Tumor-derived extracellular vesicles regulate macrophage polarization: role and therapeutic perspectives.

Extracellular vesicles (EVs) are important cell-to-cell communication mediators. This paper focuses on the regulatory role of tumor-derived EVs on macrophages. It aims to investigate the causes of tumor progression and therapeutic directions. Tumor-derived EVs can cause macrophages to shift to M1 or M2 phenotypes. This indicates they can alter the M1/M2 cell ratio and have pro-tumor and anti-inflammatory effects. This paper discusses several key points: first, the factors that stimulate macrophage polarization and the cytokines released as a result; second, an overview of EVs and the methods used to isolate them; third, how EVs from various cancer cell sources, such as hepatocellular carcinoma, colorectal carcinoma, lung carcinoma, breast carcinoma, and glioblastoma cell sources carcinoma, promote tumor development by inducing M2 polarization in macrophages; and fourth, how EVs from breast carcinoma, pancreatic carcinoma, lungs carcinoma, and glioblastoma cell sources carcinoma also contribute to tumor development by promoting M2 polarization in macrophages. Modified or sourced EVs from breast, pancreatic, and colorectal cancer can repolarize M2 to M1 macrophages. This exhibits anti-tumor activities and offers novel approaches for tumor treatment. Therefore, we discovered that macrophage polarization to either M1 or M2 phenotypes can regulate tumor development. This is based on the description of altering macrophage phenotypes by vesicle contents.

PTMs of PD-1/PD-L1 and PROTACs application for improving cancer immunotherapy.

Immunotherapy has been developed, which harnesses and enhances the innate powers of the immune system to fight disease, particularly cancer. PD-1 (programmed death-1) and PD-L1 (programmed death ligand-1) are key components in the regulation of the immune system, particularly in the context of cancer immunotherapy. PD-1 and PD-L1 are regulated by PTMs, including phosphorylation, ubiquitination, deubiquitination, acetylation, palmitoylation and glycosylation. PROTACs (Proteolysis Targeting Chimeras) are a type of new drug design technology. They are specifically engineered molecules that target specific proteins within a cell for degradation. PROTACs have been designed and demonstrated their inhibitory activity against the PD-1/PD-L1 pathway, and showed their ability to degrade PD-1/PD-L1 proteins. In this review, we describe how PROTACs target PD-1 and PD-L1 proteins to improve the efficacy of immunotherapy. PROTACs could be a novel strategy to combine with radiotherapy, chemotherapy and immunotherapy for cancer patients.

Systematic investigation of genetically determined plasma and urinary metabolites to discover potential interventional targets for colorectal cancer.

BACKGROUND: We aimed to identify plasma and urinary metabolites related to colorectal cancer (CRC) risk and elucidate their mediator role in the associations between modifiable risk factors and CRC. METHODS: Metabolite quantitative trait loci were derived from two published metabolomics genome-wide association studies (GWASs), and summary-level data were extracted for 651 plasma metabolites and 208 urinary metabolites. Genetic associations with CRC were obtained from a large-scale GWAS meta-analysis (100,204 cases; 154,587 controls) and the FinnGen cohort (4,957 cases; 304,197 controls). Mendelian randomization (MR) and colocalization analyses were performed to evaluate the causal roles of metabolites in CRC. Druggability evaluation was employed to prioritize potential therapeutic targets. Multivariable MR and mediation estimation were conducted to elucidate the mediating effects of metabolites on the associations between modifiable risk factors and CRC. RESULTS: The study identified 30 plasma metabolites and four urinary metabolites for CRC. Plasma sphingomyelin and urinary lactose, which were positively associated with CRC risk, could be modulated by drug interventions (ie, Olipudase alfa, Tilactase). Thirteen modifiable risk factors were associated with nine metabolites and eight of these modifiable risk factors were associated with CRC risk. These nine metabolites mediated the effect of modifiable risk factors (Actinobacteria, BMI, waist-hip ratio, fasting insulin, smoking initiation) on CRC. CONCLUSION: This study identified key metabolite biomarkers associated with CRC and elucidated their mediator roles in the associations between modifiable risk factors and CRC. These findings provide new insights into the etiology and potential therapeutic targets for CRC and the etiological pathways of modifiable environmental factors with CRC.

Greenhouse Gas Emissions during Oil Shale Crushing and Its Main Controlling Factors: A Contrast Study of Oil Shale in Yaojie and Fushun Areas, China.

