PBX/Knotted 1 homeobox-2 (PKNOX2) is a novel regulator of myocardial fibrosis.

Much effort has been made to uncover the cellular heterogeneities of human hearts by single-nucleus RNA sequencing. However, the cardiac transcriptional regulation networks have not been systematically described because of the limitations in detecting transcription factors. In this study, we optimized a pipeline for isolating nuclei and conducting single-nucleus RNA sequencing targeted to detect a higher number of cell signal genes and an optimal number of transcription factors. With this unbiased protocol, we characterized the cellular composition of healthy human hearts and investigated the transcriptional regulation networks involved in determining the cellular identities and functions of the main cardiac cell subtypes. Particularly in fibroblasts, a novel regulator, PKNOX2, was identified as being associated with physiological fibroblast activation in healthy hearts. To validate the roles of these transcription factors in maintaining homeostasis, we used single-nucleus RNA-sequencing analysis of transplanted failing hearts focusing on fibroblast remodelling. The trajectory analysis suggested that PKNOX2 was abnormally decreased from fibroblast activation to pathological myofibroblast formation. Both gain- and loss-of-function in vitro experiments demonstrated the inhibitory role of PKNOX2 in pathological fibrosis remodelling. Moreover, fibroblast-specific overexpression and knockout of PKNOX2 in a heart failure mouse model induced by transverse aortic constriction surgery significantly improved and aggravated myocardial fibrosis, respectively. In summary, this study established a high-quality pipeline for single-nucleus RNA-sequencing analysis of heart muscle. With this optimized protocol, we described the transcriptional regulation networks of the main cardiac cell subtypes and identified PKNOX2 as a novel regulator in suppressing fibrosis and a potential therapeutic target for future translational studies.

Novel a-linolenic acid emulsions stabilized by octenyl succinylated starch -soy protein-epigallocatechin-3-gallate complexes: Characterization and antioxidant analysis.

In this study, octenyl succinylated starch (OSAS)-soy protein (SP)-epigallocatechin-3-gallate (EGCG) complexes were designed to enhance the physical and oxidative stability of α-linolenic acid emulsions. Formations of OSAS-SP-EGCG complexes were confirmed via particle size, ξ-potential, together with fourier transform infrared (FTIR). A mixing ratio of 1:2 for OSAS to SP-EGCG resulted in ternary complexes with the highest contact angle (59.69°), indicating the hydrophobicity. Furthermore, the characteristics of α-linolenic acid emulsions (oil phase volume fractions (φ) of 10% and 20%) stabilized by OSAS-SP-EGCG complexes were investigated, including particle size, ξ-potential, emulsion stability, oxidative stability, and microstructure. These results revealed exceptional physical stability together with enhanced oxidative stability for these emulsions. Particularly, emulsions utilizing complexes having a 1:2 OSAS to SP-EGCG ratio exhibited superior emulsion stability. These findings provide theoretical support to the development of emulsions containing high levels of α-linolenic acid and for the broader application of α-linolenic acid in food products.

Mechanisms by which sheep milk consumption ameliorates insulin resistance in high-fat diet-fed mice.

Sheep milk is rich in fat, protein, vitamins and minerals and is also one of the most important sources of natural bioactives. Several biopeptides in sheep milk have been reported to possess antibacterial, antiviral and anti-inflammatory properties, and they may prevent type 2 diabetes (T2D), disease and cancer. However, the precise mechanism(s) underlying the protective role of sheep milk against T2D development remains unclear. Therefore, in the current study, we investigated the effect of sheep milk on insulin resistance and glucose intolerance in high-fat diet (HFD)-fed mice, by conducting intraperitoneal glucose tolerance tests, metabolic cage studies, genomic sequencing, polymerase chain reaction, and biochemical assays. Hyperinsulinemic-euglycemic clamp-based experiments revealed that mice consuming sheep milk exhibited lower hepatic glucose production than mice in the control group. These findings further elucidate the mechanism by which dietary supplementation with sheep milk alleviates HFD-induced systemic glucose intolerance.

Organic Semiconductor Based on N, S-Containing Crown Ether Enabling Efficient and Stable Perovskite Solar Cells.

