The roles of extracellular vesicles in gliomas: Challenge or opportunity?

Gliomas are increasingly becoming a major disease affecting human health, and current treatments are not as effective as expected. Deeper insights into glioma heterogeneity and the search for new diagnostic and therapeutic strategies appear to be urgent. Gliomas adapt to their surroundings and form a supportive tumor microenvironment (TME). Glioma cells will communicate with the surrounding cells through extracellular vesicles (EVs) carrying bioactive substances such as nucleic acids, proteins and lipids which is related to the modification to various metabolic pathways and regulation of biological behaviors, and this regulation can be bidirectional, widely existing between cells in the TME, constituting a complex network of interactions. This complex regulation can affect glioma therapy, leading to different types of resistance. Because of the feasibility of EVs isolation in various body fluids, they have a promising usage in the diagnosis and monitoring of gliomas. At the same time, the nature of EVs to cross the blood-brain barrier (BBB) confers potential for their use as drug delivery systems. In this review, we will focus on the roles and functions of EVs derived from different cellular origins in the glioma microenvironment and the intercellular regulatory networks, and explore possible clinical applications in glioma diagnosis and precision therapy.

A Self-Assembled Transdermal Nanomedicines Incorporating Pendant Disulfides for Non-Invasive, Synergistic Treatment of Melanoma.

Transdermal drug delivery system (TDDS) offers lower systemic toxicity and good patient compliance, making it a promising treatment option for skin-related cancers. However, physiological barriers in the skin frequently impede the therapeutic efficiency of TDDS. To address this, a unique self-assembled TDDS that incorporates disulfide pendant groups (termed Sup-TDDS) is presented. It is formulated with dithiolane-containing lipoic acid (LA), photosensitizers Ce6, and chemotherapeutic agents trametinib. Pendant disulfide moieties on Sup-TDDS facilitate thiol-disulfide exchange reactions with exofacial thiols on cell surfaces, thus enhancing stratum corneum penetration. In contrast to intravenous injection, topical administration of Sup-TDDS can penetrate deeper into the skin (> 500 µm) and promote drug accumulation in subcutaneous tumors. In a B16F10-bearing mouse model, Sup-TDDS treatment demonstrates significant anti-tumor effects in primary and recurrent melanoma, benefiting from the synergistic effects of Ce6 and trametinib. These results underscore that Sup-TDDS's transdermal properties allow non-invasive melanoma therapy, implying the potential of nanodrugs containing pendant disulfides for transdermal treatment of skin illnesses.

Analysis of the ideal cutoff age as a predictor of differentiated thyroid cancer using the Surveillance, Epidemiology, and End Results database.

Background: It has been discovered that the prognosis of patients with differentiated thyroid cancer (DTC) correlates with age at initial diagnosis. However, there are disagreements over the optimal cutoff age among the numerous staging and risk stratification criteria, which make it inconsistent to predict the clinical prognosis of specific DTC patients. This study aimed to determine the optimum cutoff age for diagnosis in relation to the clinical outcomes of DTC using data from the Surveillance, Epidemiology and End Results (SEER) database. Methods: The best age cutoff value was determined by the X-tile software. The link between clinical characteristics and cancer-specific survival (CSS) was examined using univariate and multivariate Cox regression models. An additional application of the independent prognostic criteria, such as age stratifications, was applied to construct a nomogram model for predicting the chances of patient survival. Results: The most accurate diagnosis cutoff age for DTC patients was suggested to be 67 years old. The multivariate analysis, using factors determined by univariate analysis, showed that age [>67 years, hazard rate (HR) =5.049, 95% confidence interval (CI): 4.509-5.653, P<0.001], sex (female, HR =0.651, 95% CI: 0.584-0.727, P<0.001), tumor size (>20 and ≤40 mm, HR =2.296, 95% CI: 1.983-2.658, P<0.001; >40 mm, HR =4.976, 95% CI: 4.304-5.752, P<0.001), lymphadenectomy (HR =1.337, 95% CI: 1.186-1.506, P<0.001), distant metastasis (HR =12.166, 95% CI: 10.749-13.769, P<0.001) and surgical treatment (HR =0.173, 95% CI: 0.144-0.210, P<0.001) were independent factors for CSS. Patients in the high-risk group had worse survival rates, and the C-index for the CSS prediction model with age (cutoff of 67) and other independent clinicopathological variables was 0.906. Conclusions: Accordingly, the optimal cutoff age for predicting death from DTC specifically is 67 years old at the time of the initial diagnosis. It might be a more suitable factor when used in risk stratification for patients with DTC.

