on transcriptome analysis, multiple signaling pathways that include the PI3K-AKT and signaling pathways that regulate the pluripotency of stem cells, were activated after GPX8 knockdown. The downregulation of GPX8 could increase the expression of the tumor stemness markers KLF4, OCT4, and CD133. The in vivo downregulation of GPX8 could also promote the subcutaneous tumor-forming and migration ability of HCC cells. MK-2206, which is a small-molecule inhibitor of AKT, could reverse the tumor-promoting effects both in vivo and in vitro. We discovered that GPX8 and the 71-kDa heat shock cognate protein (Hsc70) have a direct interaction. The phosphorylation of AKT encouraged the translocation of Hsc70 into the nucleus and the expression of the PI3K p110 subunit, thereby increasing the downregulation of GPX8. CONCLUSION: The findings from this study demonstrate the anticancer activity of GPX8 in HCC by inactivating the Hsc70/AKT pathway. The results suggest a possible therapeutic target for HCC.

The Osteocyte with SB216763-Activated Canonical Wnt Signaling Constructs a Multifunctional 4D Intelligent Osteogenic Module.

The enhancement of bioactivity in materials has become an important focus within the field of bone tissue engineering. Four-dimensional intelligent osteogenic module, an innovative fusion of 3D printing with the time axis, shows immense potential in augmenting the bioactivity of these materials, thereby facilitating autologous bone regeneration efficiently. This study focuses on novel bone repair materials, particularly bioactive scaffolds with a developmental osteogenic microenvironment prepared through 3D bioprinting technology. This research mainly creates a developmental osteogenic microenvironment named "DOME". This is primed by the application of a small amount of the small molecule drug SB216763, which activates canonical Wnt signaling in osteocytes, promoting osteogenesis and mineralization nodule formation in bone marrow stromal cells and inhibiting the formation of adipocytes. Moreover, DOME enhances endothelial cell migration and angiogenesis, which is integral to bone repair. More importantly, the DOME-PCI3D system, a 4D intelligent osteogenic module constructed through 3D bioprinting, stably supports cell growth (91.2% survival rate after 7 days) and significantly increases the expression of osteogenic transcription factors in bone marrow stromal cells and induces osteogenic differentiation and mineralization for 28 days. This study presents a novel approach for bone repair, employing 3D bioprinting to create a multifunctional 4D intelligent osteogenic module. This innovative method not only resolves challenges related to shape-matching and biological activity but also demonstrates the vast potential for applications in bone repair.

Development and Comparison of Treatment Decision Tools for Glucocorticoid-Induced Osteoporosis.

Long-term Glucocorticoid (GC) use results in compromised bone strength and fractures, and several treatment recommendations have been developed to prevent fractures, but none have been validated in a real-world setting. This study aims to create a treatment decision tool and compares this tool to the treatment suggestions from the American College of Rheumatology (ACR), International Osteoporosis Foundation and European Calcified Tissue Society (IOF-ECTS), and GC-adjusted Fracture Risk Assessment Tool (GC-FRAX), above the intervention threshold. We utilized registry data gathered at Chang Gung Memorial Hospital at Kaohsiung, Taiwan, between September 2014 and April 2021. This research is a single-center, observational, and case-controlled study. We recruited participants using prednisone for at least 2.5 mg/day or the equivalent dose for over 3 months, excluding those younger than 40, those with malignancies, or those currently undergoing anti-osteoporosis therapy. The primary endpoint was new fragility fractures within 3 years, including morphometric vertebral fractures detected at baseline and with a follow-up thoracic-lumbar spine X-ray. Participants were randomly allocated into derivation and validation sets. We developed the Steroid-Associated Fracture Evaluation (SAFE) tool in the derivation cohort by assessing the weights of exploratory variables via logistic regression. Prediction performance was compared in the validation set by the receiver operating characteristic (ROC) curve, the area under the curve (AUC), and sensitivity and specificity. A total of 424 treatment-naïve subjects were enrolled, and 83 (19.6%) experienced new fractures within 3 years. The final formula of the SAFE tool includes osteoporosis (1 point), an accumulated GC dose ≥ 750 mg within 6 months (or equivalent prednisolone of ≥4.5 mg/day for 6 months) (1 point), a BMI ≥ 23.5 (1 point), previous fractures (1 point), and elderliness of ≥70 years (2 points). In the validation set, a treatment decision based on the SAFE ≥ 2 points demonstrated an AUC of 0.65, with a sensitivity/specificity/accuracy of 75.9/54.0/58.9, with an ACR of 0.56 (100.0/11.0/31.0), IOF-ECTS 0.61 (75.9/46.0/52.7), and GC-FRAX 0.62 (82.8/42.0/51.2). Among current GIOP recommendations, the SAFE score serves as an appropriate treatment decision tool with increased accuracy and specificity.