The uncoordinated lead cations are ubiquitous in perovskite films and severely affect the efficiency and stability of perovskite solar cells (PSCs). In this work, 15-crown-5 with various heteroatoms are connected to the organic semiconductor carbazole diphenylamine, and two new compounds, CDT-S and CDT-N, are developed to modify the Pb2+ defects in perovskite films through the anti-solvent method. Apart from the oxygen atoms, there are also N atoms on crown ether ring in CDT-N, and both S and N heteroatoms in CDT-S. The heteroatoms enhance the interaction between the crown ether-based semiconductors and the undercoordinated Pb2+ defect in perovskite. Particularly, the stronger interaction between S atoms and Pb2+ further enhances the defect passivation effect of CDT-S than CDT-N, thereby more effectively suppressing the non-radiative recombination of charge carriers. Finally, the efficiency of the device treated with CDT-S is up to 23.05 %. Moreover, the unencapsulated device based on CDT-S maintained 90.5 % of the initial efficiency after being stored under dark conditions for 1000 hours, demonstrating good long-term stability. Our work demonstrates that crown ethers are promising in perovskite solar cells, and the crown ether containing multiple heteroatoms could effectively improve both efficiency and stability of devices.

DOCK1 insufficiency disrupts trophoblast function and pregnancy outcomes via DUSP4-ERK pathway.

Abnormal trophoblast function is associated with diseases such as recurrent spontaneous abortion, pre-eclampsia, and preterm birth, and endangers maternal and fetal health. However, the underlying regulatory mechanisms remain unclear. In this study, we found DOCK1 expression is decreased in the placental villi of patients with recurrent spontaneous abortion, and that its expression determined the invasive properties of extravillous trophoblasts (EVTs), highlighting a previously unknown role of DOCK1 in regulating EVT function. Furthermore, DOCK1 deficiency disturbed the ubiquitinated degradation of DUSP4, leading to its accumulation. This caused inactivation of the ERK signaling pathway, resulting in inadequate EVT migration and invasion. DOCK1 was implicated in regulating the ubiquitin levels of DUSP4, possibly by modulating the E3 ligase enzyme HUWE1. The results of our in vivo experiments confirmed that the DOCK1 inhibitor TBOPP caused miscarriage in mice by inactivating the DUSP4/ERK pathway. Collectively, our results revealed the crucial role of DOCK1 in the regulation of EVT function via the DUSP4-ERK pathway and a basis for the development of novel treatments for adverse pregnancy outcomes caused by trophoblast dysfunction.

Incorporating environmental capacity considerations to prioritize control factors for the management of heavy metals in soil.

Heavy metals (HMs) pollution threatens food security and human health. While previous studies have evaluated source-oriented health risk assessments, a comprehensive integration of environmental capacity risk assessments with pollution source analysis to prioritize control factors for soil contamination is still lacking. Herein, we collected 837 surface soil samples from agricultural land in the Nansha District of China in 2019. We developed an improved integrated assessment model to analyze the pollution sources, health risks, and environmental capacities of As, Cd, Cr, Cu, Hg, Ni, Pb, and Zn. The model graded pollution source impact on environmental capacity risk to prioritize control measures for soil HMs. All HMs except Pb exceeded background values and were sourced primarily from natural, transportation, and industrial activities (31.26%). Approximately 98.92% (children), 97.87% (adult females), and 97.41% (adult males) of carcinogenic values exceeded the acceptable threshold of 1E-6. HM pollution was classified as medium capacity (3.41 kg/hm2) with mild risk (PI = 0.52). Mixed sources of natural backgrounds, transportation, and industrial sources were identified as priority sources, and As a priority element. These findings will help prioritize control factors for soil HMs and direct resources to the most critical pollutants and sources of contamination, particularly when resources are limited.

GPR37 expression as a prognostic marker in gliomas: a bioinformatics-based analysis.