Endosome-microautophagy targeting chimera (eMIATAC) for targeted proteins degradation and enhance CAR-T cell anti-tumor therapy.

Rationale: Since oncogene expression products often exhibit upregulation or abnormally activated activity, developing a technique to regulate abnormal protein levels represent a viable approach for treating tumors and protein abnormality-related diseases. Methods: We first screened out eMIATAC components with high targeted degradation efficiency and explored the mechanism by which eMIATAC induced target protein degradation, and verified the degradation efficiency of the target protein by protein imprinting and flow cytometry. Next, we recombined eMIATAC with some controllable elements to verify the regulatable degradation performance of the target protein. Subsequently, we constructed eMIATAC that can express targeted degradation of AKT1 and verified its effect on GBM cell development in vitro and in vivo. Finally, we concatenated eMIATAC with CAR sequences to construct CAR-T cells with low BATF protein levels and verified the changes in their anti-tumor efficacy. Results: we developed a system based on the endosome-microautophagy-lysosome pathway for degrading endogenous proteins: endosome-MicroAutophagy TArgeting Chimera (eMIATAC), dependent on Vps4A instead of lysosomal-associated membrane protein 2A (LAMP2A) to bind to the chaperone Hsc70 and the protein of interest (POI). The complex was then transported to the lysosome by late endosomes, where degradation occurred similarly to microautophagy. The eMIATACs demonstrated accuracy, efficiency, reversibility, and controllability in degrading the target protein EGFP. Moreover, eMIATAC exhibited excellent performance in knocking down POI when targeting endogenous proteins in vivo and in vitro. Conclusions: The eMIATACs could not only directly knock down abnormal proteins for glioma treatment but also enhance the therapeutic effect of CAR-T cell therapy for tumors by knocking down T cell exhaustion-related proteins. The newly developed eMIATAC system holds promise as a novel tool for protein knockdown strategies. By enabling direct control over endogenous protein levels, eMIATAC has the potential to revolutionize treatment for cancer and genetic diseases.

Regulation of Hippo/YAP axis in colon cancer progression by the deubiquitinase JOSD1.

Colon cancer is a prevalent malignancy, while recent studies revealed the dys-regulation of Hippo signaling as the important driver for colon cancer progression. Several studies have indicated that post-translational modifications on YAP play crucial roles in both Hippo signaling activity and cancer progression. This raises a puzzling question about why YAP/TAZ, an auto-inhibitory pathway, is frequently over-activated in colon cancer, despite the suppressive cascade of Hippo signaling remaining operational. The protein stability of YAP is subject to a tiny balance between ubiquitination and deubiquitination processes. Through correlation analysis of DUBs (deubiquitinases) expression and Hippo target gene signature in colon cancer samples, we found JOSD1 as a critical deubiquitinase for Hippo signaling and colon cancer progression. JOSD1 could facilitate colon cancer progression and in colon cancer, inhibition of JOSD1 via shRNA has been demonstrated to impede tumorigenesis. Furthermore, molecular mechanism studies have elucidated that JOSD1 enhances the formation of the Hippo/YAP transcriptome by impeding K48-linked polyubiquitination on YAP. ChIP assays have shown that YAP binds to JOSD1's promoter region, promoting its gene transcription. These results suggest that JOSD1 is involved in both activating and being targeted by the Hippo signaling pathway in colon cancer. Consequently, a positive regulatory loop between JOSD1 and Hippo signaling has been identified, underscoring their interdependence during colon cancer progression. Thus, targeting JOSD1 may represent a promising therapeutic approach for managing colon cancer.

Silencing CK19 regulates ferroptosis by affecting the expression of GPX4 and ACSL4 in oral squamous cell carcinoma in vivo and in vitro.