A promise for neuronal repair: reprogramming astrocytes into neurons in vivo.

Massive loss of neurons following brain injury or disease is the primary cause of central nervous system dysfunction. Recently, much research has been conducted on how to compensate for neuronal loss in damaged parts of the nervous system and thus restore functional connectivity among neurons. Direct somatic cell differentiation into neurons using pro-neural transcription factors, small molecules, or microRNAs, individually or in association, is the most promising form of neural cell replacement therapy available. This method provides a potential remedy for cell loss in a variety of neurodegenerative illnesses, and the development of reprogramming technology has made this method feasible. This article provides a comprehensive review of reprogramming, including the selection and methods of reprogramming starting cell populations as well as the signaling methods involved in this process. Additionally, we thoroughly examine how reprogramming astrocytes into neurons can be applied to treat stroke and other neurodegenerative diseases. Finally, we discuss the challenges of neuronal reprogramming and offer insights about the field.

Clinical Efficacy of Neoadjuvant Chemotherapy plus Modified Radical Mastectomy for Stage II-III Breast Cancer Patients and Its Influence on Serum Tumor Markers.

Objective: This research aims to assess the clinical efficacy of neoadjuvant chemotherapy (NACT) in combination with modified radical mastectomy (MRM) for stage II-III breast cancer (BC) patients and its impact on serum tumor markers (STMs). Methods: The study included 119 stage II-III BC patients treated between June 2018 and June 2021. Among them, 55 cases underwent MRM (reference group), while 64 cases received NACT followed by MRM (research group). We compared intraoperative parameters (blood loss, operation time, hospital stay), clinical outcomes, the incidence of postoperative adverse events (AEs), changes in STMs (CA125, CA153, CEA), and one-year postoperative quality of life (QOL). Results: In comparison to the reference group, the research group exhibited significantly lower intraoperative blood loss, shorter operation times, reduced hospital stays, and higher rates of disease remission. Notably, the research group experienced a lower overall incidence of AEs, including skin flap necrosis, subscalp effusion, infection, and upper limb lymphedema. Postoperatively, all STMs in the research group exhibited statistically significant reductions and were lower than those in the reference group. Additionally, all QOL subscales demonstrated improvements and higher scores in the research group. Conclusions: NACT followed by MRM represents an effective approach for enhancing surgical outcomes and clinical efficacy in stage II-III BC patients. This combination therapy also reduces the risk of postoperative AEs and leads to favorable changes in STMs and postoperative QOL levels.

Multiomics analysis reveals metabolic subtypes and identifies diacylglycerol kinase α (DGKA) as a potential therapeutic target for intrahepatic cholangiocarcinoma.

