In situ repolarization of tumor-associated macrophages with synergic nanoformulation to reverse immunosuppressive TME in mouse breast cancer for cancer therapy.

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Fenamates: Forgotten treasure for cancer treatment and prevention: Mechanisms of action, structural modification, and bright future.

Fenamates as classical nonsteroidal anti-inflammatory agents are widely used for relieving pain. Preclinical studies and epidemiological data highlight their chemo-preventive and chemotherapeutic potential for cancer. However, comprehensive reviews of fenamates in cancer are limited. To accelerate the repurposing of fenamates, this review summarizes the results of fenamates alone or in combination with existing chemotherapeutic agents. This paper also explores targets of fenamates in cancer therapy, including COX, AKR family, AR, gap junction, FTO, TEAD, DHODH, TAS2R14, ion channels, and DNA. Besides, this paper discusses other mechanisms, such as regulating Wnt/ß-catenin, TGF-ß, p38 MAPK, and NF-κB pathway, and the regulation of the expressions of Sp, EGR-1, NAG-1, ATF-3, ErbB2, AR, as well as the modulation of the tumor immune microenvironment. Furthermore, this paper outlined the structural modifications of fenamates, highlighting their potential as promising leads for anticancer drugs.

Heavy Boron-Doped Silicon Tunneling Inter-layer Enables Efficient Silicon Heterojunction Solar Cells.

P-type hydrogenated nanocrystalline silicon (nc-Si:H) has been used as a hole-selective layer for efficient n-type crystalline silicon heterojunction (SHJ) solar cells. However, the presence of an additional valence band offset at the interface between intrinsic amorphous hydrogenated silicon and p-type nc-Si:H films will limit the hole carrier transportation. In this work, it has been found that when a heavily boron-doped silicon oxide layer deposited with high hydrogen dilution to silane (pB) was inserted into their interface, the fill factor of SHJ solar cells increases 3% absolutely because of the reduced valence band offset and the increased opportunity to provide a hopping tunnel assisted by the doping energy level and valence band tail states. Furthermore, the additional boron incorporation in intrinsic amorphous silicon adjacent to pB helps to enhance the built-in electric field, thus increasing the hole selectivity. By these means, the power conversion efficiency was improved from 23.9% to approximately 25%.

Modulation of π-Electron Density in Ultrathin 2D Layers of Graphite Carbon Nitride for Efficient Photocatalytic Hydrogen Production.

The rational design and synthesis of novel semiconductor nano-/quantum materials have been ambitiously pursued in the field of photocatalysis as the technology is promising and critical for attaining future energy and environmental sustainability. Herein, the integrity of aromatic carbon into graphitic carbon nitride (CN) at the same molecular plane with a few 2D layers is achieved by using modulated precursors of CN, forming carbon regulated ultrathin CN (CUCN) with improved charge transfer kinetics and photocatalytic hydrogen production. The grafted graphite rings adjacent to carbon nitride frameworks induce a significant rearrangement and relocalization of the overall framework, and form conjugated sp2 hybridized interfaces and internal electric fields that drive the separation and directional transfer of photogenerated electrons from CN sheets towards intralayer graphite regions, where the photocatalytic hydrogen evolution reaction occurs extensively, yielding largely increased HER rate of 2231.8 µmol g-1 h-1 by 8.2 times relative to CN, as well as a remarkable apparent quantum yield of 2.93% under monochromatic light at 420 nm. The high physicochemical stability and low synthesis cost of CUCN make it a potential benchmark photocatalyst that can be readily modified via element doping, heterojunction introduction, defect engineering, and so on, to further enhance its HER performance.

Urinary Equol and Equol-Predicting Microbial Genera Are Favorably Associated with Body Fat Measures among Chinese Adults.