To analyze the mechanism of how interfering with the cytokeratin 19 (CK19) pathway via the ferroptosis pathway affects tumor biological behaviors in the process of oral squamous cell carcinoma (OSCC) development. TCGA was used to analyze the expression of CK19 in pan-cancer and head and neck squamous cell carcinoma (HNSC) and to explore the ferroptosis-related genes related to HNSC. The effect of silencing CK19 on the migration ability of HSC-4 cells was verified by wound healing and migration assay. HSC-4 cells with silencing of CK19 and tumor-bearing nude mouse model were constructed. RT-qPCR, immunofluorescence and western blot were used to analyze the expression of ferroptosis-related genes. CK19 is highly expressed in human OSCC and nude mice. The migration ability of cells in the CK19-silenced group was lower than that of the control group. In vivo and in vitro, CK19 was negatively correlated with the expression of ACSL4 and positively correlated with the expression of GPX4. Compared with the control group, GPX4 expression was down-regulated and ACSL4 expression was up-regulated in the CK19-silenced group. Silencing CK19 also increased intracellular Fe2+ content and MDA content. Silencing CK19 can affect the expression of GPX4 and ACSL4 to regulate ferroptosis and at the same time increase the content of MDA, Fe2+ and ROS levels, thereby activating the regulation of ferroptosis pathway in the development of OSCC.

DNMT3A promotes glioma growth and malignancy via TNF-α/NF-κB signaling pathway.

Background: DNMT3A is the main molecule responsible for DNA methylation in cells. DNMT3A affects the progression of inflammation, degenerative diseases, and malignant tumors, and exhibits significant aberrantly expression in tumor tissues. Methods: Transcriptome data and relevant clinical information were downloaded from The Cancer Genome Atlas (TCGA), Chinese Glioma Genome Atlas (CGGA), and Gene Expression Omnibus (GEO) datasets. Differential expression analysis and prognostic analysis were conducted based on above statistics. We constructed a clinical prognostic model and identified DNMT3A as an independent prognostic factor to accurately predict patient prognosis. Differential gene enrichment analysis revealed that DNMT3A affects the progression of glioma through multiple pathways, among which the tumor necrosis factor-α (TNF-α)/nuclear factor-kappa B (NF-κB) pathway shows a strong correlation. Immunological analysis also revealed a certain correlation between DNMT3A and tumor immunity. We demonstrated through gene editing that DNMT3A can affect the release of TNF-α in cells, thereby affecting the progression of glioma. Functional experiments have also demonstrated that DNMT3A plays a crucial role in tumors. Results: RNA-sequencing and survival analyses of lower-grade glioma (LGG) patients in TCGA, CGGA, and GEO cohorts showed that high DNMT3A expression correlated with poor prognosis of LGG patients. Univariate and multivariate Cox regression analyses showed that DNMT3A expression was an independent prognostic indicator in LGG. The prognosis prediction nomogram with age, World Health Organization (WHO) grading, and DNMT3A expression showed reliable performance in predicting the 1-, 3-, and 5-year overall survival (OS) of LGG patients. Functional enrichment analysis, gene set enrichment analysis (GSEA), and ESTIMATE algorithm analyses showed that DNMT3A expression was associated with the tumor infiltration of immune cells and predicted response to immunotherapy in two immunotherapy cohorts of pan-cancer patients. Furthermore, short hairpin RNA (shRNA)-mediated knockdown of DNMT3A in the LGG cell lines suppressed proliferation, migration, and invasion of LGG cells by downregulating the TNF-α/NF-κB signaling pathway. Conclusions: Our data showed that DNMT3A was a potential prognostic biomarker in glioma. DNMT3A promoted proliferation and malignancy of LGG cells through the TNF-α/NF-κB signaling pathway. DNMT3A is a promising therapeutic target for treating patients with LGG.

A novel immune-related long noncoding RNA (lncRNA) pair model to predict the prognosis of triple-negative breast cancer.