Geological bodies are important sources of greenhouse gas (GHG) emissions. Organic-rich oil shale in sedimentary basins is a good gas source rock, the GHG in which will be released into the atmosphere during crushing to affect climate change. Quantitative calculations of GHG emissions during oil shale crushing were carried out on oil shales from the Yaojie (YJ) and Fushun (FS) mining areas in China. Organic geochemistry, X-ray diffraction, and pore structure analysis experiments, as well as the relationship between storage time and GHG emissions, were analyzed to investigate the main controlling factors of GHG release in different types of oil shales. The results showed that the CH4 and CO2 released from the YJ oil shale were 0.002-0.145 mL/g and 0.011-0.054 mL/g, respectively; the CH4 and CO2 released from the FS oil shale were 0.0001-0.0008 mL/g and 0.002-0.045 mL/g, respectively. Residual CH4 release was closely related to total organic carbon (TOC) and maturity: the CH4 released from the organic-rich and mature YJ oil shale was much higher than that of the FS oil shale, which is relatively organic-lean and immature. The control factors of the released CO2 vary in different regions: CO2 released from the YJ oil shale was somewhat affected by the TOC, while that released from the FS oil shale was mainly controlled by carbonate minerals and their contributing pores. The results of pore structure and organic maceral analyses indicated that both organic and inorganic pores of the YJ oil shale are occupied by asphaltenes, forming a key gas preservation mechanism of residual CH4 and CO2 as solutes dissolved in asphaltenes. In addition, CO2 has a greater absorptive capacity than CH4 and is therefore more difficult to release during the same crushing time. As oil shale is stored for longer periods, residual CH4 will be preferentially released to the atmosphere, while residual CO2 will be released in large quantities during crushing.

Genetic predisposition, modifiable lifestyles, and their joint effects on human lifespan: evidence from multiple cohort studies.

OBJECTIVE: To investigate the associations across genetic and lifestyle factors with lifespan. DESIGN: A longitudinal cohort study. SETTING: UK Biobank. PARTICIPANTS: 353 742 adults of European ancestry, who were recruited from 2006 to 2010 and were followed up until 2021. EXPOSURES: A polygenic risk score for lifespan with long (highest quintile) risk categories and a weighted healthy lifestyle score, including no current smoking, moderate alcohol consumption, regular physical activity, healthy body shape, adequate sleep duration, and a healthy diet, categorised into favourable, intermediate, and unfavourable lifestyles. MAIN OUTCOME MEASURES: Lifespan defined as the date of death or the censor date minus the date of birth. RESULTS: Of the included 353 742 participants of European ancestry with a median follow-up of 12.86 years, 24 239 death cases were identified. Participants were grouped into three genetically determined lifespan categories including long (20.1%), intermediate (60.1%), and short (19.8%), and into three lifestyle score categories including favourable (23.1%), intermediate (55.6%), and unfavourable (21.3%). The hazard ratio (HR) of death for individuals with a genetic predisposition to a short lifespan was 1.21 (95% CI 1.16 to 1.26) compared to those with a genetic predisposition to a long lifespan. The HR of death for individuals in the unfavourable lifestyle category was 1.78 (95% CI 1.71 to 1.85), compared with those in the favourable lifestyle category. Participants with a genetic predisposition to a short lifespan and an unfavourable lifestyle had 2.04 times (95% CI 1.87 to 2.22) higher rates of death compared with those with a genetic predisposition to a long lifespan and a favourable lifestyle. No multiplicative interaction was detected between the polygenic risk score of lifespan and the weighted healthy lifestyle score (p=0.10). The optimal combination of healthy lifestyles, including never smoking, regular physical activity, adequate sleep duration, and a healthy diet, was derived to decrease risk of premature death (death before 75 years). CONCLUSION: Genetic and lifestyle factors were independently associated with lifespan. Adherence to healthy lifestyles could largely attenuate the genetic risk of a shorter lifespan or premature death. The optimal combination of healthy lifestyles could convey better benefits for a longer lifespan, regardless of genetic background.

Cassia Seed Gum Films Incorporated with Partridge Tea Extract as an Edible Antioxidant Food Packaging Film for Preservation of Chicken Jerky.

The use of edible packaging films to delay food spoilage has attracted widespread attention. In this study, partridge tea extract (PTE) was added to cassia gum (CG) to prepare CG/PTE films. The microstructure, optical, mechanical, barrier, and antioxidant properties of CG/PTE films were investigated, and the effect of PTE on CG films was shown. The films had high transparency and smooth surface structure. Additionally, PTE significantly improved the elongation at break and antioxidant activity of films. At 2.5% of PTE, the 2,2-Diphenyl-1-picrylhydrazyl (DPPH) radical scavenging rate of the film was 46.88% after diluting 50 times, indicating excellent antioxidant property, which could be applied to food preservation. After 9 days of storage, the thiobarbituric acid reactive substances values (TBARS) of chicken jerk packaged with films containing 0% and 2.5% PTE increased from 0.12% to 1.04% and 0.11% to 0.40%, respectively. This study suggests that CG/PTE films can be used to preserve cooked meat.

Microbial production of sulfur-containing amino acids using metabolically engineered Escherichia coli.