BACKGROUND: Many studies have investigated the intake of dietary isoflavones in relation to obesity risk, whereas the association using objective biomarkers of isoflavones, particularly equol (a gut-derived metabolite of daidzein with greater bioavailability than other isoflavones) has been less studied. In addition, the associations between equol and gut microbiota profile at the population level remain to be fully characterized. OBJECTIVES: We aimed to identify equol-predicting microbial species and to investigate the associations of equol-predicting microbial species and urinary excretion of isoflavones including glycitein, genistein, daidzein, and equol with diverse obesity markers in free living-individuals. METHODS: In this 1-y longitudinal study of 754 community-dwelling adults, urinary isoflavones, fecal microbiota, height, weight, and circumferences of waist and hip were measured at baseline and again after 1 y. Liver fat [indicated by the controlled attenuation parameter (CAP)] and other body composition were also measured after 1 y. Linear models and linear mixed-effects models were used to analyze the associations for single measure and repeated measures, respectively. RESULTS: Among 305 participants (median age: 50 y, IQR, 37-59 y) including 138 males and 167 females, higher urinary excretion of equol was associated with lower CAP (ß = -0.013, P < 0.001) and body fat mass (ß= -0.014, P = 0.046). No association was found between any other urinary isoflavones and obesity markers (all P > 0.05). We identified 21 bacterial genera whose relative abundance were positively associated with urinary equol concentrations (all Pfalsediscovery rate < 0.05), and constructed an equol-predicting microbial score to reflect the overall equol-producing potential of host gut microbiota. This score was inversely associated with CAP (ß = -0.040, P = 0.011). CONCLUSIONS: High urinary equol concentrations and equol-predicting microbial species could be favorably associated with liver fat and other obesity markers.

Urinary Equol and Equol-Predicting Microbial Species Are Favorably Associated With Cardiometabolic Risk Markers in Chinese Adults.

BACKGROUND: The association between soy isoflavones intake and cardiometabolic health remains inconclusive. We investigated the associations of urinary biomarkers of isoflavones including daidzein, glycitein, genistein, equol (a gut microbial metabolite of daidzein), and equol-predicting microbial species with cardiometabolic risk markers. METHODS AND RESULTS: In a 1-year study of 305 Chinese community-dwelling adults aged ≥18 years, urinary isoflavones, fecal microbiota, blood pressure, blood glucose and lipids, and anthropometric data were measured twice, 1 year apart. Brachial-ankle pulse wave velocity was also measured after 1 year. A linear mixed-effects model was used to analyze repeated measurements. Logistic regression was used to calculate the adjusted odds ratio (aOR) and 95% CI for the associations for arterial stiffness. Each 1 µg/g creatinine increase in urinary equol concentrations was associated with 1.47%, 0.96%, and 3.32% decrease in triglycerides, plasma atherogenic index, and metabolic syndrome score, respectively (all P<0.05), and 0.61% increase in high-density lipoprotein cholesterol (P=0.025). Urinary equol was also associated with lower risk of arterial stiffness (aOR, 0.28 [95% CI, 0.09-0.90]; Ptrend=0.036). We identified 21 bacterial genera whose relative abundance was positively associated with urinary equol (false discovery rate-corrected P<0.05) and constructed a microbial species score to reflect the overall equol-predicting capacity. This score (per 1-point increase) was inversely associated with triglycerides (percentage difference=-1.48%), plasma atherogenic index (percentage difference=-0.85%), and the risk of arterial stiffness (aOR, 0.27 [95% CI, 0.08-0.88]; all P<0.05). CONCLUSIONS: Our findings suggest that urinary equol and equol-predicting microbial species may improve cardiometabolic risk parameters in Chinese adults.

Urinary enterolignans and enterolignan-predicting microbial species are favourably associated with liver fat and other obesity markers.

