Search

Abstract Background The emergence of new molecular targeted drugs marks a breakthrough in asthma treatment, particularly for severe cases. Yet, options for moderate-to-severe asthma treatment remain limited, highlighting the urgent need for novel therapeutic drug targets. In this study, we aimed to identify new treatment targets for asthma using the Mendelian randomization method and large-scale genome-wide association data (GWAS). Methods We utilized GWAS data from the UK Biobank (comprising 56,167 patients and 352,255 control subjects) and the FinnGen cohort (including 23,834 patients and 228,085 control subjects). Genetic instruments for 734 plasma proteins and 154 cerebrospinal fluid proteins were derived from recently published GWAS. Bidirectional Mendelian randomization analysis, Steiger filtering, colocalization, and phenotype scanning were employed for reverse causal inference detection, further substantiating the Mendelian randomization results. A protein-protein interaction network was also constructed to reveal potential associations between proteins and asthma medications. Results Under Bonferroni significance conditions, Mendelian randomization analysis revealed causal relationships between seven proteins and asthma. In plasma, we observed that an increase of one standard deviation in IL1R1[1.30 (95% CI 1.20–1.42)], IL7R[1.07 (95% CI 1.04–1.11)], ECM1[1.03 (95% CI 1.02–1.05)], and CD200R1[1.18 (95% CI 1.09–1.27)] were associated with an increased risk of asthma, while an increase in ADAM19 [0.87 (95% CI 0.82–0.92)] was found to be protective. In the brain, each 10-fold increase in IL-6 sRa [1.29 (95% CI 1.15–1.45)] was associated with an increased risk of asthma, while an increase in Layilin [0.61 (95% CI 0.51–0.73)] was found to be protective. None of the seven proteins exhibited a reverse causal relationship. Colocalization analysis indicated that ECM1 (coloc.abf-PPH4 = 0.953), IL-6 sRa (coloc.abf-PPH4 = 0.966), and layilin (coloc.abf-PPH4 = 0.975) shared the same genetic variation as in asthma. Conclusion A causal relationship exists between genetically determined protein levels of IL1R1, IL7R, ECM1, CD200R1, ADAM19, IL-6 sRa, and Layilin (LAYN) and asthma. Moreover, the identified proteins may serve as attractive drug targets for asthma, especially ECM1 and Layilin (LAYN). However, further research is required to comprehensively understand the roles of these proteins in the occurrence and progression of asthma.

Objective: Esophageal cancer (EC) ranks eighth among cancers in cancer-related deaths globally, and ~44% of new cases occur in China. We sought to describe the clinical characteristics and treatment landscape of EC in China before the approval of immunotherapy in 2020. Methods: CHANNEL was a large, retrospective study using patient-level data from 14 hospitals/cancer centers across China, including adults initiating therapy for newly diagnosed EC (January to December 2018). Demographics, clinicopathologic characteristics, and treatment patterns over 6 months were descriptively summarized. Results: Of 3,493 patients, 75.7% were men, the mean age was 64.1 years, and 75.0% had no family history of cancer. Most (92.8%) had squamous cell carcinoma, with a primary lesion in the middle esophagus (56.4%). Among patients with resectable EC, 92.9% received initial surgery, and 7.1% received neoadjuvant therapy, primarily chemotherapy (85.5% platinum-taxane). Among patients with unresectable early or locally advanced EC, 50.8% and 49.2% received palliative and radical therapy, respectively, as the initial treatment, primarily chemotherapy (66.5% platinum-taxane) and chemoradiotherapy (50.8% platinum-taxane), respectively. Adjuvant therapy was administered to 22.9% of patients undergoing initial surgery, and 2.4% receiving neoadjuvant therapy and surgery. Among patients with advanced EC, 84.6% received systemic therapy as an initial treatment, primarily chemotherapy (61.5% platinum-taxane). Conclusions: Before the approval of immunotherapy in China, most patients with resectable early or locally advanced EC underwent radical surgery without preoperative treatment, whereas most patients with advanced EC received platinum-taxane chemotherapy. These findings highlight the need for novel EC treatments before immunotherapy was introduced, and provide a baseline for evaluating the benefits of immunotherapy, now that this treatment is widely used in this setting.

Abstract Background Abdominal fluid collection (AFC) is one of the most common complications after pancreatic surgery, yet there are few recommendations on how to manage it. Most cases of AFC only require observation, while others may require more invasive techniques. Unfortunately, there are no drugs that effectively promote the absorption of AFCs. The aim of this study was to evaluate the potential efficacy of Glauber’s salt solution for promoting the absorption of AFCs after pancreatectomy. Methods This study included 196 patients who underwent pancreatomy and had AFCs on at least 2 cross-sectional follow-up CT images between 2020 and 2022. AFCs were defined as effusion with a diameter ≥ 3 cm and located around the pancreatic resection margin. We retrospectively investigated the relationship between Glauber’s salt concentration and clinical variables. Results The rate of clinically significant pancreatic fistula (grades B + C) was significantly higher in the control group (62.8% vs. 40.7%, P = 0.014). The median maximum diameter of the AFC was smaller, and the median time for the AFC to decrease to 30 mm in diameter was shorter in the Glauber’s salt group than in the control group (41.9 mm vs. 53.5 mm, P = 0.008; 35.5 d vs. 100 d, P

Background: Mounting evidence underscores the importance of cell communication within the tumor microenvironment, which is pivotal in tumor proliferation, invasion, and metastasis. Exosomes play a crucial role in cell-to-cell communication. Although single-cell RNA sequencing (scRNA-seq) provides insights into individual cell transcriptional characteristics, it falls short of comprehensively capturing exosome-mediated intercellular communication. Method: We analyzed Pancreatic Ductal Adenocarcinoma (PDAC) tissues, separating supernatant and precipitate for exosome purification and single-cell nucleus suspension. We then constructed Single-nucleus RNA sequencing (snRNA-seq) and small RNA-seq libraries from these components. Our bioinformatic analysis integrated these sequences with ligand-receptor analysis and public miRNA data to map the cell communication network. Results: We established intercellular communication networks using bioinformatic analysis to track exosome miRNA effects and ligand-receptor pairs. Significantly, hsa-miR-1293 emerged as a prognostic biomarker for pancreatic cancer, linked to immune evasion, increased myeloid-derived suppressor cells, and poorer prognosis. Targeting this miRNA may enhance anti-tumor immunity and improve outcomes. Conclusion: Our study offers a novel approach to constructing intercellular communication networks using snRNA-seq and exosome-small RNA sequencing. By integrating miRNA tracing with ligand-receptor analysis, we illuminate the complex interactions in the pancreatic cancer microenvironment, highlighting the pivotal role of miRNAs and identifying potential biomarkers and therapeutic targets.