BACKGROUND: Intrahepatic cholangiocarcinoma (iCCA) is a highly heterogeneous and lethal hepatobiliary tumor with few therapeutic strategies. The metabolic reprogramming of tumor cells plays an essential role in the development of tumors, while the metabolic molecular classification of iCCA is largely unknown. Here, we performed an integrated multiomics analysis and metabolic classification to depict differences in metabolic characteristics of iCCA patients, hoping to provide a novel perspective to understand and treat iCCA. METHODS: We performed integrated multiomics analysis in 116 iCCA samples, including whole-exome sequencing, bulk RNA-sequencing and proteome analysis. Based on the non-negative matrix factorization method and the protein abundance of metabolic genes in human genome-scale metabolic models, the metabolic subtype of iCCA was determined. Survival and prognostic gene analyses were used to compare overall survival (OS) differences between metabolic subtypes. Cell proliferation analysis, 5-ethynyl-2'-deoxyuridine (EdU) assay, colony formation assay, RNA-sequencing and Western blotting were performed to investigate the molecular mechanisms of diacylglycerol kinase α (DGKA) in iCCA cells. RESULTS: Three metabolic subtypes (S1-S3) with subtype-specific biomarkers of iCCA were identified. These metabolic subtypes presented with distinct prognoses, metabolic features, immune microenvironments, and genetic alterations. The S2 subtype with the worst survival showed the activation of some special metabolic processes, immune-suppressed microenvironment and Kirsten rat sarcoma viral oncogene homolog (KRAS)/AT-rich interactive domain 1A (ARID1A) mutations. Among the S2 subtype-specific upregulated proteins, DGKA was further identified as a potential drug target for iCCA, which promoted cell proliferation by enhancing phosphatidic acid (PA) metabolism and activating mitogen-activated protein kinase (MAPK) signaling. CONCLUSION: Via multiomics analyses, we identified three metabolic subtypes of iCCA, revealing that the S2 subtype exhibited the poorest survival outcomes. We further identified DGKA as a potential target for the S2 subtype.

YTHDF2-mediated regulations bifurcate BHPF-induced programmed cell deaths.

N6-methyladenosine (m6A) is a critical regulator in the fate of RNA, but whether and how m6A executes its functions in different tissues remains largely obscure. Here we report downregulation of a crucial m6A reader, YTHDF2, leading to tissue-specific programmed cell deaths (PCDs) upon fluorene-9-bisphenol (BHPF) exposure. Currently, Bisphenol A (BPA) substitutes are widely used in plastic manufacturing. Interrogating eight common BPA substitutes, we detected BHPF in 14% serum samples of pregnant participants. In a zebrafish model, BHPF caused tissue-specific PCDs triggering cardiac and vascular defects. Mechanistically, BHPF-mediated downregulation of YTHDF2 reduced YTHDF2-facilitated translation of m6A-gch1 for cardiomyocyte ferroptosis, and decreased YTHDF2-mediated m6A-sting1 decay for caudal vein plexus (CVP) apoptosis. The two distinct YTHDF2-mediated m6A regulations and context-dependent co-expression patterns of gch1/ythdf2 and tnfrsf1a/ythdf2 contributed to YTHDF2-mediated tissue-specific PCDs, uncovering a new layer of PCD regulation. Since BHPF/YTHDF2-medaited PCD defects were also observed in mammals, BHPF exposure represents a potential health threat.

Causal effects of genetically predicted endometriosis on breast cancer: a two-sample Mendelian randomization study.

This study used a Mendelian randomization (MR) approach to investigate the causal relationship between genetically predicted endometriosis (EMS) and breast cancer risk. A total of 122,977 cases and 105,974 controls were included in the analysis, with gene-level summary data obtained from the Breast Cancer Association Consortium (BCAC). An inverse variance-weighting approach was applied to assess the causal relationship between EMS and breast cancer risk, and weighted median and MR-Egger regression methods were used to evaluate pleiotropy. Results showed a causal relationship between EMS and a decreased risk of overall breast cancer (odds ratio [OR] 0.95; 95% CI 0.90-0.99, p = 0.02). Furthermore, EMS was associated with a lower risk for estrogen receptor (ER)-positive breast cancer in a subgroup analysis based on immunohistochemistry type (OR 0.91; 95% CI 0.86-0.97, p = 0.005). However, there was no causal association between ER-negative breast cancer and survival (OR 1.00; 95% CI 0.94-1.06, p = 0.89). Pleiotropy was not observed. These findings provide evidence of a relationship between EMS and reduced breast cancer risk in invasive breast cancer overall and specific tissue types, and support the results of a previous observational study. Further research is needed to elucidate the mechanisms underlying this association.