Aims: Plant-derived lignans may protect against obesity, while their bioactivity needs gut microbial conversion to enterolignans. We used repeated measures to identify enterolignan-predicting microbial species and investigate whether enterolignans and enterolignan-predicting microbial species are associated with obesity. Methods: Urinary enterolignans, fecal microbiota, body weight, height, and circumferences of the waist (WC) and hips (HC) were repeatedly measured at the baseline and after 1 year in 305 community-dwelling adults in Huoshan, China. Body composition and liver fat [indicated by the controlled attenuation parameter (CAP)] were measured after 1 year. Multivariate-adjusted linear models and linear mixed-effects models were used to analyze single and repeated measurements, respectively. Results: Enterolactone and enterodiol levels were both inversely associated with the waist-to-hip ratio, body fat mass (BFM), visceral fat level (VFL), and liver fat accumulation (all P < 0.05). Enterolactone levels were also associated with lower WC (ß = -0.0035 and P = 0.013) and HC (ß = -0.0028 and P = 0.044). We identified multiple bacterial genera whose relative abundance was positively associated with the levels of enterolactone (26 genera) and enterodiol (22 genera, all P false discovery rate < 0.05), and constructed the enterolactone-predicting microbial score and enterodiol-predicting microbial score to reflect the overall enterolignan-producing potential of the host gut microbiota. Both these scores were associated with lower body weight and CAP (all P < 0.05). The enterolactone-predicting microbial score was also inversely associated with the BFM (ß = -0.1128 and P = 0.027) and VFL (ß = -0.1265 and P = 0.044). Conclusion: Our findings support that modulating the host gut microbiome could be a potential strategy to prevent obesity by enhancing the production of enterolignans.

An IrRuOx catalyst supported by oxygen-vacant Ta oxide for the oxygen evolution reaction and proton exchange membrane water electrolysis.

The sustainable development of proton exchange membrane water electrolysis (PEMWE) requires a dramatic reduction in Ir while maintaining good catalytic activity and stability for the oxygen evolution reaction (OER). Herein, high-surface-area Ta2O5 with abundant oxygen vacancies is synthesized via a facile process, followed by anchoring IrRuOx onto a Ta2O5 support (IrRuOx/Ta2O5). IrRuOx and Ta2O5 work synergistically to afford excellent catalytic performance for the acidic OER. At 0.3 mgIr cm-2, IrRuOx/Ta2O5 only needed an overpotential of 235 mV to deliver 10 mA cm-2 in an acidic half cell and needed a cell potential of 1.91 V to deliver 2 A cm-2 in a PEM water electrolyzer. The characterization results show that doping Ir into RuOx significantly improves the stability and the electrochemically active surface area of RuOx. In IrRuOx/Ta2O5, IrRuOx interacts with Ta2O5 through more electron-rich Ir, indicating strong synergy between the catalyst and the support. The use of a metal oxide support improves the catalyst dispersion, optimizes electronic structures, facilitates mass transport, and stabilizes active sites. This work demonstrates that compositing Ir with less expensive Ru and anchoring catalyst nanoparticles on platinum-group metal (PGM)-free metal oxide supports represents one of the most promising strategies to reduce Ir loading and achieve an activity-stability trade-off. Such a strategy can benefit future catalyst design for other energy storage and conventional processes.

Oleic acid-PPARγ-FABP4 loop fuels cholangiocarcinoma colonization in lymph node metastases microenvironment.

BACKGROUND AND AIMS: Lymph node metastasis is a significant risk factor for patients with cholangiocarcinoma, but the mechanisms underlying cholangiocarcinoma colonization in the lymph node microenvironment remain unclear. We aimed to determine whether metabolic reprogramming fueled the adaptation and remodeling of cholangiocarcinoma cells to the lymph node microenvironment. APPROACH AND RESULTS: Here, we applied single-cell RNA sequencing of primary tumor lesions and paired lymph node metastases from patients with cholangiocarcinoma and revealed significantly reduced intertumor heterogeneity and syntropic lipid metabolic reprogramming of cholangiocarcinoma after metastasis to lymph nodes, which was verified by pan-cancer single-cell RNA sequencing analysis, highlighting the essential role of lipid metabolism in tumor colonization in lymph nodes. Metabolomics and in vivo CRISPR/Cas9 screening identified PPARγ as a crucial regulator in fueling cholangiocarcinoma colonization in lymph nodes through the oleic acid-PPARγ-fatty acid-binding protein 4 positive feedback loop by upregulating fatty acid uptake and oxidation. Patient-derived organoids and animal models have demonstrated that blocking this loop impairs cholangiocarcinoma proliferation and colonization in the lymph node microenvironment and is superior to systemic inhibition of fatty acid oxidation. PPARγ-regulated fatty acid metabolic reprogramming in cholangiocarcinoma also contributes to the immune-suppressive niche in lymph node metastases by producing kynurenine and was found to be associated with tumor relapse, immune-suppressive lymph node microenvironment, and poor immune checkpoint blockade response. CONCLUSIONS: Our results reveal the role of the oleic acid-PPARγ-fatty acid-binding protein 4 loop in fueling cholangiocarcinoma colonization in lymph nodes and demonstrate that PPARγ-regulated lipid metabolic reprogramming is a promising therapeutic target for relieving cholangiocarcinoma lymph node metastasis burden and reducing further progression.