BACKGROUND: Gliomas are the most frequently diagnosed primary brain tumors, and are associated with multiple molecular aberrations during their development and progression. GPR37 is an orphan G protein-coupled receptor (GPCR) that is implicated in different physiological pathways in the brain, and has been linked to various malignancies. The aim of this study was to explore the relationship between GPR37 gene expression and the clinicopathological factors, patient prognosis, tumor-infiltrating immune cell signature GSEA and methylation levels in glioma. METHODS: We explored the diagnostic value, clinical relevance, and molecular function of GPR37 in glioma using TCGA, STRING, cBioPortal, Tumor Immunity Estimation Resource (TIMER) database and MethSurv databases. Besides, the "ssGSEA" algorithm was conducted to estimate immune cells infiltration abundance, with 'ggplot2' package visualizing the results. Immunohistochemical staining of clinical samples were used to verify the speculations of bioinformatics analysis. RESULTS: GPR37 expression was significantly higher in the glioma tissues compared to the normal brain tissues, and was linked to poor prognosis. Functional annotation of GPR37 showed enrichment of ether lipid metabolism, fat digestion and absorption, and histidine metabolism. In addition, GSEA showed that GPR37 was positively correlated to the positive regulation of macrophage derived foam cell differentiation, negative regulation of T cell receptor signaling pathway, neuroactive ligand receptor interaction, calcium signaling pathway, and negatively associated with immunoglobulin complex, immunoglobulin complex circulating, ribosome and spliceosome mediated by circulating immunoglobulin etc. TIMER2.0 and ssGSEA showed that GPR37 expression was significantly associated with the infiltration of T cells, CD8 T cell, eosinophils, macrophages, neutrophils, NK CD56dim cells, NK cells, plasmacytoid DCs (pDCs), T helper cells and T effector memory (Tem) cells. In addition, high GPR37 expression was positively correlated with increased infiltration of M2 macrophages, which in turn was associated with poor prognosis. Furthermore, GPR37 was positively correlated with various immune checkpoints (ICPs). Finally, hypomethylation of the GPR37 promoter was associated with its high expression levels and poor prognosis in glioma. CONCLUSION: GPR37 had diagnostic and prognostic value in glioma. The possible biological mechanisms of GPR37 provide novel insights into the clinical diagnosis and treatment of glioma.

Single-Cell RNA Sequencing of Coronary Perivascular Adipose Tissue From End-Stage Heart Failure Patients Identifies SPP1+ Macrophage Subpopulation as a Target for Alleviating Fibrosis.

BACKGROUND: Perivascular adipose tissue (PVAT) is vital for vascular homeostasis, and PVAT dysfunction is associated with increased atherosclerotic plaque burden. But the mechanisms underlining coronary PVAT dysfunction in coronary atherosclerosis remain elusive. METHODS: We performed single-cell RNA sequencing of the stromal vascular fraction of coronary PVAT from 3 groups of heart transplant recipients with end-stage heart failure, including 3 patients with nonobstructive coronary atherosclerosis, 3 patients with obstructive coronary artery atherosclerosis, and 4 nonatherosclerosis control subjects. Bioinformatics was used to annotate the cellular populations, depict the cellular developmental trajectories and interactions, and explore the differences among 3 groups of coronary PVAT at the cellular and molecular levels. Pathological staining, quantitative real-time polymerase chain reaction, and in vitro studies were performed to validate the key findings. RESULTS: Ten cell types were identified among 67 936 cells from human coronary PVAT. Several cellular subpopulations, including SPP1+ (secreted phosphoprotein 1) macrophages and profibrotic fibroadipogenic progenitor cells, were accumulated in PVAT surrounding atherosclerotic coronary arteries compared with nonatherosclerosis coronary arteries. The fibrosis percentage was increased in PVAT surrounding atherosclerotic coronary arteries, and it was positively associated with the grade of coronary artery stenosis. Cellular interaction analysis suggested OPN (osteopontin) secreted by SPP1+ macrophages interacted with CD44 (cluster of differentiation 44)/integrin on fibroadipogenic progenitor cells. Strikingly, correlation analyses uncovered that higher level of SPP1 in PVAT correlates with a more severe fibrosis degree and a higher coronary stenosis grade. In vitro studies showed that conditioned medium from atherosclerotic coronary PVAT promoted the migration and proliferation of fibroadipogenic progenitor cells, while such effect was prevented by blocking CD44 or integrin. CONCLUSIONS: SPP1+ macrophages accumulated in the PVAT surrounding atherosclerotic coronary arteries, and they promoted the migration and proliferation of fibroadipogenic progenitor cells via OPN-CD44/integrin interaction and thus aggravated the fibrosis of coronary PVAT, which was positively correlated to the coronary stenosis burden. Therefore, SPP1+ macrophages in coronary PVAT may participate in the progression of coronary atherosclerosis.