Effect of adding gelatin on the stability of water in water emulsions formed by mixtures of amylopectin and guar gum.

Stable water in water (W/W) emulsions of guar rich droplets dispersed in an amylopectin rich continuous phase (G/A) and the inverse (A/G) can be achieved by adding gelatin and inducing microphase separation of the latter by cooling. In this research, the effect of gelatin on the emulsion stability was further studied by storing the emulsions at 10, 20 and 25 °C. The visual aspect, the microstructure, and the viscosity of the emulsions were investigated at different times during storage at different temperatures and pH. It was found that depending on the conditions, the gelatin phase wetted the interface or formed small discrete microdomains that adsorbed at the interface and dispersed in the bulk phases. The observed differences in morphology and stability are related to the interplay of the rates of aggregation, phase separation of gelatin, which itself depend on the gelatin concentration, temperature and pH. Emulsions could be prepared in this manner that were stable for at least one week and remained visually homogeneous. We believe that this is a promising method to stabilize W/W emulsions as long as the components of the emulsion are incompatible with aggregated gelatin.

Integrated single cell and bulk sequencing analysis identifies tumor reactive CXCR6+ CD8 T cells as a predictor of immune infiltration and immunotherapy outcomes in hepatocellular carcinoma.

Background: Various immune cell types in the tumor microenvironment (TME) of hepatocellular carcinoma (HCC) have been identified as important parameters associated with prognosis and responsiveness to immunotherapy. However, how various factors influence immune cell infiltration remains incompletely understood. Hence, we investigated the single cell multi-omics landscape of immune infiltration in HCC, particularly key gene and cell subsets that influence immune infiltration, thus potentially linking the immunotherapy response and immune cell infiltration. Methods: We grouped patients with HCC according to immune cell infiltration scores calculated by single sample gene set enrichment analysis (ssGSEA). Differential expression analysis, functional enrichment, clinical trait association, gene mutation analysis, tumor immune dysfunction and exclusion (TIDE) and prognostic model construction were used to investigate the immune infiltration landscape through multi-omics. Stepwise regression was further used to identify key genes regulating immune infiltration. Single cell analysis was performed to explore expression patterns of candidate genes and investigate associated cellular populations. Correlation analysis, ROC analysis, Immunotherapy cohorts were used to explore and confirm the role of key gene and cellular population in predicting immune infiltration state and immunotherapy response. Immunohistochemistry and multiplexed fluorescence staining were used to further validated our results. Results: Patients with HCC were clustered into high and low immune infiltration groups. Mutations of CTNNB1 and TTN were significantly associated with immune infiltration and altered enrichment of cell populations in the TME. TIDE analysis demonstrated that T cell dysfunction and the T cell exclusion score were elevated in the high and low infiltration groups, respectively. Six risk genes and five risk immune cell types were identified and used to construct risk scores and a nomogram model. CXCR6 and LTA, identified by stepwise regression, were highly associated with immune infiltration. Single cell analysis revealed that LTA was expressed primarily in tumor infiltrating T lymphocytes and partial B lymphocytes, whereas CXCR6 was enriched predominantly in T and NK cells. Notably, CXCR6+ CD8 T cells were characterized as tumor enriched cells that may be potential predictors of high immune infiltration and the immune-checkpoint blockade response, and may serve as therapeutic targets. Conclusion: We constructed a comprehensive single cell and multi-omics landscape of immune infiltration in HCC, and delineated key genes and cellular populations regulating immune infiltration and immunotherapy response, thus providing insights into the mechanisms of immune infiltration and future therapeutic control.