Enhanced visible light photocatalytic activity of octopod Ag3PO4 microcrystals with high index crystal faces.

Novel octopod shaped Ag3PO4 microcrystals were successfully fabricated by a simple ion exchange method under the conditions of a hot water bath using [Ag(NH3)2]+ solution and Na2HPO4 solution as the precursors. Meanwhile, sphere and cube shaped Ag3PO4 microcrystals were also prepared followed by changing reaction materials as well as temperature. The surface morphology, microstructure and photocatalytic performance were investigated on the three different shaped crystals respectively. Compared to sphere and cube counterparts, the obtained octopod shaped Ag3PO4 crystals possess 8 symmetric feet with sharp tips and exhibit higher photocatalytic activity and better cycle stability. After further exploring its formation process, UV-vis diffusion reflectance properties as well as photocurrent transient response, it was found that the Ag3PO4 octopod had exposed high index crystal faces, and possessed a narrow band gap as well as high photoexcited transient charge separation efficiency. The results show that the improved photocatalytic activity of octopod shaped Ag3PO4 is mainly due to the synergistic action of the strong light absorption capacity and high carrier separation efficiency. These results highlight the tremendous practical application of octopod Ag3PO4 microcrystals in visible light photocatalysis.

The Combination of SHOX2 and RASSF1A DNA Methylation Had a Diagnostic Value in Pulmonary Nodules and Early Lung Cancer.

INTRODUCTION: The study explored the effects of SHOX2 and RASSF1A DNA methylation in lung cancer (LC). METHOD: Bronchoalveolar lavage fluid (BALF) samples as well as LC and normal adjacent tissues were collected from 72 LC patients and 35 patients with benign pulmonary nodules. Quantitative analysis of SHOX2 and RASSF1A DNA methylation was performed in benign pulmonary nodules and different stages of LC. The diagnostic value of SHOX2 and RASSF1A DNA methylation in LC and benign pulmonary nodules was determined by receiver operating characteristics analysis. Gain/loss-of-function experiments were constructed in LC cells and mouse models of xenograft and pulmonary nodule metastasis. The levels of SHOX2 and transfer-associated genes were tested through quantitative reverse transcription polymerase chain reaction and Western blot. Malignant phenotype of LC cells was assessed by functional experiment. The tumor volume and weight of mice in xenograft models were measured. Pulmonary nodule metastasis was determined through HE staining assay. 5-azacytidine appeared as a positive control drug. RESULT: SHOX2 DNA methylation or RASSF1A DNA methylation had diagnostic efficiency in pulmonary nodules and early LC, with the two combined having better diagnostic value. SHOX2 expression was upregulated in LC. Similar to 5-azacytidine, SHOX2 knockdown inhibited LC cell viability, migration, and invasion in vitro as well as restrained LC tumorigenesis and pulmonary nodule metastasis in vivo, whereas overexpressed SHOX2 had the opposite effects. CONCLUSION: The combination of SHOX2 and RASSF1A DNA methylation had a diagnostic value in pulmonary nodules and early LC. SHOX2 positively modulated the tumorigenesis and metastasis of LC by regulating DNA methylation processes.

RIPK1 inhibitors: A key to unlocking the potential of necroptosis in drug development.