Background: Breast cancer (BC) is the most prevalent cancer type and is the principal cause of cancer-related death in women. Anti-programmed cell death protein 1/programmed cell death ligand 1 (PD-1/PD-L1) immunotherapy has shown promising effects in metastatic triple-negative breast cancer (TNBC), but the potential factors affecting its efficacy have not been elucidated. Immune-related long noncoding RNAs (irlncRNAs) have been reported to be involved in immune escape to influence the carcinogenic process through the PD-1/PD-L1 signaling pathway. Therefore, exploring the potential regulatory mechanism of irlncRNAs in PD-1/PD-L1 immunotherapy in TNBC is of great importance. Methods: We retrieved transcriptome profiling data from The Cancer Genome Atlas (TCGA) and identified differentially expressed irlncRNA (DEirlncRNA) pairs. Least absolute shrinkage and selection operator (LASSO) regression analysis was performed to construct a risk assessment model. Results: Receiver operating characteristic (ROC) curve analysis indicated that the risk model may serve as a potential prediction tool in TNBC patients. Clinical stage and risk score were proved to be independent prognostic predictors by univariate and multivariate Cox regression analyses. Subsequently, we investigated the correlation between the risk model and tumor-infiltrating immune cells and immune checkpoints. Finally, we identified USP30-AS1 through the StarBase and Multi Experiment Matrix (MEM) databases, predicted the potential target genes of USP30-AS1, and then discovered that these target genes were closely associated with immune responses. Conclusions: Our study constructed a risk assessment model by irlncRNA pairs regardless of expression levels, which contributed to predicting the efficacy of immunotherapy in TNBC. Furthermore, the lncRNA USP30-AS1 in the model was positively correlated with the expression of PD-L1 and provided a potential therapeutic target for TNBC.

Comprehensive analyses of m1A regulator-mediated modification patterns determining prognosis in lower-grade glioma (running title: m1A in LGG).

N1-methyladenosine (m1A) modification is a crucial post-transcriptional regulatory mechanism of messenger RNA (mRNA) in living organisms. Few studies have focused on analysis of m1A regulators in lower-grade gliomas (LGG). We employed the Nonnegative Matrix Factorization (NMF) technique on The Cancer Genome Atlas (TCGA) dataset to categorize LGG patients into 2 groups. These groups exhibited substantial disparities in terms of both overall survival (OS) and levels of infiltrating immune cells. We collected the significantly differentially expressed immune-related genes between the 2 clusters, and performed LASSO regression analysis to obtain m1AScores, and established an m1A-related immune-related gene signature (m1A-RIGS). Next, we categorized all patients with LGG into high- and low-risk subgroups, predictive significance of m1AScore was confirmed by conducting univariate/multivariate Cox regression analyses. Additionally, we confirmed variations in immune-related cells and ssGSEA and among the high-/low-risk subcategories in the TCGA dataset. Finally, our study characterized the effects of MSR1 and BIRC5 on LGG cells utilizing Edu assay and flow cytometry to explore the effects of modulation of these genes on glioma. The results of this study suggested that m1A-RIGS may be an excellent prognostic indicator for patients with LGG, and could also promote development of novel immune-based treatment strategies for LGG. Additionally, BIRC5 and MSR1 may be potential therapeutic targets for LGG.

Smart Nanocarriers for the Treatment of Retinal Diseases.

Retinal diseases, such as age-related macular degeneration, diabetic retinopathy, and retinoblastoma, stand as the leading causes of irreversible vision impairment and blindness worldwide. Effectively administering drugs for retinal diseases poses a formidable challenge due to the presence of complex ocular barriers and elimination mechanisms. Over time, various approaches have been developed to fabricate drug delivery systems for improving retinal therapy including virus vectors, lipid nanoparticles, and polymers. However, conventional nanocarriers encounter issues related to the controllability, efficiency, and safety in the retina. Therefore, the development of smart nanocarriers for effective or more invasive long-term treatment remains a desirable goal. Recently, approaches have surfaced for the intelligent design of nanocarriers, leveraging specific responses to external or internal triggers and enabling multiple functions for retinal therapy such as topical administration, prolonged drug release, and site-specific drug delivery. This Review provides an overview of prevalent retinal pathologies and related pharmacotherapies to enhance the understanding of retinal diseases. It also surveys recent developments and strategies employed in the intelligent design of nanocarriers for retinal disease. Finally, the challenges of smart nanocarriers in potential clinical retinal therapeutic applications are discussed to inspire the next generation of smart nanocarriers.

Metaplastic regeneration in the mouse stomach requires a reactive oxygen species pathway.