Disease-modifying anti-rheumatic drugs associated with different diabetes risks in patients with rheumatoid arthritis.

OBJECTIVES: Patients with rheumatoid arthritis are prone to developing diabetes, which may lead to various sequelae and even cardiovascular diseases, the most common cause of death in such patients. Previous research has shown that some rheumatoid arthritis treatments may help prevent the development of diabetes. This study aimed to investigate whether patients using disease-modifying anti-rheumatic drugs (DMARDs) may have different levels of risk for diabetes and to analyse other risk factors for diabetes. METHODS: This cohort study used data from the Chang Gung Research Database. 5530 adults with rheumatoid arthritis but without diabetes were eligible for the analysis. The endpoint of this study was new-onset diabetes, defined as an HbA1c value ≥7% during follow-up. The entire follow-up period was divided into monthly subunits. These 1-month units were then divided into methotrexate (MTX) monotherapy, any biological DMARDs (bDMARDs), MTX combination, other conventional DMARDs (cDMARDs) and non-DMARDs. RESULTS: A total of 546 participants (9.87%) developed diabetes between 2001 and 2018. The risk of diabetes was significantly lower in the bDMARD periods (HR 0.51; 95% CI 0.32 to 0.83), MTX combination periods (HR 0.50; 95% CI 0.32 to 0.78) and other cDMARD periods (HR 0.56; 95% CI 0.37 to 0.84) than in the MTX monotherapy periods. Individual drug analysis showed that hydroxychloroquine (HR 0.52; 95% CI 0.42 to 0.65) reduced the risk of diabetes. Tumour necrosis factor-α inhibitors (HR 0.69; 95% CI 0.46 to 1.03) tended to be protective. CONCLUSION: Patients with rheumatoid arthritis may have different levels of risk of diabetes depending on the treatment options.

Autophagy suppression facilitates macrophage M2 polarization via increased instability of NF-κB pathway in hepatocellular carcinoma.

The tumor microenvironment is a highly heterogeneous circumstance composed of multiple components, while tumor-associated macrophages (TAMs) are major innate immune cells with highly plastic and are always educated by tumor cells to structure an advantageous pro-tumor immune microenvironment. Despite emerging evidence focalizing the role of autophagy in other immune cells, the regulatory mechanism of autophagy in macrophage polarization remains poorly understood. Herein, we demonstrated that hepatocellular carcinoma (HCC) cells educated macrophages toward M2-like phenotype polarization under the condition of coculture. Moreover, we observed that inhibition of macrophage autophagy promoted M2-like macrophage polarization, while the tendency was impeded when autophagy was motivated. Mechanistically, macrophage autophagy inhibition inactivates the NF-κB pathway by increasing the instability of TAB3 via ubiquitination degradation, which leads to the M2-like phenotype polarization of macrophages. Both immunohistochemistry staining using human HCC tissues and experiment in vivo verified autophagy inhibition is correlated with M2 macrophage polarization. Altogether, we illustrated that macrophage autophagy was involved in the process of HCC cells domesticating M2 macrophage polarization via the NF-κB pathway. These results provide a new target to interfere with the polarization of macrophages to M2-like phenotype during HCC progression.

Methyltransferase like 3 inhibition limits intrahepatic cholangiocarcinoma metabolic reprogramming and potentiates the efficacy of chemotherapy.