The Cellular Structure and Mechanical Properties of Polypropylene/Nano-CaCO3/Ethylene-propylene-diene-monomer Composites Prepared by an In-Mold-Decoration/Microcellular-Injection-Molding Process.

Polypropylene (PP)-composite foams were prepared by a combination process of microcellular injection molding (MIM) and in-mold decoration (IMD). The effect of ethylene propylene diene monomer (EPDM) on the crystallization properties, rheological properties, microstructure, and mechanical properties of PP-composite foams was studied. The effect of the additives on the strength and toughness of PP-composite foam as determined by the multiscale simulation method is discussed. The results showed that an appropriate amount of EPDM was beneficial to the cell growth and toughening of the PP blends. When the content of EPDM was 15 wt%, the PP-composite foams obtained the minimum cellular size, the maximum cellular density, and the best impact toughness. At the same time, the mesoscopic simulation shows that the stress concentration is the smallest, which indicates that 15 wt% EPDM has the best toughening effect in these composite materials.

Histone chaperone SSRP1 is required for apoptosis inhibition and mitochondrial function in HCC via transcriptional promotion of TRAP1.

Epigenetic regulation contributes to human health and disease, especially cancer, but the mechanisms of many epigenetic regulators remain obscure. Most research is focused on gene regulatory processes, such as mRNA translation and DNA damage repair, rather than the effects on biological functions like mitochondrial activity and oxidative phosphorylation. Here, we identified an essential role for the histone chaperone structure-specific recognition protein 1 (SSRP1) in mitochondrial oxidative respiration in hepatocellular carcinoma, and found that SSRP1 suppression led to mitochondrial damage and decreased oxidative respiration. Further, we focused on TNF receptor-associated protein 1 (TRAP1), the only member of the heat shock protein 90 (HSP90) family, which directly interacts with selected respiratory complexes and affects their stability and activity. We confirmed that SSRP1 downregulation caused a decrease in TRAP1 expression at both the mRNA and protein levels. A chromatin immunoprecipitation assay also showed that SSRP1 could deposit in the TRAP1 promoter region, indicating that SSRP1 maintains mitochondrial function and reactive oxygen species levels through TRAP1. Additionally, rescue experiments and animal experiments confirmed the mechanism of SSRP1 and TRAP1 interaction. In summary, we identified a new mechanism that connects mitochondrial respiration and apoptosis, via SSRP1.

Circ_0073228 serves as a competitive endogenous ribonucleic acid to facilitate proliferation and inhibit apoptosis of hepatocellular carcinoma cells by the miR-139-5p/deoxyribonuclease II axis.

BACKGROUND: Hepatocellular carcinoma (HCC) is a common malignancy and has extremely poor prognosis and outcome. Homo sapiens deoxyribonuclease II (DNASE2) has been reported to participate in HCC progression. Here, the role of DNASE2 in HCC cells and the putative upstream circRNA that mediates DNASE2 expression was investigated. METHODS: The expression of RNAs in liver hepatocellular carcinoma (LIHC) samples was analyzed by bioinformatic analysis. The proliferation, apoptosis, migration, invasion, and gene expression in HCC cells were investigated using a Cell Counting Kit -8, colony formation, flow cytometry analysis, wound healing, transwell, western blotting, and a quantitative reverse transcriptase-PCR. The binding relationship among circ_0073228, miR-139-5p and DNASE2 was measured by RNA pulldown and luciferase reporter assays. RESULTS: DNASE2 knockdown inhibited proliferation and promoted apoptosis of HCC cells, whereas DNASE2 overexpression showed the opposite results. miR-139-5p targeted DNASE2 and suppressed its expression. Overexpression of miR-139-5p inhibited malignant phenotypes of HCC cells. RPS23-derived circ_0073228, which bound to miR-139-5p, was found to be upregulated in HCC cells. Inhibition of miR-139-5p or overexpression of DNASE2 counteracted the inhibitory effects of circ_0073228 knockdown on HCC cell progression. CONCLUSIONS: circ_0073228 serves as an oncogene to facilitate growth and inhibit apoptosis of HCC cells by regulating the miR-139-5p/DNASE2 axis.