In pyloric metaplasia, mature gastric chief cells reprogram via an evolutionarily conserved process termed paligenosis to re-enter the cell cycle and become spasmolytic polypeptide-expressing metaplasia (SPEM) cells. Here, we use single-cell RNA sequencing (scRNA-seq) following injury to the murine stomach to analyze mechanisms governing paligenosis at high resolution. Injury causes induced reactive oxygen species (ROS) with coordinated changes in mitochondrial activity and cellular metabolism, requiring the transcriptional mitochondrial regulator Ppargc1a (Pgc1α) and ROS regulator Nf2el2 (Nrf2). Loss of the ROS and mitochondrial control in Ppargc1a-/- mice causes the death of paligenotic cells through ferroptosis. Blocking the cystine transporter SLC7A11(xCT), which is critical in lipid radical detoxification through glutathione peroxidase 4 (GPX4), also increases ferroptosis. Finally, we show that PGC1α-mediated ROS and mitochondrial changes also underlie the paligenosis of pancreatic acinar cells. Altogether, the results detail how metabolic and mitochondrial changes are necessary for injury response, regeneration, and metaplasia in the stomach.

Predictive role of E2F6 in cancer prognosis and responses of immunotherapy.

BACKGROUND: E2F6 is a member of the E2F transcription factor family. Numerous studies have demonstrated that E2F6 is critical to cancer development and progression, but its role in cancer immunotherapy remains unclear. METHODS: Genotype-Tissue Expression (GTEx) and The Cancer Genome Atlas (TCGA) databases were used to obtain RNA-seq data for cancer and normal tissues, and we utilized the cBioPortal to analyze E2F6 genomic alterations in pan-cancer. The protein localization of E2F6 was obtained using the Human Protein Atlas (HPA), and the upregulation of E2F6 expression in clinical glioblastoma multiforme (GBM) tissues was detected by Western blot analysis. The ComPPI website was used to analyze the protein interaction information of E2F6. To evaluate the role of E2F6 in pan-cancer prognosis, we used univariate Cox regression and Kaplan-Meier methods, and gene set enrichment analysis (GSEA) was utilized to identify markers associated with E2F6 expression in tumors. TIMER 2.0 was used to study E2F6-related immune cell infiltration in tumor tissues, and the correlation of E2F6 with immunotherapy biomarkers was investigated using Spearman correlation analysis. The role of E2F6 in the cell cycle was analyzed by flow cytometry, and the Cell Counting Kit-8 (CCK-8) and colony formation assays were utilized to determine the proliferative ability of cells. RESULTS: In most tumor types, E2F6 was highly expressed and was a good predictor of prognosis. E2F6 was significantly related to markers of immune activation, tumor immune cell infiltration, and immune regulators. Furthermore, E2F6 knockdown significantly attenuated the proliferative ability of glioma cells. Finally, E2F6 effectively predicted anti-programmed cell death 1 (PD1) treatment response. CONCLUSION: E2F6 is an effective biomarker that predicts the prognosis of cancer patients treated with anti-immune checkpoint therapy.

Investigation on the ultraviolet spectral radiation characteristics of two-phase flow plume based on OH and alumina particles.

Ultraviolet detection has advantages over radar and infrared detection, such as low background radiation and high resolution. The UV spectral radiation characteristics of exhaust plume are of extremely great research significance as the main parameters for aircraft detection. We used the BEM-2 two-phase flow plume as the object of study, calculated the scattering characteristics of alumina particles and the UV absorption coefficient of OH in the plume based on the MIE theory and the line-by-line integration method, established the UV radiation transfer model of aircraft plume under gas-solid coupling, simulated the UV spectral radiation characteristics of the plume, and compared them with experimental results. The results show that due to the drastic changes of temperature and pressure at the Mach and non-Mach disks in the plume, the value of OH absorption coefficient fluctuates up and down along the axial direction with the position of the Mach disk; at 261nm, 282nm, and 306nm, the spectral radiation intensity of alumina particles accounts for approximately 96%, 85%, and 73% of the total spectral radiation intensity of the plume, respectively, which are much higher than the proportion of OH gas spectral radiation intensity, but in the infrared wave band, the influence of particle scattering characteristics on the spectral radiation intensity of the plume is much lower compared to the UV wave band; the overall radial range of the UV spectral radiation intensity of the plume is relatively narrow and its tail exhibits a converging shape, showing a good consistency with the experimental results.

Advances in immunotherapy for triple-negative breast cancer.