Abstract An imbalance between the adipogenesis and osteogenesis of bone marrow mesenchymal stem cells (BMSCs) is considered the basic pathogenesis of osteoporosis. Although actin cytoskeleton remodelling plays a crucial role in the differentiation of BMSCs, the role of actin cytoskeleton remodelling in the adipogenesis of BMSCs and postmenopausal osteoporosis (PMOP) has remained elusive. Glia maturation factor-beta (GMFB) has a unique role in remodelling the polymerization/depolymerization cycles of actin. We observed that GMFB expression was increased in bone tissue from both ovariectomized (OVX) rats and PMOP patients. GMFB knockout inhibited the accumulation of bone marrow adipocytes and increased bone mass in the OVX rat model. The inhibition of adipocyte differentiation in GMFB knockout BMSCs was mediated via actin cytoskeleton remodelling and the Ca2+-calcineurin-NFATc2 axis. Furthermore, we found that GMFB shRNA treatment in vivo had favourable effects on osteoporosis induced by OVX. Together, these findings suggest a pathological association of the GMFB with PMOP and highlight the potential of the GMFB as a therapeutic target for osteoporosis patients.

Abstract Background Small cell lung carcinoma (SCLC) is characterized by -poor prognosis, -high predilection for -metastasis, -proliferation, and -absence of newer therapeutic options. Elucidation of newer pathways characterizing the disease may allow for development of targeted therapies and consequently favorable outcomes. Methods The current study explored the combinatorial action of arsenic trioxide (ATO) and apatinib (APA) in vitro and in vivo. In vitro models were tested using -H446 and -H196 SCLC cell lines. The ability of drugs to reduce -metastasis, -cell proliferation, and -migration were assessed. Using bioinformatic analysis, differentially expressed genes were determined. Gene regulation was assessed using gene knock down models and confirmed using Western blots. The in vivo models were used to confirm the resolution of pathognomic features in the presence of the drugs. Growth factor receptor bound protein (GRB) 10 expression levels of human small cell lung cancer tissues and adjacent tissues were detected by IHC. Results In combination, ATO and APA were found to significantly reduce -cell proliferation, -migration, and -metastasis in both the cell lines. Cell proliferation was found to be inhibited by activation of Caspase-3, -7 pathway. In the presence of drugs, it was found that expression of GRB10 was stabilized. The silencing of GRB10 was found to negatively regulate the VEGFR2/Akt/mTOR and Akt/GSK-3β/c-Myc signaling pathway. Concurrently, absence of metastasis and reduction of tumor volume were confirmed in vivo. The immunohistochemical results confirmed that the expression level of GRB10 in adjacent tissues was significantly higher than that in human small cell lung cancer tissues. Conclusions Synergistically, ATO and APA have a more significant impact on inhibiting cell proliferation than each drug independently. ATO and APA may be mediating its action through the stabilization of GRB10 thus acting as a tumor suppressor. We thus, preliminarily report the impact of GRB10 stability as a target for SCLC treatment.

Abstract Background Chemotherapy remains the standard first-line treatment for pancreatic adenocarcinoma, but with limited efficacy. We aimed to explore the feasibility of adding the PARP inhibitor fuzuloparib to mFOLFIRINOX in the locally advanced/metastatic (LA/M) setting. Methods This was the dose-escalation and -expansion, phase 1b portion of a phase 1b/2 study. Patients were given oral fuzuloparib at escalating doses starting at 30 mg twice daily (BID) plus intravenous mFOLFIRINOX q2w for 8–12 cycles, followed by maintenance fuzuloparib at 150 mg BID. Cohorts at the maximal tolerated dose (MTD) and lower dose of fuzuloparib were expanded. Primary endpoints were dose-limiting toxicity (DLT), MTD, and recommended phase 2 dose (RP2D). Results As of data cutoff on Jan 15, 2023, 39 patients were recruited. 12 patients were enrolled during dose escalation (30 mg [n = 4]; 60 mg [n = 6]; 100 mg [n = 2]). DLT occurred in 1 patient in 60 mg cohort and 1 patient in 100 mg cohort. 60 mg BID was determined to be the MTD, and then 60 and 30 mg cohorts were expanded to 22 and 15 patients, respectively. The most common grade ≥ 3 treatment-related adverse events were hematologic toxicities. Efficacy in 60 mg cohort seemed to be most favorable, with an objective response rate of 50.0% (95% CI, 26.0–74.0) and disease control rate of 94.4% (95% CI, 72.7–99.9). Conclusions First-line fuzuloparib plus mFOLFIRINOX followed by maintenance fuzuloparib was generally safe and showed encouraging anti-tumor activity in patients with LA/M pancreatic adenocarcinoma. The RP2D of fuzuloparib combination was 60 mg BID. Trial registration ClinicalTrials.gov, NCT04228601.