N6-methyladenosine (m6A) RNA methylation and its associated methyltransferase like 3 (METTL3) are involved in the development and maintenance of various tumors. The present study aimed to evaluate the cross-talk of METTL3 with glucose metabolism and reveal a novel mechanism for intrahepatic cholangiocarcinoma (ICC) progression. Real-time quantitative PCR, western blotting, and immunohistochemistry analyses suggested that METTL3 was highly expressed in ICC, which was correlated with poor patient prognosis. Immunoprecipitation sequencing of m6A-RNA showed that METTL3 upregulated m6A modification of NFAT5, which recruited IGF2BP1 for NFAT5 mRNA stabilization. Elevated expression of NFAT5 increased the expression of the gluconeogenesis-related genes GLUT1 and PGK1, resulting in enhanced aerobic glycolysis, proliferation, and tumor metastasis of ICC. Moreover, higher METTL3 expression was observed in tumor tissues of ICC patients with activated ICC glucose metabolism. Importantly, STM2457, a highly potent METTL3 inhibitor, which inhibited METTL3 activity and acted synergistically with gemcitabine, suggests that reprogramming RNA epigenetic modifications may serve as a potential therapeutic strategy. Overall, our findings highlighted the role of METTL3-mediated m6A modification of NFAT5 in activating glycolytic reprogramming in ICC and proposed that the METTL3/NFAT5 axis was a clinical target for the management of ICC chemoresistance by targeting cancer glycolysis.

Transcriptomic analysis reveals the potential biological mechanism of AIS and lung adenocarcinoma.

Introduction: Acute ischemic stroke (AIS) and lung adenocarcinoma (LUAD) are associated with some of the highest morbidity and mortality rates worldwide. Despite reports on their strong correlation, the causal relationship is not fully understood. The study aimed to identify and annotate the biological functions of hub genes with clinical diagnostic efficacy in AIS and LUAD. Methods: Transcriptome and single-cell datasets were obtained from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA). We identified the differentially expressed genes (DEGs) upregulated in AIS and LUAD and found 372 genes intersecting both datasets. Hub genes were identified using protein-protein interaction (PPI) networks, and the diagnostic and prognostic utility of these hub genes was then investigated using receiver operating characteristic (ROC) curves, survival analysis, and univariable Cox proportional hazard regression. Single-cell analysis was used to detect whether the hub genes were expressed in tumor epithelial cells. The immune microenvironment of AIS and LUAD was assessed using the CIBERSORT algorithm. The protein expression of these hub genes was tracked using the Human Protein Atlas (HPA). We calculated the number of positive cells using the digital pathology software QuPath. Finally, we performed molecular docking after using the Enrichr database to predict possible medicines. Results: We identified the molecular mechanisms underlying hub genes in AIS and LUAD and found that CCNA2, CCNB1, CDKN2A, and CDK1 were highly expressed in AIS and LUAD tissue samples compared to controls. The hub genes were mainly involved in the following pathways: the cell cycle, cellular senescence, and the HIF-1 signaling pathway. Using immunohistochemical slices from the HPA database, we confirmed that these hub genes have a high diagnostic capability for AIS and LUAD. Further, their high expression is associated with poor prognosis. Finally, curcumin was tested as a potential medication using molecular docking modeling. Discussion: Our findings suggest that the hub genes we found in this study contribute to the development and progression of AIS and LUAD by altering the cellular senescence pathway. Thus, they may be promising markers for diagnosis and prognosis.

m6A Modification Mediates Exosomal LINC00657 to Trigger Breast Cancer Progression Via Inducing Macrophage M2 Polarization.

BACKGROUND: Exosome-mediated transfer of long noncoding RNAs (lncRNAs) is critical for the cell-cell crosstalk in the tumor microenvironment. Nevertheless, the role of breast cancer (BC) cell-derived exosomal lncRNA in macrophage polarization during the development of BC remains unclear. METHODS: The key lncRNAs carried by BC cell-derived exosomes were identified by RNA-seq. CCK-8, flow cytometry, and transwell assay were conducted to analyze the role of LINC00657 in BC cells. In addition, immunofluorescence, qRT-PCR, western blot, and MeRIP-PCR were used to evaluate the function and underlying mechanism of exosomal LINC00657 in macrophage polarization. RESULTS: LINC00657 was distinctly upregulated in BC-derived exosomes and it was associated with increased m6A methylation modification levels. In addition, the depletion of LINC00657 significantly diminished the proliferative activity, migration and invasion potential of BC cells, and it also accelerated cell apoptosis. Exosomal LINC00657 from MDA-MB-231 cells could facilitate macrophage M2 activation, thus stimulating BC development in turn. Furthermore, LINC00657 activated the TGF-ß signaling pathway by sequestering miR-92b-3p in macrophages. CONCLUSION: Exosomal LINC00657 secreted by BC cells could induce macrophage M2 activation, and these macrophages preferentially contributed to the malignant phenotype of BC cells. These results improve our understanding of BC and suggest a new therapeutic strategy for patients with BC.