BACKGROUND: Immunotherapy has recently emerged as a treatment strategy which stimulates the human immune system to kill tumor cells. Tumor immunotherapy is based on immune editing, which enhances the antigenicity of tumor cells and increases the tumoricidal effect of immune cells. It also suppresses immunosuppressive molecules, activates or restores immune system function, enhances anti-tumor immune responses, and inhibits the growth f tumor cell. This offers the possibility of reducing mortality in triple-negative breast cancer (TNBC). MAIN BODY: Immunotherapy approaches for TNBC have been diversified in recent years, with breakthroughs in the treatment of this entity. Research on immune checkpoint inhibitors (ICIs) has made it possible to identify different molecular subtypes and formulate individualized immunotherapy schedules. This review highlights the unique tumor microenvironment of TNBC and integrates and analyzes the advances in ICI therapy. It also discusses strategies for the combination of ICIs with chemotherapy, radiation therapy, targeted therapy, and emerging treatment methods such as nanotechnology, ribonucleic acid vaccines, and gene therapy. Currently, numerous ongoing or completed clinical trials are exploring the utilization of immunotherapy in conjunction with existing treatment modalities for TNBC. The objective of these investigations is to assess the effectiveness of various combined immunotherapy approaches and determine the most effective treatment regimens for patients with TNBC. CONCLUSION: This review provides insights into the approaches used to overcome drug resistance in immunotherapy, and explores the directions of immunotherapy development in the treatment of TNBC.

Direct cytoplasmic delivery of RNAi therapeutics through a non-lysosomal pathway for enhanced gene therapy.

The first approved RNAi therapeutics, ONPATTRO, in 2017 moves the concept of RNA interference (RNAi) therapy from research to clinical reality, raising the hopes for the treatment of currently incurable diseases. However, RNAi therapeutics are still facing two main challenges-susceptibility to enzymatic degradation and low ability to escape from endo/lysosome into the cytoplasm. Therefore, we developed disulfide-based nanospheres (DBNPs) as universal vehicles to achieve efficient RNA delivery to address these problems. Notably, the DBNPs possess unique and desirable features, including improved resistance to nuclease degradation, direct cytoplasmic delivery through thiol-mediated cellular uptake, and cytosolic environment-responsive release, greatly enhancing the bioavailability of RNA therapeutics. Additionally, DBNPs are superior in terms of overcoming formidable physiological barriers, including vascular barriers and impermeable tumor tissues. Owning to these advantages, the DBNPs exhibit efficient gene silencing effect when delivering either small interfering RNA (siRNA) or microRNA in various cell lines and generate remarkable growth inhibition in the zebrafish and mouse model of pancreatic tumors as compared to traditional delivery vectors, such as PEI. Therefore, DBNPs have potential application prospect in RNAi therapy both in vitro and in vivo. STATEMENT OF SIGNIFICANCE: RNA interference (RNAi) therapeutics could target and alter any disease-related mRNA translation, thus have great potential in clinical application. Delivery efficiency of RNA modalities into cell cytoplasm is the main problem that currently limit RNAi therapeutics to release their full potential. Most of the known delivery materials suffer from the endo/lysosomal entrapment and enzymatic degradation during endocytosis-dependent uptake, resulting unsatisfied efficiency of the cytoplasmic release. Here, we developed disulfide-based nanospheres could directly transfer RNA modalities into the cytoplasm and significantly enhance the delivery efficiency, thus holding great potential in RNAi therapy.

Impact of Traditional Chinese Medicine on Prognosis of Patients with Hepatocellular Carcinoma: A Retrospective Cohort Study.

BACKGROUND: In a previous study, we found that traditional Chinese medicine (TCM) alleviated the clinical symptoms and improved the quality of life (QoL) in patients with hepatocellular carcinoma (HCC). OBJECTIVES: A cohort was continuously followed up to determine the impact of the TCM adjuvant therapies on the prognosis of HCC after conventional treatments. METHODS: We did a retrospective monocentric cohort study including 175 eligible patients. The participants who received TCM adjuvant therapies were termed as TCM group. For the purpose of stratification analysis, the patients who received TCM adjuvant therapies over 3 months per year were further classified into the high frequency group, while the rest of the TCM users were classified into the low frequency group. Non-users were recorded as the control group. The primary outcome was overall survival (OS) and the secondary outcome was the mean progression-free survival (mPFS) primarily introduced in this study, referring to the time from initial diagnosis to the latest progression over the number of disease progressions. Analyses used Cox proportional hazards and Kaplan-Meier (K-M) methods, adjusted for stratification factors. RESULTS: Until June 30, 2021, 56 patients survived, 21 patients were lost to follow-up, and 98 patients died from the disease. Each disease progression of every individual was recorded, and most of the PFS was within 1 year. The baseline data of the allocated groups were balanced, the result revealed that TCM adjuvant therapies might have little influence on OS (P = .129). However, the 1, 3, and 5-year progression-free survival rates of the patients in TCM and control group were 68.75%, 37.50%; 25.00%, 8.33% and 8.33%, 2.08%, respectively, indicating TCM use significantly extended the mPFS, and decreased the risk of disease progression by a factor of 0.676 (P = .006). In the patients with BCLC stage B HCC, compared with controls, a 37-month median OS advantage in the high frequency group was noted (P = .045); and the high frequency of TCM use significantly suppressed disease progression (P = .001). CONCLUSIONS: The present study revealed that TCM adjuvant therapies could postpone disease progression in HCC. Furthermore, using TCM over 3 months per year might extend OS in patients with intermediate HCC.