Mitochondrial-Targeted Triphenylphosphonium-Hydroxycamptothecin Conjugate and Its Nano-Formulations for Breast Cancer Therapy: In Vitro and In Vivo Investigation.

Mitochondria are involved in various stages of cancer cell diffusion and metastasis. Therefore, targeting tumor mitochondria with antineoplastic medicines to cause mitochondria to initiate apoptosis may be an effective strategy for cancer therapy. Here, in order to enhance the anti-tumor efficacy of the antineoplastic agent hydroxycamptothecin (HCPT), the mitochondrial targeting ligand 4-(carboxybutyl) triphenylphosphine bromide (TPP) was attached to HCPT by an ester linkage. The resultant TPP-HCPT (TH) conjugate could self-assemble into nano-aggregates, with a mean particle size of 203.2 nm and a polydispersity index (PDI) value of 0.312. The TH conjugate could also co-assembly with mPEG3000-PLGA5000 into nanoparticles (TH-NPs), with a mean diameter of 86.41 nm, a PDI value of 0.256 and a zeta potential of -0.125 mV. In contrast to HCPT injections, TH aggregates displayed enhanced cellular uptake, mitochondria-targetability and cytotoxicity against 4T1 cells, while TH-NPs showed even better improvement than TH aggregates. In the in vivo study, TH aggregates displayed higher anti-tumor efficacy in 4T1 tumor-bearing mice than HCPT injections (tumor inhibition rate, 55.71% vs. 69.17%), and TH-NPs displayed more superior anti-tumor effects (tumor inhibition rate, 80.02%). In conclusion, our research demonstrated that the TPP-HCPT conjugate and its nano-formulations, including TH aggregates and TH-NPs, may be a promising mitochondria-targeting anticancer medicine for cancer therapy. As far as we know, this is the first report in which TPP and HCPT have been conjugated directly for this aim.

Stat3 shRNA delivery with folate receptor-modified multi-functionalized graphene oxide particles for combined infrared radiation and gene therapy in hepatocellular carcinoma.

As a vital oncogene, a variety of inhibitors targeting Stat3 and its various upstream signaling pathways has been explored. Since small molecules, peptidomimetics and other peptide inhibitors usually lead to side effects and difficult administration, gene therapeutics that have characteristics of low toxicity and high targeting, make them an attractive alternative for targeting Stat3. A major challenge to this approach is the lack of safe delivery systems for in-vivo applications. Among the various siRNA delivery systems, nanoparticles emerge as a new tool for gene delivery with high biocompatibility, low cost, and minimal toxicity. In this study, we developed a graphene oxide (GO)-based nanocarrier, GO-polyethyleneimine (PEI)-polyethylene glycol (PEG)-folic acid (FA), as a tool targeting for Stat3-specific shRNA to mouse hepatoma cells in vitro and in vivo . Infrared photothermal therapy was combined in vivo since GO has the characteristic of infrared absorbability. Our results suggest a significant tumor growth inhibition after treatment with GO-PEI-PEG-FA- sh-Stat3 combined with infrared photothermal therapy. Thus, GO-PEI-PEG-FA appears to be a novel nano-transformer that could be used in the clinics in future.

LDHA deficiency inhibits trophoblast proliferation via the PI3K/AKT/FOXO1/CyclinD1 signaling pathway in unexplained recurrent spontaneous abortion.