Factors associated with subclinical inflammation of wrist joints in rheumatoid arthritis patients with low or no disease activity- a RA ultrasound registry study.

BACKGROUND: To evaluate the factors to predict subclinical inflammation of wrist joints in patients with RA who are in clinical remission or low disease activity. METHODS: Gray scale and power Doppler ultrasound were performed on the dorsal radio-lunate of both wrists. The presence of synovitis, comorbidities, and use of disease modifying anti-rheumatic drugs were recorded. A Multivariable forward logistical regression model was used to identify factors associated with subclinical inflammation. RESULTS: There were 1248 patients (1010 females, 238 males; mean age: 60.0 ± 10.5 years ). 57.4% of patients in complete remission and low disease activity had sonographic inflammation. Multivariable forward logistic regression analysis indicated that male sex, smoking are positively associated with inflammation and that age, alcohol consumption, and use of methotrexate, glucocorticoid, or a biological therapy are negatively associated with inflammation. Use of biological agents decreased the risk of inflammation by 40.9%. CONCLUSIONS: There was evidence of subclinical inflammation in most patients who were in low or no disease activity, those with biological therapy had lower risk of subclinical inflammation.

Development of a deep pathomics score for predicting hepatocellular carcinoma recurrence after liver transplantation.

BACKGROUND AND PURPOSE: Tumor recurrence after liver transplantation (LT) impedes the curative chance for hepatocellular carcinoma (HCC) patients. This study aimed to develop a deep pathomics score (DPS) for predicting tumor recurrence after liver transplantation using deep learning. PATIENTS AND METHODS: Two datasets of 380 HCC patients who underwent LT were enrolled. Residual convolutional neural networks were used to identify six histological structures of HCC. The individual risk score of each structure and DPS were derived by a modified DeepSurv network. Cox regression analysis and Concordance index were used to evaluate the prognostic significance. The cellular exploration of prognostic immune biomarkers was performed by quantitative and spatial proximity analysis according to three panels of 7-color immunofluorescence. RESULTS: The overall classification accuracy of HCC tissue was 97%. At the structural level, immune cells were the most significant tissue category for predicting post-LT recurrence (HR 1.907, 95% CI 1.490-2.440). The C-indices of DPS achieved 0.827 and 0.794 in the training and validation cohorts, respectively. Multivariate analysis for recurrence-free survival (RFS) showed that DPS (HR 4.795, 95% CI 3.017-7.619) was an independent risk factor. Patients in the high-risk subgroup had a shorter RFS, larger tumor diameter and a lower proportion of clear tumor borders. At the cellular level, a higher infiltration of intratumoral NK cells was negatively correlated with recurrence risk. CONCLUSIONS: This study established an effective DPS. Immune cells were the most significant histological structure related to HCC recurrence. DPS performed well in post-LT recurrence prediction and the identification of clinicopathological features.

Somatic Cell Reprogramming for Nervous System Diseases: Techniques, Mechanisms, Potential Applications, and Challenges.