Phosphoenolpyruvate carboxykinases as emerging targets in cancer therapy.

Metabolic reprogramming is commonly accompanied by alterations in the expression of metabolic enzymes. These metabolic enzymes not only catalyze the intracellular metabolic reaction, but also participate in a series of molecular events to regulate tumor initiation and development. Thus, these enzymes may act as promising therapeutic targets for tumor management. Phosphoenolpyruvate carboxykinases (PCKs) are the key enzymes involved in gluconeogenesis, which mediates the conversion of oxaloacetate into phosphoenolpyruvate. Two isoforms of PCK, namely cytosolic PCK1 and mitochondrial PCK2, has been found. PCK not only participates in the metabolic adaptation, but also regulates immune response and signaling pathways for tumor progression. In this review, we discussed the regulatory mechanisms of PCKs expression including transcription and post-translational modification. We also summarized the function of PCKs in tumor progression in different cellular contexts and explores its role in developing promising therapeutic opportunities.

Dimerization of Transmembrane Proteins in Cancer Immunotherapy.

Transmembrane proteins (TMEMs) are integrated membrane proteins that span the entire lipid bilayer and are permanently anchored to it. TMEMs participate in various cellular processes. Some TMEMs usually exist and perform their physiological functions as dimers rather than monomers. TMEM dimerization is associated with various physiological functions, such as the regulation of enzyme activity, signal transduction, and cancer immunotherapy. In this review, we focus on the dimerization of transmembrane proteins in cancer immunotherapy. This review is divided into three parts. First, the structures and functions of several TMEMs related to tumor immunity are introduced. Second, the characteristics and functions of several typical TMEM dimerization processes are analyzed. Finally, the application of the regulation of TMEM dimerization in cancer immunotherapy is introduced.

Comparative life cycle assessment of ammonia production by coke oven gas via single and coproduction processes.

As an abundant H2-rich byproduct from coking production, coke oven gas (COG) is a favorable feedstock for ammonia production. Recently, three COG-based ammonia processes have been applied, including single process, coproduction of ammonia with methanol, and coproduction of ammonia with liquefied natural gas (LNG). To systematically evaluate the environmental impacts of three COG routes, a comparative life cycle assessment was conducted with industrial data. Besides, the effects of ammonia synthesis pressure and electricity sources to the total LCA result were discussed. The results indicate that the environmental impacts of COG-based single ammonia route are mainly generated from ammonia production stage, accounting for 69.63 % of the overall normalized results, in which electricity and COG are the dominated contributors. Therefore, employing electricity from renewables like wind, solar, hydro and nuclear could dramatically mitigate the environmental impacts with a reduction of 36.3 %-70.7 % in most environmental indicators. Scenario analysis proves that reducing synthesis pressure from 31.4 MPa to 15 MPa does not show remarkable environmental benefits as expected since higher pressure is more conducive to ammonia synthesis. In comparison with coal based and natural gas-based ammonia routes, COG routes have obvious energy-saving benefit. In three COG-based ammonia routes, the two coproduction routes accounted for 49.1 % and 78.6 % of the energy depletion as single production due to highly efficient utilization of resources and energy. Coproduction of ammonia with methanol route exhibits better environmental performance than these in coproduction of ammonia with LNG route. Therefore, coproduction of ammonia with methanol route is more favorable in COG to ammonia processes. This study intends to provide a valuable reference for COG utilization and ammonia production options through the life cycle aspect.