Abstract Olaparib has been approved as a therapeutic option for metastatic pancreatic ductal adenocarcinoma patients with BRCA1/2 mutations. However, a significant majority of pancreatic cancer patients have inherent resistance or develop tolerance to olaparib. It is crucial to comprehend the molecular mechanism underlying olaparib resistance to facilitate the development of targeted therapies for pancreatic cancer. In this study, we conducted an analysis of the DepMap database to investigate gene expression variations associated with olaparib sensitivity. Our findings revealed that NLRP4 upregulation contributes to increased resistance to olaparib in pancreatic cancer cells, both in vitro and in vivo. RNA sequencing and Co-IP MS analysis revealed that NLRP4 is involved in the DNA damage response and autophagy pathway. Our findings confirmed that NLRP4 enhances the capacity for DNA repair and induces the production of significant levels of reactive oxygen species (ROS) and autophagy in response to treatment with olaparib. Specifically, NLRP4-generated mitochondrial ROS promote autophagy in pancreatic cancer cells upon exposure to olaparib. However, NLRP4-induced ROS do not affect DNA damage. The inhibition of mitochondrial ROS using MitoQ and autophagy using chloroquine (CQ) may render cells more susceptible to the effects of olaparib. Taken together, our findings highlight the significant roles played by NLRP4 in the processes of autophagy and DNA repair when pancreatic cancer cells are treated with olaparib, thereby suggesting the potential therapeutic utility of olaparib in pancreatic cancer patients with low NLRP4 expression.

Doctoral student creativity is critical for technological innovation and knowledge production. Based on the extended scientific and technical human capital (STHC) theory, a moderated mediation model was constructed to explore how supportive supervision is associated with doctoral student creativity through the simultaneous mediating effects of academic buoyancy and network ties and the moderating role of family support. A sample of 637 doctoral students from China participated in this study. In particular, the findings suggest that supportive supervision is positively related to doctoral student creativity through the simultaneous indirect effects of both academic buoyancy and network ties, while the mediating effect of academic buoyancy is stronger than that of network ties. Moreover, the significant moderation effect of family support on the relationship between network ties, academic buoyancy, and creativity reveals that students with greater family support are more likely to benefit from the academic buoyancy while leading the mediating effect of network ties to be dispensable, implying that family support can be a double-edged sword. The findings provide implications for supervision that can improve doctoral student creativity by attaching importance to social capital and psychological capital while considering the nuanced influence that family support may exert.

Background: The distribution of adverse events (AEs) triggered by immune checkpoint inhibitors (ICIs) across different cancer types has never been demonstrated. Methods: Randomised controlled trials exclusively assessing ICI monotherapy in cohorts of over 100 patients were considered. Our primary outcome was a comprehensive summary of the distribution of all-grade treatment-related adverse events (TRAEs) as well as serious TRAEs (CTCAE grade 3 or higher) across different malignancies. The study is registered with PROSPERO CRD42023387934. Findings: 75 trials that enrolled over 100 patients were included. While investigating the incidence of each TRAE across various cancers, we found special linkages existed between certain TRAEs and particular cancer types. In anti-PD-1 monotherapy group, melanoma patients experienced the most frequent fatigue (31.1 %, 95 % CI 29.7%–32.5 %); the incidences of severe pneumonitis and other respiratory disorders were highest in Hodgkin lymphoma (4.1 %, 95 % CI 1.5%–8.6 %; 4.1 %, 95 % CI 1.5%–8.6 %, respectively). Among individuals undergoing single-agent anti-PD-L1, higher frequency of all-grade pruritus occurred in 19.0 % of renal cell carcinoma (RCC) patients (95 % CI 15.2%–23.2 %), and the highest probability of developing other severe musculoskeletal disorders was observed in patients with RCC (6.2 %, 95 % CI 4.0%–9.0 %). In anti-CTLA-4 monotherapy, the incidences of both all-grade and severe diarrhea occurred most frequently in prostate cancer patients (41.9 %, 95 % CI 37.9%–47.9; 14.8 %, 95 % CI 11.5%–18.7 %, respectively). Interpretation: This is the first comprehensive study addressing the distribution of various TRAEs across cancer types. Our research emphasizes the significance of considering cancer-specific TRAEs when using ICIs for treatment.

Olaparib has been approved as a treatment for metastatic pancreatic ductal adenocarcinoma in patients with BRCA1 (BRCA1 DNA repair associated) or BRCA2 mutations. However, a large portion of pancreatic cancer patients either exhibit inherent resistance or develop resistance over time. Understanding the molecular mechanisms that drive this resistance is crucial to develop more effective targeted therapies. In this study, we found that NLRP4 (NLR family pyrin domain containing 4) upregulation is associated with increased resistance to olaparib in pancreatic cancer. In addition, NLRP4 plays a role in both the DNA damage response (DDR) and autophagy. Specifically, NLRP4 enhances DNA repair capacity and leads to increased reactive oxygen species (ROS) production and autophagy upon olaparib treatment. Notably, NLRP4-generated mitochondrial ROS promote autophagy without directly impacting DNA damage. Inhibition of either mitochondrial ROS production with MitoQ or autophagy with chloroquine (CQ) could sensitize pancreatic cancer cells to olaparib. These findings emphasize NLRP4’s role in promoting both autophagy and DNA repair in response to olaparib, suggesting that patients with low NLRP4 expression might respond more favorably to olaparib treatment.

Currently, chemotherapy remains occupying a pivotal place in the treatment of pancreatic ductal adenocarcinoma (PDAC). Nonetheless, the emergence of drug resistance in recent years has limited the clinical efficacy of chemotherapeutic agents, especially gemcitabine (GEM). Through bioinformatics analysis, AT-rich Interactive Domain-containing Protein 3A (ARID3A), one of transcription factors, is discovered to possibly participate in this progress. This study thoroughly investigates the potential role of ARID3A in the malignant progression and GEM chemoresistance of PDAC and explores the underlying mechanisms. The results indicate that ARID3A knockdown suppresses tumor development and enhances the sensitivity of PDAC cells to GEM in vitro and vivo. Mechanically, CUT&Tag profiling sequencing, RNA‐sequencing and functional studies demonstrates that decreased ARID3A expression alleviates the transcriptional inhibition of phosphatase and tensin homolog (PTEN), consequently leading to glutathione peroxidase 4 (GPX4) depletion and increased lipid peroxidation levels. Activated ferroptosis induced by the inhibition of GPX4 subsequently restricts tumor progression and reduces GEM resistance in PDAC. This research identifies the ferroptosis regulatory pathway of ARID3A-PTEN-GPX4 axis and reveals its critical role in driving the progression and chemoresistance of pancreatic cancer. Notably, both inhibition of ARID3A and enhancement of ferroptosis can increase chemosensitivity to GEM, which offers a promising opportunity for developing therapeutic strategies to combat acquired chemotherapy resistance in pancreatic cancer.