Within the field of medical science, there is a great deal of interest in investigating cell death pathways in the hopes of discovering new drugs. Over the past two decades, pharmacological research has focused on necroptosis, a cell death process that has just been discovered. Receptor-interacting protein kinase 1 (RIPK1), an essential regulator in the cell death receptor signalling pathway, has been shown to be involved in the regulation of important events, including necrosis, inflammation, and apoptosis. Therefore, researching necroptosis inhibitors offers novel ways to treat a variety of disorders that are not well-treated by the therapeutic medications now on the market. The research and medicinal potential of RIPK1 inhibitors, a promising class of drugs, are thoroughly examined in this study. The journey from the discovery of Necrostatin-1 (Nec-1) to the recent advancements in RIPK1 inhibitors is marked by significant progress, highlighting the integration of traditional medicinal chemistry approaches with modern technologies like high-throughput screening and DNA-encoded library technology. This review presents a thorough exploration of the development and therapeutic potential of RIPK1 inhibitors, a promising class of compounds. Simultaneously, this review highlights the complex roles of RIPK1 in various pathological conditions and discusses potential inhibitors discovered through diverse pathways, emphasizing their efficacy against multiple disease models, providing significant guidance for the expansion of knowledge about RIPK1 and its inhibitors to develop more selective, potent, and safe therapeutic agents.

The triangular relationship between traditional Chinese medicines, intestinal flora, and colorectal cancer.

Over the past decade, colorectal cancer has reported a higher incidence in younger adults and a lower mortality rate. Recently, the influence of the intestinal flora in the initiation, progression, and treatment of colorectal cancer has been extensively studied, as well as their positive therapeutic impact on inflammation and the cancer microenvironment. Historically, traditional Chinese medicine (TCM) has been widely used in the treatment of colorectal cancer via promoted cancer cell apoptosis, inhibited cancer metastasis, and reduced drug resistance and side effects. The present research is more on the effect of either herbal medicine or intestinal flora on colorectal cancer. The interactions between TCM and intestinal flora are bidirectional and the combined impacts of TCM and gut microbiota in the treatment of colon cancer should not be neglected. Therefore, this review discusses the role of intestinal bacteria in the progression and treatment of colorectal cancer by inhibiting carcinogenesis, participating in therapy, and assisting in healing. Then the complex anticolon cancer effects of different kinds of TCM monomers, TCM drug pairs, and traditional Chinese prescriptions embodied in apoptosis, metastasis, immune suppression, and drug resistance are summarized separately. In addition, the interaction between TCM and intestinal flora and the combined effect on cancer treatment were analyzed. This review provides a mechanistic reference for the application of TCM and intestinal flora in the clinical treatment of colorectal cancer and paves the way for the combined development and application of microbiome and TCM.

Saying no to SARS-CoV-2: the potential of nitric oxide in the treatment of COVID-19 pneumonia.

Nitric oxide (NO), a gaseous free radical produced from L-arginine catalyzed by NO synthase, functions as an important signaling molecule in the human body. Its antiviral activity was confirmed in the 1990s, and has been studied more extensively since the outbreak of the SARS pandemic in 2003. In the fight against the ongoing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, some recent studies have revealed the potential of NO in the treatment of coronavirus disease 2019 (COVID-19). The progress in this field, including several noteworthy clinical trials of inhaled NO for the treatment of COVID-19 and the emergency approval of NO nasal spray by the regulatory agencies of Israel, Bahrain, Thailand and Indonesia for the treatment of COVID-19 pneumonia, offers a new perspective for addressing the raging coronavirus infection and greatly broadens the clinical application of NO therapy. This review aims to explore the underlying molecular mechanisms of NO-based therapy against SARS-CoV-2, including direct viral inhibition, immune regulation, and protection against pulmonary and cardiovascular symptoms. Furthermore, the potential therapeutic applications of inhaled NO, NO donors and drugs involved in the NO pathway are discussed. In the context of a global vaccination campaign and newly proposed strategy of "coexistence with COVID-19," the advantages of NO therapies as symptomatic and adjuvant treatments are expected to deliver breakthroughs in the treatment of COVID-19.

N/P co-doped MXene hollow microcapsules by surfactants assisted hydrothermal-freeze drying for adjustable permeability.