Dysregulated trophoblast proliferation, invasion, and apoptosis may cause several pregnancy-associated complications, such as unexplained recurrent spontaneous abortion (URSA). Recent studies have shown that metabolic abnormalities, including glycolysis inhibition, may dysregulate trophoblast function, leading to URSA. However, the underlying mechanisms remain unclear. Herein, we found that lactate dehydrogenase A (LDHA), a key enzyme in glycolysis, was significantly reduced in the placental villus of URSA patients. The human trophoblast cell line HTR-8/SVneo was used to investigate the possible LDHA-mediated regulation of trophoblast function. LDHA knockdown in HTR-8/SVneo cells induced G0/G1 phase arrest and increased apoptosis, whereas LDHA overexpression reversed these effects. Next, RNA sequencing combined with Kyoto Encyclopedia of Genes and Genomes analysis demonstrated that the PI3K/AKT signaling pathway is potentially affected by downstream genes of LDHA. Especially, we found that LDHA knockdown decreased the phosphorylation levels of PI3K, AKT, and FOXO1, resulting in a significant downregulation of CyclinD1. In addition, treatment with an AKT inhibitor or FOXO1 inhibitor also verified that the PI3K/AKT/FOXO1 signaling pathway influenced the gene expression of CyclinD1 in trophoblast. Moreover, p-AKT expression correlated positively with LDHA expression in syncytiotrophoblasts and extravillous trophoblasts in first-trimester villus. Collectively, this study revealed a new regulatory pathway for LDHA/PI3K/AKT/FOXO1/CyclinD1 in the trophoblast cell cycle and proliferation.

Mesoporous Ti4O7 Spheres with Enhanced Zinc-Anchoring Effect for High-Performance Zinc-Nickel Batteries.

Zinc-nickel batteries are promising competitors for next-generation power supply due to their benefits of high safety, high working voltage, and attractive rate performance. However, their practical applications are plagued by their poor cycling performance, stemming from uneven redistribution of zinc during cycling that results in dendrite formation and shape changes of the electrode. In this work, mesoporous Ti4O7 microspheres are prepared and are employed as additives of a zinc anode. Notably, the presence of mesopores provides abundant chemisorption sites for Zn(OH)42- ions, inhibiting severe zinc redistribution in the electrode. Moreover, due to the good electrical conductivity and mesopores that serve as ion diffusion channels, the reaction reactivity and reversibility of the zinc electrode are greatly facilitated. As a result, the fabricated zinc-nickel battery with mesoporous Ti4O7 additives (ms-Ti4O7) exhibits an enhanced discharge capacity and a significantly prolonged cycling life. Even at a current of 10 A (∼138 mA cm-2), the ms-Ti4O7-modified anode demonstrates stable operation for longer than 718 h (700 cycles) with a discharge voltage of 1.2 V, which is much longer than those of a ZnO anode (192 h, 117 cycles) and a Ti4O7-particle (p-Ti4O7)-modified battery (590 h, 443 cycles). Furthermore, due to the anchoring effect for Zn(OH)42- and the uniform electric field, the effect of mesoporous Ti4O7 on inhibiting dendrite formation and shape change of the zinc electrode is highlighted.

Analysis on heterogeneity of hepatocellular carcinoma immune cells and a molecular risk model by integration of scRNA-seq and bulk RNA-seq.

Background: Studies have shown that hepatocellular carcinoma (HCC) heterogeneity is a main cause leading to failure of treatment. Technology of single-cell sequencing (scRNA) could more accurately reveal the essential characteristics of tumor genetics. Methods: From the Gene Expression Omnibus (GEO) database, HCC scRNA-seq data were extracted. The FindCluster function was applied to analyze cell clusters. Autophagy-related genes were acquired from the MSigDB database. The ConsensusClusterPlus package was used to identify molecular subtypes. A prognostic risk model was built with the Least Absolute Shrinkage and Selection Operator (LASSO)-Cox algorithm. A nomogram including a prognostic risk model and multiple clinicopathological factors was constructed. Results: Eleven cell clusters labeled as various cell types by immune cell markers were obtained from the combined scRNA-seq GSE149614 dataset. ssGSEA revealed that autophagy-related pathways were more enriched in malignant tumors. Two autophagy-related clusters (C1 and C2) were identified, in which C1 predicted a better survival, enhanced immune infiltration, and a higher immunotherapy response. LASSO-Cox regression established an eight-gene signature. Next, the HCCDB18, GSA14520, and GSE76427 datasets confirmed a strong risk prediction ability of the signature. Moreover, the low-risk group had enhanced immune infiltration and higher immunotherapy response. A nomogram which consisted of RiskScore and clinical features had better prediction ability. Conclusion: To precisely assess the prognostic risk, an eight-gene prognostic stratification signature was developed based on the heterogeneity of HCC immune cells.