Schizophrenia significantly impacts cognitive and behavioral functions and is primarily treated with second-generation antipsychotics (SGAs) such as olanzapine. Despite their efficacy, these drugs are linked to serious metabolic side effects which can diminish patient compliance, worsen psychiatric symptoms and increase cardiovascular disease risk. This study explores the hypothesis that SGAs affect the molecular determinants of synaptic plasticity and brain activity, particularly focusing on the lateral septum (LS) and its interactions within hypothalamic circuits that regulate feeding and energy expenditure. Utilizing functional ultrasound imaging, RNA sequencing, and weighted gene co-expression network analysis, we identified significant alterations in the functional connection between the hypothalamus and LS, along with changes in gene expression in the LS of mice following prolonged olanzapine exposure. Our analysis revealed a module closely linked to increases in body weight and adiposity, featuring genes primarily involved in lipid metabolism pathways, notably Apoa1, Apoc3, and Apoh. These findings suggest that olanzapine may influence body weight and adiposity through its impact on lipid metabolism-related genes in the LS. Therefore, the neural circuits connecting the LS and LH, along with the accompanying alterations in lipid metabolism, are likely crucial factors contributing to the weight gain and metabolic side effects associated with olanzapine treatment.

Summary: Background: The widespread involvement of tumor-infiltrating B cells highlights their potential role in tumor behavior. However, B cell heterogeneity in PDAC remains unexplored. Studying TIL-Bs in PDAC aims to identify new treatment strategies. Methods: We performed single-cell RNA sequencing to study the heterogeneity of B cells in PDAC. The prognostic and immunologic value of the identified CD38+ B cells was explored in FUSCC (n = 147) and TCGA (n = 176) cohorts. Flow cytometry was conducted to characterize the relationship between CD38+ B cells and other immune cells, as well as their phenotypic features. In vitro and in vivo experiments were performed to assess the putative effect of CD38+ B cells on antitumor immunity. Findings: The presence of CD38+ B cells in PDAC was associated with unfavorable clinicopathological features and poorer overall survival (p

Abstract Background Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis, and its molecular mechanisms are unclear. Nucleolar and spindle-associated protein 1 (NUSAP1), an indispensable mitotic regulator, has been reported to be involved in the development of several types of tumors. The biological function and molecular mechanism of NUSAP1 in PDAC remain controversial. This study explored the effects and mechanism of NUSAP1 in PDAC. Methods Differentially expressed genes (DEGs) were screened. A protein‒protein interaction (PPI) network was constructed to identify hub genes. Experimental studies and tissue microarray (TMA) analysis were performed to investigate the effects of NUSAP1 in PDAC and explore its mechanism. Results Network analysis revealed that NUSAP1 is an essential hub gene in the PDAC transcriptome. Genome heterogeneity analysis revealed that NUSAP1 is related to tumor mutation burden (TMB), loss of heterozygosity (LOH) and homologous recombination deficiency (HRD) in PDAC. NUSAP1 is correlated with the levels of infiltrating immune cells, such as B cells and CD8 T cells. High NUSAP1 expression was found in PDAC tissues and was associated with a poor patient prognosis. NUSAP1 promoted cancer cell proliferation, migration and invasion, drives the epithelial-mesenchymal transition and reduces AMPK phosphorylation. Conclusions NUSAP1 is an essential hub gene that promotes PDAC progression and leads to a dismal prognosis by drives the epithelial-mesenchymal transition and reduces AMPK phosphorylation.

Abstract Research into the potential benefits of artificial intelligence for comprehending the intricate biology of cancer has grown as a result of the widespread use of deep learning and machine learning in the healthcare sector and the availability of highly specialized cancer datasets. Here, we review new artificial intelligence approaches and how they are being used in oncology. We describe how artificial intelligence might be used in the detection, prognosis, and administration of cancer treatments and introduce the use of the latest large language models such as ChatGPT in oncology clinics. We highlight artificial intelligence applications for omics data types, and we offer perspectives on how the various data types might be combined to create decision-support tools. We also evaluate the present constraints and challenges to applying artificial intelligence in precision oncology. Finally, we discuss how current challenges may be surmounted to make artificial intelligence useful in clinical settings in the future.

Abstract Cholesterol is an essential structural component of membranes that contributes to membrane integrity and fluidity. Cholesterol homeostasis plays a critical role in the maintenance of cellular activities. Recently, increasing evidence has indicated that cholesterol is a major determinant by modulating cell signaling events governing the hallmarks of cancer. Numerous studies have shown the functional significance of cholesterol metabolism in tumorigenesis, cancer progression and metastasis through its regulatory effects on the immune response, ferroptosis, autophagy, cell stemness, and the DNA damage response. Here, we summarize recent literature describing cholesterol metabolism in cancer cells, including the cholesterol metabolism pathways and the mutual regulatory mechanisms involved in cancer progression and cholesterol metabolism. We also discuss various drugs targeting cholesterol metabolism to suggest new strategies for cancer treatment.