The assembly of MXene materials into microcapsules has drawn great attentions due to their unique properties. However, rational design and synthesis of MXene-based microcapsules with specific nanostructures at the molecular scale remains challenging. Herein, we report a strategy to synthesize N/P co-doped MXene hollow flower-like microcapsules with adjustable permeability via dual surfactants assisted hydrothermal-freeze drying method. In contrast to anionic surfactants, cationic surfactants exhibited effective electrostatic interactions with MXene nanosheets during the hydrothermal process. Manipulation of dual surfactants in hydrothermal process realized N and P co-doping of MXene to improve flexibility and promoted the generation of abundant internal cavities in flower-like microcapsules. Based on the unique microstructure, the prepared hollow flower-like microcapsules showed excellent performance, stability and reusability in size-selective release of small organic molecules. Moreover, the release rate can be controlled by turning the oxidation state and type of MXene. The strategy delineates promising prospects for the design of MXene-based microcapsules with specific structures.

Progress in the treatment of malignant ascites.

Malignant ascites occurs as a symptom of the terminal stage of cancer, affecting the quality of life through abdominal distension, pain, nausea, anorexia, dyspnea and other symptoms. We describe the current main drug treatments in addition to surgery according to the traditional and new strategies. Traditional treatments were based on anti-tumor chemotherapy and traditional Chinese medicine treatments, as well as diuretics to relieve the patient's symptoms. New treatments mainly involve photothermal therapy, intestinal therapy and targeted immunity. This study emphasizes that both traditional and new therapies have certain advantages and disadvantages, and medication should be adjusted according to different periods of use and different patients. In conclusion, this article reviews the literature to systematically describe the primary treatment modalities for malignant ascites.

Preparation of hydrophobic porous Au-Ag alloy nanoparticle arrays and their SERS properties.

In this study, we prepared porous Au-Ag alloy nanoparticle arrays with hydrophobic surfaces through the polystyrene colloidal crystal template combined with the chemical etching method to realize rapid SERS detection for biochemical molecules. In the preparation process, the pore size of Au-Ag alloy nanoparticles could be adjusted by changing the deposition time of the Ag element. Furthermore, after depositing the Au film on the surface of the porous nanoparticle arrays, their surface changed from hydrophilic to hydrophobic. The hydrophobic surface can drive target molecules to locally aggregate. Meanwhile, the hydrophobic surface also possessed a large number of active "hot spots" due to the porous structure. For these reasons, the porous Au-Ag alloy nanoparticle arrays can enable rapid and trace SERS detection, which provide the material basis for the subsequent construction of the high-quality SERS substrate.

Transcriptome analysis reveals molecular mechanisms of lymphocystis formation caused by lymphocystis disease virus infection in flounder (Paralichthys olivaceus).

Lymphocystis disease is frequently prevalent and transmissible in various teleost species worldwide due to lymphocystis disease virus (LCDV) infection, causing unsightly growths of benign lymphocystis nodules in fish and resulting in huge economic losses to aquaculture industry. However, the molecular mechanism of lymphocystis formation is unclear. In this study, LCDV was firstly detected in naturally infected flounder (Paralichthys olivaceus) by PCR, histopathological, and immunological techniques. To further understand lymphocystis formation, transcriptome sequencing of skin nodule tissue was performed by using healthy flounder skin as a control. In total, RNA-seq produced 99.36%-99.71% clean reads of raw reads, of which 91.11%-92.89% reads were successfully matched to the flounder genome. The transcriptome data showed good reproducibility between samples, with 3781 up-regulated and 2280 down-regulated differentially expressed genes. GSEA analysis revealed activation of Wnt signaling pathway, Hedgehog signaling pathway, Cell cycle, and Basal cell carcinoma associated with nodule formation. These pathways were analyzed to interact with multiple viral infection and tumor formation pathways. Heat map and protein interaction analysis revealed that these pathways regulated the expression of cell cycle-related genes such as ccnd1 and ccnd2 through key genes including ctnnb1, lef1, tcf3, gli2, and gli3 to promote cell proliferation. Additionally, cGMP-PKG signaling pathway, Calcium signaling pathway, ECM-receptor interaction, and Cytokine-cytokine receptor interaction associated with nodule formation were significantly down-regulated. Among these pathways, tnfsf12, tnfrsf1a, and tnfrsf19, associated with pro-apoptosis, and vdac2, which promotes viral replication by inhibiting apoptosis, were significantly up-regulated. Visual analysis revealed significant down-regulation of cytc, which expresses the pro-apoptotic protein cytochrome C, as well as phb and phb2, which have anti-tumor activity, however, casp3 was significantly up-regulated. Moreover, bcl9, bcl11a, and bcl-xl, which promote cell proliferation and inhibit apoptosis, were significantly upregulated, as were fgfr1, fgfr2, and fgfr3, which are related to tumor formation. Furthermore, RNA-seq data were validated by qRT-PCR, and LCDV copy numbers and expression patterns of focused genes in various tissues were also investigated. These results clarified the pathways and differentially expressed genes associated with lymphocystis nodule development caused by LCDV infection in flounder for the first time, providing a new breakthrough in molecular mechanisms of lymphocystis formation in fish.