Nervous system diseases present significant challenges to the neuroscience community due to ethical and practical constraints that limit access to appropriate research materials. Somatic cell reprogramming has been proposed as a novel way to obtain neurons. Various emerging techniques have been used to reprogram mature and differentiated cells into neurons. This review provides an overview of somatic cell reprogramming for neurological research and therapy, focusing on neural reprogramming and generating different neural cell types. We examine the mechanisms involved in reprogramming and the challenges that arise. We herein summarize cell reprogramming strategies to generate neurons, including transcription factors, small molecules, and microRNAs, with a focus on different types of cells.. While reprogramming somatic cells into neurons holds the potential for understanding neurological diseases and developing therapeutic applications, its limitations and risks must be carefully considered. Here, we highlight the potential benefits of somatic cell reprogramming for neurological disease research and therapy. This review contributes to the field by providing a comprehensive overview of the various techniques used to generate neurons by cellular reprogramming and discussing their potential applications.

Inhibition of autophagy in macrophage promotes IL-1ß-mediated hepatocellular carcinoma progression via inflammasome accumulation and self-recruitment.

Hepatocellular carcinoma (HCC) has a complex and changeable tumor microenvironment. Despite emerging evidence focusing on autophagy process within immune cells, the function and regulatory mechanism of macrophage autophagy in tumor progression remains unclear. Our results of multiplex-immunohistochemistry and RNA-sequencing identified the reduced levels of autophagy in tumor macrophages in the HCC microenvironment, associated with a poor prognosis and increased microvascular metastasis in HCC patients. Specifically, HCC suppressed the macrophage autophagy initiation through the up-regulation of mTOR and ULK1 phosphorylation at Ser757. Knockdown of autophagy-related proteins to further inhibit autophagy significantly boosted the metastatic potential of HCC. Mechanistically, the accumulation of NLRP3 inflammasome mediated by autophagy inhibition promoted the cleavage, maturation, and release of IL-1ß, which facilitated the HCC progression, eventually accelerating HCC metastasis via the epithelial-mesenchymal transition. Autophagy inhibition provoked macrophage self-recruitment through the CCL20-CCR6 signaling was also a crucial account of HCC progression. Recruited macrophages mediated the cascade amplification of IL-1ß and CCL20 to form a novel pro-metastatic positive feedback loop through promoting HCC metastasis and increased macrophage recruitment, respectively. Notably, targeting IL-1ß/IL-1 receptor signaling impaired lung metastasis induced by macrophage autophagy inhibition in a mice HCC lung metastasis model. In summary, this study highlighted that inhibition of tumor macrophage autophagy facilitated HCC progression by increasing IL-1ß secretion via NLRP3 inflammasome accumulation and by macrophage self-recruitment through the CCL20 signaling pathway. Interruption of this metastasis-promoting loop by IL-1ß blockade may provide a promising therapeutic strategy for HCC patients.

Inorganic arsenic exposure promotes malignant progression by HDAC6-mediated down-regulation of HTRA1.

Inorganic arsenic (iAs) has been a human health concern and is associated with intestinal malignancies. However, the molecular mechanisms of the iAs-induced oncogenic process in intestine epithelial cells remain elusive, partly because of the known hormesis effect of arsenic. Here, we established that six-month exposure to iAs at a concentration similar to those found in contaminated drinking water could promote malignant characteristics, including enhanced proliferation and migration, resistance to apoptosis, and mesenchymal-like transition in Caco-2 cells. Transcriptome analysis and mechanism study revealed that key genes and pathways involved in cell adhesion, inflammation and oncogenic regulation were altered during chronic iAs exposure. Specifically, we uncovered that down-regulation of HTRA1 was essential for the iAs-induced acquisition of the cancer hallmarks. Further, we evidenced that the loss of HTRA1 during iAs-exposure could be restored by HDAC6 inhibition. Caco-2 cells with chronic exposure to iAs exhibited enhanced sensitivity to WT-161, a specific inhibitor of HDAC6, when used alone than in combination with a chemotherapeutic agent. These findings provide valuable information for understanding the mechanisms of arsenic-induced carcinogenesis and facilitating the health management of populations in arsenic-polluted areas.