Abstract Background Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy. Radical surgical resection offers the only potential cure. There is increasing agreement that radical antegrade modular pancreatosplenectomy (RAMPS) may benefit patients with tumors in the body and tail of the pancreas. To address this, the Chinese Study Group for Pancreatic Cancer (CSPAC)-3 trial is proposed to compare the effect of RAMPS and standard retrograde pancreatosplenectomy (SRPS) on patient survival and preoperative safety Methods The randomized controlled trial will be multicenter and two-armed with blinded outcomes and intention-to-treat analysis. Three hundred patients with resectable body and tail pancreatic adenocarcinoma will be enrolled and randomly assigned to RAMPS or SRPS. Adjuvant chemotherapy based on an initial regimen will be recommended 4–6 weeks after surgery if no serious complication occurs. The hypothesis that RAMPS improves survival outcomes compared with SRPS will be tested using a superiority trial. The primary outcome will be overall survival (OS). Secondary outcomes will include recurrence-free survival (RFS), R0 resection rate, the number of harvested lymph nodes, postoperative complications, and quality of life scores. Discussion The use of RAMPS has increased over the past decade. It is reported that RAMPS is superior to SRPS in improving both the rate of R0 resection and lymph node yield. Despite these advantages, however, there is little high-level documentation of the superiority of RAMPS in terms of survival and this needs to be investigated. To address this issue, CSPAC has instigated the first prospective, randomized phase III control trials, aiming to explore the optimal surgical strategy for improving the prognosis and OS of patients with left-sided pancreatic cancer Trial registration Chinese Clinical Trial Registry ChiCTR2100053844; pre-results. Registered on December 1, 2021.

Abstract Over decades, researchers have focused on the epigenetic control of DNA-templated processes. Histone modification, DNA methylation, chromatin remodeling, RNA modification, and noncoding RNAs modulate many biological processes that are crucial to the development of cancers. Dysregulation of the epigenome drives aberrant transcriptional programs. A growing body of evidence suggests that the mechanisms of epigenetic modification are dysregulated in human cancers and might be excellent targets for tumor treatment. Epigenetics has also been shown to influence tumor immunogenicity and immune cells involved in antitumor responses. Thus, the development and application of epigenetic therapy and cancer immunotherapy and their combinations may have important implications for cancer treatment. Here, we present an up-to-date and thorough description of how epigenetic modifications in tumor cells influence immune cell responses in the tumor microenvironment (TME) and how epigenetics influence immune cells internally to modify the TME. Additionally, we highlight the therapeutic potential of targeting epigenetic regulators for cancer immunotherapy. Harnessing the complex interplay between epigenetics and cancer immunology to develop therapeutics that combine thereof is challenging but could yield significant benefits. The purpose of this review is to assist researchers in understanding how epigenetics impact immune responses in the TME, so that better cancer immunotherapies can be developed.

Abstract Excessive osteoclast activation, which depends on dramatic changes in actin dynamics, causes osteoporosis (OP). The molecular mechanism of osteoclast activation in OP related to type 1 diabetes (T1D) remains unclear. Glia maturation factor beta (GMFB) is considered a growth and differentiation factor for both glia and neurons. Here, we demonstrated that Gmfb deficiency effectively ameliorated the phenotype of T1D-OP in rats by inhibiting osteoclast hyperactivity. In vitro assays showed that GMFB participated in osteoclast activation rather than proliferation. Gmfb deficiency did not affect osteoclast sealing zone (SZ) formation but effectively decreased the SZ area by decreasing actin depolymerization. When GMFB was overexpressed in Gmfb-deficient osteoclasts, the size of the SZ area was enlarged in a dose-dependent manner. Moreover, decreased actin depolymerization led to a decrease in nuclear G-actin, which activated MKL1/SRF-dependent gene transcription. We found that pro-osteoclastogenic factors (Mmp9 and Mmp14) were downregulated, while anti-osteoclastogenic factors (Cftr and Fhl2) were upregulated in Gmfb KO osteoclasts. A GMFB inhibitor, DS-30, targeting the binding site of GMFB and Arp2/3, was obtained. Biocore analysis revealed a high affinity between DS-30 and GMFB in a dose-dependent manner. As expected, DS-30 strongly suppressed osteoclast hyperactivity in vivo and in vitro. In conclusion, our work identified a new therapeutic strategy for T1D-OP treatment. The discovery of GMFB inhibitors will contribute to translational research on T1D-OP.

Reasonable control of grouting parameters was the key to improving the pile-soil interaction. However, quantitative analysis on the effect of grouting parameters on the pile-soil interaction was still lacking. This article developed an intelligent post-grouting system for precise control and quantitative analysis of grouting parameters. The conventional preparation method for shear tests were improved in this article. By changing the normal stress of the pile-soil interface during grouting, the test sample could simulate the grout distribution of the pile-soil interface at different depths. Through the improved experimental methods, a more accurate analysis of the mechanism for the pile-soil interaction was achieved. And the effectiveness of the intelligent post-grouting system was further verified by the case application. The results indicated that increasing the grout volume could improve the interface shear strength when the normal stress and grouting pressure were constant. This improvement effect caused by increasing grout volume decreased when the normal stress was high. Increasing the grouting pressure increased the interface shear strength when the normal stress and the grout volume remained constant. This improvement effect caused by increasing grouting pressure decreased when the grout volume was small. By appropriately controlling the two grouting parameters, the cohesion and the shear strength of the pile-soil interface were increased by 5.8–18.8 times and 1.16–2.91 times, respectively. The results indicated that the intelligent post-grouting system could accurately control the grouting parameters and effectively improve the pile-soil interaction of bored piles. The intelligent post-grouting system effectively reduced geotechnical engineering risks and improved the bearing capacity of pile.

为高效鉴定食用油脂加工厂污水处理过程的气味组成，采用感官检验以臭阈值量化不同处理工序污水的臭味浓度，并采用气相色谱-离子迁移谱法（GC-IMS）对其挥发性化合物进行分析，并对鉴定出的挥发性化合物进行指纹图谱和主成分分析。结果表明：污水经过处理臭阈值明显降低；GC-IMS鉴定出43种化合物，基本均为含氧有机物，包括酮类、醇类、醛类、酯类、酸类及其他类；总体上各处理工序污水挥发性物质总数和臭阈值的变化规律一致；各处理工序挥发性化合物存在一定差异。综上，GC-IMS是分析食用油脂加工厂污水处理过程气味变化的有效方法。 In order to effectively identify odorants in wastewater treatment process in edible oil plant, the odor concentration of wastewater from different treatment processes was quantified by the threshold odor number(TON) through sensory examination, and the volatile organic compounds (VOCs) were identified using gas chromatography-ion mobility spectrometry (GC-IMS) and analysed by fingerprint plot and principal component analysis. The results showed that the TON of wastewater was significantly reduced after treatment. Forty-three compounds were identified by GC-IMS, all of which were basically oxygen-containing organic compounds including ketones, alcohols, aldehydes, esters, acids and others. The change rule of TON of wastewater was overall consistent with volatile compounds among the treatment processes. There was a variation in VOCs′ overallcomposition among the treatment processes. In conclusion, the GC-IMS technique is an efficient method for analyzing the odor variation of wastewater treatment in edible oil plant.