Identification of a Novel Prognostic Signature Based on N-Linked Glycosylation and Its Correlation with Immunotherapy Response in Hepatocellular Carcinoma.

Background: The complex tumor microenvironment of hepatocellular carcinoma (HCC) has led to a low response to immune checkpoints inhibitors (ICIs) and a poor prognosis. PD-L1, as one of the indications for ICIs, is rich in glycosylation modifications, which result in untimely ICIs. Our study constructed a prognostic model based on N-linked glycosylation related genes for predicting the prognosis and the response to ICIs. Methods: The list of N-linked glycosylation related genes is from the AmiGO2 database. The patients in The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) cohorts were enrolled. The Cox regression was performed to develop a prognostic model and patients were divided into a low- and high-risk subgroups. The role of signature in HCC was well investigated by prognostic analysis, gene set enrichment analysis, and immune infiltration analysis. 21 recurrent HCC patients who received postoperative adjuvant ICIs were recruited to evaluate the relationship between immunotherapy response and the signature. In vitro studies were conducted to investigate the oncogenic effects of DDOST, STT3A and TMEM165 in HCC. Results: 59 N-linked glycosylation related differentially expressed genes were screened from HCC and normal tissues in the TCGA cohort. The prognostic model was developed with DDOST, STT3A and TMEM165. The risk score could be an independent prognostic factor. Patients in the high-risk subgroup showed a worse prognosis than patients in the low-risk one. ssGSEA showed that patients in the low-risk subgroup tended to be in the immune-activated state, with higher levels of B cell and macrophage cell infiltrations and lower levels of regulatory T cell (Treg) infiltrations in both TCGC and GEO cohorts. Immunohistochemistry studies showed that DDOST, STT3A and TMEM165 are highly expressed in tumor tissues and patients with a high-risk score correlated with poor progression free survival and worse immunotherapeutic response. Furthermore, the proliferation of HCC cells was reduced after the knockdown of DDOST, as well as upon the knockdown of STT3A and TMEM165. Conclusion: In this study, we establish that the risk model based on N-linked glycosylation related genes could efficiently predict the prognosis and tumor microenvironment immune state of HCC patients, and the risk score could serve as a novel indicator of immunotherapy.

Emerging advances in hydrogel-based therapeutic strategies for tissue regeneration.

Significant developments in cell therapy and biomaterial science have broadened the therapeutic landscape of tissue regeneration. Tissue damage is a complex biological process in which different types of cells play a specific role in repairing damaged tissues and growth factors strictly regulate the activity of these cells. Hydrogels have become promising biomaterials for tissue regeneration if appropriate materials are selected and the hydrogel properties are well-regulated. Importantly, they can be used as carriers for living cells and growth factors due to the high water-holding capacity, high permeability, and good biocompatibility of hydrogels. Cell-loaded hydrogels can play an essential role in treating damaged tissues and open new avenues for cell therapy. There is ample evidence substantiating the ability of hydrogels to facilitate the delivery of cells (stem cell, macrophage, chondrocyte, and osteoblast) and growth factors (bone morphogenetic protein, transforming growth factor, vascular endothelial growth factor and fibroblast growth factor). This paper reviewed the latest advances in hydrogels loaded with cells or growth factors to promote the reconstruction of tissues. Furthermore, we discussed the shortcomings of the application of hydrogels in tissue engineering to promote their further development.