Glucocorticoids combined with tofacitinib in the treatment of Castleman's disease: A case report.

BACKGROUND: Castleman's disease (CD), also known as vascular follicular lymphadenopathy is a rare proliferative disease of lymphoid tissue of unknown etiology that is clinically classified as unicentric CD (UCD) or multicentric CD (MCD) depending on lymph node involvement. At present, idiopathic MCD (iMCD) is treated with interleukin-6 inhibitors, but some patients have poor clinical outcomes. This paper reports on a case of iMCD that achieved a good therapeutic effect after treatment with glucocorticoids combined with tofacitinib. The relevant data are summarized and reported below. CASE SUMMARY: This paper reports on a case of MCD in a 49-year-old female with persistent peritoneal effusion as the first manifestation and combined with multiple lymphadenopathies. Lymph node biopsy showed Castleman's disease-like changes. The ascites subsided after treatment with glucocorticoids and tofacitinib, indicating that the treatment was effective. CONCLUSION: The combination of glucocorticoids with tofacitinib is an effective regimen for the treatment of CD.

A hypoxia-related prognostic model predicts overall survival and treatment response in hepatocellular carcinoma.

Hypoxia and hypoxia-related genes regulate tumor initiation and progression. However, the exact roles that hypoxia plays in hepatocellular carcinoma (HCC) remain unclear. In the present study, we calculated the hypoxia score of each sample in the GSE14520 training set by single-sample gene set enrichment analysis (ssGSEA). Then, weighted gene coexpression network analysis (WGCNA) was utilized to identify gene modules most correlated with hypoxia. Least absolute shrinkage and selection operator (LASSO) Cox regression analysis was utilized to further compress the candidate genes. We constructed the hypoxia-related prognostic risk score (HPRS) model based on the genes' corresponding Cox regression coefficients. Univariate and multivariate Cox analyses of the hypoxia score and clinicopathological characteristics showed that the hypoxia score and stage were the main risk factors affecting the overall survival of patients. Based on WGCNA, we identified 41 key hypoxia-related gene modules and screened out nine core genes to construct the HPRS model. Importantly, high-HPRS patients have a worse prognosis, while low-HPRS patients have a better prognosis. Further research showed that various immune cells, such as CD8 T cells, cytotoxic cells, and DCs, were significantly enriched in the low-HPRS group compared with the high-HPRS group. Notably, patients in the low-HPRS group were less likely to benefit from immunotherapy and chemotherapy than those in the high-HPRS group. In summary, we identified and validated a hypoxia-derived gene model that could serve as a potential biomarker to predict prognosis and therapeutic response in HCC.

RSL3 triggers glioma stem cell differentiation via the Tgm2/AKT/ID1 signaling axis.

RSL3 is a synthetic molecule that inactivates glutathione peroxidase 4 to induce ferroptosis. However, its effect on glioma stem cells (GSC) remains unclear. In this study, we found that RSL3 significantly suppressed GSC proliferation and induced their differentiation into astrocytes, which was accompanied by the downregulation of stemness-related markers, including Nestin and Sox2. Combined transcriptome and proteome analyses further revealed that RSL3 promoted GSC differentiation by suppressing transglutaminase 2 (Tgm2), but not by ferroptosis-related pathways. Tgm2 overexpression in CSC2078 cells rescued the changes in stemness-related markers and differentiation caused by RSL3, which was mediated by inhibitor of DNA binding 1 (ID1) activation. Further studies identified ID1 as a downstream signaling target of Tgm2. Blocking the phosphoinositide-3 kinase (PI3K)/Akt pathway with LY294002 suppressed PI3K, p-Akt, and ID1 levels but not Tgm2. Tgm2 overexpression abrogated the changes in PI3K, p-Akt, and ID1 levels caused by LY294002. Taken together, we demonstrate that RSL3 does not induce ferroptosis; instead, it inhibits GSC proliferation and triggers their differentiation by suppressing the Tgm2/Akt/ID1 signaling axis.