A novel form of cell death, cuproptosis, was recently identified to be mediated by the binding of copper to lipoylated enzymes of the tricarboxylic acid cycle. Cuproptosis-related genes (CRGs) may play a crucial role in the progression of pancreatic adenocarcinoma (PAAD), which often exhibits metabolic reprogramming. In the present study, univariate Cox regression analysis and Kaplan–Meier survival analysis were performed to identify prognostic CRGs. Data from the Cancer Therapeutics Response Portal and the Genomics of Drug Sensitivity in Cancer database were downloaded for drug sensitivity analysis. DLAT was identified as the only prognostic CRG in PAAD (HR = 2.72; 95% CI, 1.10–6.74). Functional enrichment analyses indicated that the basic function of DLAT is closely related to metabolism, and multiple tumor-promoting and immune response-related pathways were enriched in DLAT-high PAAD samples. The influence of DLAT and related genes on cancer immunity was evaluated by comprehensive immune infiltration analyses, which revealed the value of these genes as biomarkers for evaluating the sensitivity to immunotherapy. Additionally, high DLAT expression induced drug resistance, and significantly increased resistance to commonly used chemotherapeutics in PAAD, such as gemcitabine, oxaliplatin, 5-fluorouracil, and irinotecan. In conclusion, our study preliminarily revealed the prognostic value of DLAT, which is correlated with PAAD progression, chemoresistance, and immune infiltration, providing a valuable reference for PAAD treatment. However, our findings need to be confirmed by further in vivo and in vitro experiments.

Abstract As a critical component of the tumor microenvironment (TME), cancer‐associated fibroblasts (CAFs) play important roles in cancer initiation and progression. Well‐known signaling pathways, including the transforming growth factor‐β (TGF‐β), Hedgehog (Hh), Notch, Wnt, Hippo, nuclear factor kappa‐B (NF‐κB), Janus kinase (JAK)/signal transducer and activator of transcription (STAT), mitogen‐activated protein kinase (MAPK), and phosphoinositide 3‐kinase (PI3K)/AKT pathways, as well as transcription factors, including hypoxia‐inducible factor (HIF), heat shock transcription factor 1 (HSF1), P53, Snail, and Twist, constitute complex regulatory networks in the TME to modulate the formation, activation, heterogeneity, metabolic characteristics and malignant phenotype of CAFs. Activated CAFs remodel the TME and influence the malignant biological processes of cancer cells by altering the transcriptional and secretory characteristics, and this modulation partially depends on the regulation of signaling cascades. The results of preclinical and clinical trials indicated that therapies targeting signaling pathways in CAFs demonstrated promising efficacy but were also accompanied by some failures (e.g., NCT01130142 and NCT01064622). Hence, a comprehensive understanding of the signaling cascades in CAFs might help us better understand the roles of CAFs and the TME in cancer progression and may facilitate the development of more efficient and safer stroma‐targeted cancer therapies. Here, we review recent advances in studies of signaling pathways in CAFs and briefly discuss some future perspectives on CAF research.

Growing evidence indicates a potential correlation between necroptosis and pancreatic cancer, and the relationship between necroptosis, immune infiltration and the microenvironment in pancreatic cancer has drawn increasing attention. However, two-dimensional phenotype and prognostic assessment systems based on a combination of necroptosis and immunity have not been explored. In our present study, we explored the pancancer genomics signature of necroptosis-related molecules, identifying necroptosis-related molecule mutation profiles, expression profiles, and correlations between expression levels and methylation/CNV levels. We identified distinct necroptotic as well as immune statuses in pancreatic cancer, and a high necroptosis phenotype and high immunity phenotype both indicated better prognosis than a low necroptosis phenotype and low immunity phenotype. The two-dimensional phenotype we constructed has ideal discriminative effects on pancreatic cancer prognosis, inflammation, and the immune microenvironment. The ''high-necroptosis and high-immunity (HNHI)'' group exhibited the best prognosis and the highest proportion of infiltrating immune cells. The NI score can be used to predict patient prognosis and is correlated with the immune microenvironment score, chemotherapeutic drug IC50, and tumor mutational burden. In addition, it may be useful for predicting the effect of individualized chemotherapy and immunotherapy. Our study also revealed that SLC2A1 is associated with both necroptosis and immunity and acts as a potential oncogene in pancreatic cancer. In conclusion, the two-dimensional phenotype and NI score we developed are promising tools for clinical multiomics applications and prediction of chemotherapy and immunotherapy response and present benefits in terms of precision medicine and individualized treatment decision-making for pancreatic cancer patients.

Intratumor heterogeneity of positron emission tomography-computed tomography (PET-CT) is reflected by variable 18F-fluorodeoxyglucose (FDG) uptake. Increasing evidence has shown that neoplastic and non-neoplastic components can affect the total 18F-FDG uptake in tumors. Cancer-associated fibroblasts (CAFs) is considered as the main non-neoplastic components in tumor microenvironment (TME) of pancreatic cancer. Our study aims to explore the impact of metabolic changes in CAFs on heterogeneity of PET-CT. A total of 126 patients with pancreatic cancer underwent PET-CT and endoscopic ultrasound elastography (EUS-EG) before treatment. High maximum standardized uptake value (SUVmax) from the PET-CT was positively correlated with the EUS-derived strain ratio (SR) and indicated poor prognosis of patients. In addition, single-cell RNA analysis showed that CAV1 affected glycolytic activity and correlated with glycolytic enzyme expression in fibroblasts in pancreatic cancer. We also observed the negative correlation between CAV1 and glycolytic enzyme expression in the tumor stroma by using immunohistochemistry (IHC) assay in the SUVmax-high and SUVmax-low groups of pancreatic cancer patients. Additionally, CAFs with high glycolytic activity contributed to pancreatic cancer cell migration, and blocking CAF glycolysis reversed this process, suggesting that glycolytic CAFs promote malignant biological behavior in pancreatic cancer. In summary, our research demonstrated that the metabolic reprogramming of CAFs affects total 18F-FDG uptake in tumors. Thus, an increase in glycolytic CAFs with decreased CAV1 expression promotes tumor progression, and high SUVmax may be a marker for therapy targeting the neoplastic stroma. Further studies should clarify the underlying mechanisms.

Abstract Many types of human cells self-destruct to maintain biological homeostasis and defend the body against pathogenic substances. This process, called regulated cell death (RCD), is important for various biological activities, including the clearance of aberrant cells. Thus, RCD pathways represented by apoptosis have increased in importance as a target for the development of cancer medications in recent years. However, because tumor cells show avoidance to apoptosis, which causes treatment resistance and recurrence, numerous studies have been devoted to alternative cancer cell mortality processes, namely necroptosis, pyroptosis, ferroptosis, and cuproptosis; these RCD modalities have been extensively studied and shown to be crucial to cancer therapy effectiveness. Furthermore, evidence suggests that tumor cells undergoing regulated death may alter the immunogenicity of the tumor microenvironment (TME) to some extent, rendering it more suitable for inhibiting cancer progression and metastasis. In addition, other types of cells and components in the TME undergo the abovementioned forms of death and induce immune attacks on tumor cells, resulting in enhanced antitumor responses. Hence, this review discusses the molecular processes and features of necroptosis, pyroptosis, ferroptosis, and cuproptosis and the effects of these novel RCD modalities on tumor cell proliferation and cancer metastasis. Importantly, it introduces the complex effects of novel forms of tumor cell death on the TME and the regulated death of other cells in the TME that affect tumor biology. It also summarizes the potential agents and nanoparticles that induce or inhibit novel RCD pathways and their therapeutic effects on cancer based on evidence from in vivo and in vitro studies and reports clinical trials in which RCD inducers have been evaluated as treatments for cancer patients. Lastly, we also summarized the impact of modulating the RCD processes on cancer drug resistance and the advantages of adding RCD modulators to cancer treatment over conventional treatments.

Pancreatic ductal adenocarcinoma (PDAC) is a highly heterogeneous cancer with limited understanding of its classification and tumor microenvironment. Here, by analyzing single-nucleus RNA sequencing of 43, 817 tumor cells from 15 PDAC tumors and non-tumor, we find that hypoxia signatures were heterogeneous across samples and were potential regulators for tumor progression and more aggressive phenotype. Hypoxia-high PDAC tends to present a basal/squamous-like phenotype and has significantly increased outgoing signaling, which enhances tumor cell stemness and promotes metastasis, angiogenesis, and fibroblast differentiation in PDAC. Hypoxia is related to an extracellular matrix enriched microenvironment, and increased possibility of TP53 mutation in PDAC. TP63 is a specific marker of squamous-like phenotype, and presents elevated transcriptome levels in most hypoxia PDAC tumors. In summary, our research highlights the potential linkage of hypoxia, tumor progression and genome alteration in PDAC, leading to further understand of the formation of inter-tumoral and intra-tumoral heterogenous in PDAC. Our study extends the understanding of the diversity and transition of tumor cells in PDAC, which provides insight into future PDAC management.

Abstract Liquid–liquid phase separation (LLPS) is a novel principle for explaining the precise spatial and temporal regulation in living cells. LLPS compartmentalizes proteins and nucleic acids into micron-scale, liquid-like, membraneless bodies with specific functions, which were recently termed biomolecular condensates. Biomolecular condensates are executors underlying the intracellular spatiotemporal coordination of various biological activities, including chromatin organization, genomic stability, DNA damage response and repair, transcription, and signal transduction. Dysregulation of these cellular processes is a key event in the initiation and/or evolution of cancer, and emerging evidence has linked the formation and regulation of LLPS to malignant transformations in tumor biology. In this review, we comprehensively summarize the detailed mechanisms of biomolecular condensate formation and biophysical function and review the recent major advances toward elucidating the multiple mechanisms involved in cancer cell pathology driven by aberrant LLPS. In addition, we discuss the therapeutic perspectives of LLPS in cancer research and the most recently developed drug candidates targeting LLPS modulation that can be used to combat tumorigenesis.

Objective: The present study aimed to document the economic profiles of inactivated COVID-19 vaccines in Hong Kong SAR, Indonesia, mainland China, Philippines, Singapore, and Thailand, the evidence on which is currently absent. Methods: Decision tree models were developed to assess the cost-effectiveness of two doses of inactivated COVID-19 vaccines at a population vaccination rate of 50% in the base case, which was an estimate of feasible vaccination coverage according to previous studies. Epidemiological, mortality, cost, and health state utility information were sourced from the literature. Vaccine efficacy against COVID-19 cases by severity were estimated using meta-analyses of publicly accessible phase 3 trial results of inactivated vaccines. The health outcomes were quantified as quality-adjusted life years (QALYs) and compared across the vaccination and no vaccination strategies. In scenario analyses, incidence and vaccination rates were changed semi-continuously over spectrums, the results of which were presented as contour lines informing the efficiency frontiers of vaccination strategies. One-way and probabilistic sensitivity analyses were also conducted. Results: The vaccination strategy was dominant in all jurisdictions in the base case by producing 105.18, 98.15, 99.70, 60.48, 112.00, and 103.47 QALYs while saving US$40.26 million, US$5.26 million, US$7.60 million, US$5.91 million, US$21.33 million, and US$7.18 million in Hong Kong SAR, Indonesia, mainland China, Philippines, Singapore, and Thailand per every 100,000 vaccinated individuals, respectively. Results were robust in alternative model specifications. Conclusions: Inactivated COVID-19 vaccines may be cost-saving options in Hong Kong SAR, Indonesia, mainland China, Philippines, Singapore, and Thailand. Mass vaccination programs using inactivated COVID-19 vaccines should be considered in these jurisdictions.

Background: Lung adenocarcinoma (LUAD) is the most frequently occurring lung cancer worldwide, with increasing death rates. It belongs to the non-small cell lung cancer (NSCLC) type and has a strong association with previous smoking history. Growing evidence has demonstrated the significance of adenosine-to-inosine RNA editing (ATIRE) dysregulation in cancer. The aim of the present study was to evaluate ATIRE events that might be clinically useful or tumorigenic.Methods: To explore survival-related ATIRE events in LUAD, its ATIRE profiles, gene expression data, and corresponding patients’ clinical information were downloaded from the Cancer Genome Atlas (TCGA) and the synapse database. We evaluated 10441 ATIRE in 440 LUAD patients from the TCGA database. ATIRE profiles were merged with TCGA survival data. We selected prognostic ATIRE sites, using a univariate Cox analysis (p < 0.001). Cox proportional hazards regression and lasso regression analysis were used to determine survival-related ATIRE sites, create risk ratings for those sites, and build a prognostic model and a nomogram for assessing overall survival (OS). Six ATIRE sites were used in the prognostic model construction and patients were randomly divided into a validation cohort (n = 176) and a training cohort (n = 264). The “Pheatmap” program was used to create risk curves that included risk score, survival time, and expression of ATIRE sites. We also determined the clinical prediction model’s discrimination. The decision curve analysis and the 1-, 2-, and 3-year corrective curves were simultaneously used to evaluate the nomogram. We also evaluated the relationship between the amount of ATIRE sites and host gene expression and the impact of ATIRE expression on transcriptome expression.Results: The pyroglutamyl-peptidase I (PGPEP1) chr19:18476416A > I, ankyrin repeat domain 36B pseudogene 1 (ANKRD36BP1) (dist = 3,795), T-box transcription factor (TBX19) (dist = 29815) chr1:168220463A > I, Syntrophin Beta 2 (SNTB2) chr16:69338598A > I, hook microtubule-tethering protein 3 (HOOK3) chr8:42883441A > I, NADH dehydrogenase flavoprotein 3 (NDUFV3) chr21:44329452A > I, and FK506-binding protein 11 (FKBP11) chr12:49316769A > I were used in the prognostic model construction. High levels of risk score were significantly associated with worse OS and progression-free survival. Tumour stage and risk score were related to OS in LUAD patients. The predictors were among the prognostic nomogram model’s risk score, age, gender, and tumor stage. The calibration plot and C-index (0.718) demonstrated the significant accuracy of nomogram’s predictions. ATIRE level was markedly elevated in tumor tissues and was highly variable between patients.Conclusion: Events involving ATIRE in LUAD were highly functional and clinically relevant. The RNA editing-based model provides a solid framework for further investigation of the functions of RNA editing in non-coding areas and may be used as a unique method for predicting LUAD survival.

Increasing evidence has confirmed that cancer-associated fibroblasts (CAFs) recruit and induce regulatory T cells (Tregs) and macrophages but inhibit cytotoxic T lymphocyte infiltration to a certain extent, indicating that CAFs have a significant influence on the immunosuppressive microenvironment. However, the effect of CAFs on the immune microenvironment and immunotherapy response in pancreatic cancer remains unclear. Our research identified remarkable variation in CAF-associated molecules in multiple cancer types at the genetic and transcriptome levels. Two phenotypes were identified for 476 pancreatic cancer samples, and the different phenotypes exhibited significant variation in immune and inflammatory characteristics. Phenotype 1 exhibited higher levels of immune infiltration and lower expression of tumor-associated gene signatures than phenotype 2. We used a multipart approach to assess the prognostic value of CAF-associated molecules and constructed a CAF score model that could accurately predict patient prognosis. The CAF score accurately predicted infiltrating immune cell abundance, chemosensitivity, and the response to immunotherapy. Additionally, we found that the CAF-associated molecule FGFR4 may promote the proliferation and migration and inhibit the apoptosis of pancreatic cancer cells and is correlated with immune infiltration, suggesting its potential role as an oncogene. CAFs may promote the malignant biological behavior of pancreatic cancer through FGFR4. In summary, our research highlights potential relationships of the dysregulation of CAF-associated molecules with genome alterations and carcinogenesis in multiple malignancies. Our CAF-associated phenotypes and scoring system may enhance the understanding of pancreatic cancer chemotherapy sensitivity and immunotherapy response, providing new insights for personalized chemotherapy and immunotherapy.

Pancreatic ductal adenocarcinoma (PDAC) is a highly fatal malignancy that is characterized by an immunosuppressive microenvironment. The immune suppression in PDAC is largely driven by heterogeneous stromal and tumor cells. However, how adipocyte in the tumor microenvironment (TME) is related to the immune cell infiltration in PDAC has rarely been published. We identified adipocytes by performing bioinformatics analyses, and explored the clinical outcomes and TME characters in PDAC with different levels of adipocyte infiltration. Interestingly, in contrast to adiposity, high adipocyte infiltration in the TME was related to significantly increased median overall survival and a lower total tumor mutational burden. Functionally, high adipocyte infiltration was associated with the immune response, particularly with the abundant cytokine infiltration in PDAC samples. Moreover, adipocyte infiltration in the TME was positively associated with anticancer signatures in the immune microenvironment. Immunohistochemistry and RT-PCR were performed with PDAC tissue samples from our center to study the expression of adipocytes in PDAC. The mature adipocytes were strongly associated with the immune composition and prognosis of patients with PDAC. Primary adipocytes were isolated from mice to construct a PDAC transplantation tumor model. In vivo experiments showed that adipocytes elicited increased CD8+ T cell infiltration and potent antitumor activity in tumor-bearing mice. Overall, we innovatively found that adipocytes facilitated the antitumor immune response in the TME by performing mouse experiments and analyzing PDAC samples. This study provides a new perspective on the activation of the immune microenvironment in PDAC.