L-Cysteine and L-methionine, as the only two sulfur-containing amino acids among the canonical 20 amino acids, possess distinct characteristics and find wide-ranging industrial applications. The use of different organisms for fermentative production of L-cysteine and L-methionine is gaining increasing attention, with Escherichia coli being extensively studied as the preferred strain. This preference is due to its ability to grow rapidly in cost-effective media, its robustness for industrial processes, the well-characterized metabolism, and the availability of molecular tools for genetic engineering. This review focuses on the genetic and molecular mechanisms involved in the production of these sulfur-containing amino acids in E. coli. Additionally, we systematically summarize the metabolic engineering strategies employed to enhance their production, including the identification of new targets, modulation of metabolic fluxes, modification of transport systems, dynamic regulation strategies, and optimization of fermentation conditions. The strategies and design principles discussed in this review hold the potential to facilitate the development of strain and process engineering for direct fermentation of sulfur-containing amino acids.

COL5A1 promotes triple-negative breast cancer progression by activating tumor cell-macrophage crosstalk.

Triple-negative breast cancer (TNBC) is an exceptionally aggressive subtype of breast cancer. Despite the recognized interplay between tumors and tumor-associated macrophages in fostering drug resistance and disease progression, the precise mechanisms leading these interactions remain elusive. Our study revealed that the upregulation of collagen type V alpha 1 (COL5A1) in TNBC tissues, particularly in chemoresistant samples, was closely linked to an unfavorable prognosis. Functional assays unequivocally demonstrated that COL5A1 played a pivotal role in fueling cancer growth, metastasis, and resistance to doxorubicin, both in vitro and in vivo. Furthermore, we found that the cytokine IL-6, produced by COL5A1-overexpressing TNBC cells actively promoted M2 macrophage polarization. In turn, TGFß from M2 macrophages drived TNBC doxorubicin resistance through the TGFß/Smad3/COL5A1 signaling pathway, establishing a feedback loop between TNBC cells and macrophages. Mechanistically, COL5A1 interacted with TGM2, inhibiting its K48-linked ubiquitination-mediated degradation, thereby enhancing chemoresistance and increasing IL-6 secretion. In summary, our findings underscored the significant contribution of COL5A1 upregulation to TNBC progression and chemoresistance, highlighting its potential as a diagnostic and therapeutic biomarker for TNBC.

Bone marrow stromal cells dictate lanosterol biosynthesis and ferroptosis of multiple myeloma.

Ferroptosis has been demonstrated a promising way to counteract chemoresistance of multiple myeloma (MM), however, roles and mechanism of bone marrow stromal cells (BMSCs) in regulating ferroptosis of MM cells remain elusive. Here, we uncovered that MM cells were more susceptible to ferroptotic induction under the interaction of BMSCs using in vitro and in vivo models. Mechanistically, BMSCs elevated the iron level in MM cells, thereby activating the steroid biosynthesis pathway, especially the production of lanosterol, a major source of reactive oxygen species (ROS) in MM cells. We discovered that direct coupling of CD40 ligand and CD40 receptor constituted the key signaling pathway governing lanosterol biosynthesis, and disruption of CD40/CD40L interaction using an anti-CD40 neutralizing antibody or conditional depletion of Cd40l in BMSCs successfully eliminated the iron level and lanosterol production of MM cells localized in the Vk*MYC Vk12653 or NSG mouse models. Our study deciphers the mechanism of BMSCs dictating ferroptosis of MM cells and highlights the therapeutic potential of non-apoptosis strategies for managing refractory or relapsed MM patients.

A Nomogram for Predicting the Risk of Deep Vein Thrombosis in Patients With Acute Ischemic Stroke During the COVID-19.

Deep vein thrombosis (DVT) is an important complication of stroke. As coronavirus disease 2019 (COVID-19) enters the stage of persistent and long-term management, the clinical management of DVT in stroke patients may require adjustment. The present study evaluated whether there was an increased risk of DVT in stroke patients during the COVID-19 period. Furthermore, we analyzed the possible risk factors and developed an easy-to-use nomogram to predict DVT in stroke patients during the long-term management of COVID-19. A total of 7087 stroke patients during the COVID-19 period and 14,174 patients with age, sex, and National Institutes of Health Stroke Scale (NIHSS) scores matched before the period from four centers were included. The incidence of DVT in stroke patients during the COVID-19 period (20.5%) was significantly higher than that before this period (15.9%, P < .001). Age, body mass index, smoking, D-dimer, physical activity level, NIHSS score, and intermittent pneumatic compression were significant predictors of DVT during the COVID-19 period (P < .05). A nomogram was constructed; internal and external validations showed high accuracy, and decision curve analysis showed excellent clinical applicability. This nomogram could evaluate the risk of DVT after stroke and assist in its early prevention during the long-term management of COVID-19.

Construction of an Enzymatically Controlled DNA Nanomachine for One-Step Imaging of Telomerase in Living Cells.

Telomerase is a basic reverse transcriptase that maintains the telomere length in cells, and accurate and specific sensing of telomerase in living cells is critical for medical diagnostics and disease therapeutics. Herein, we demonstrate for the first time the construction of an enzymatically controlled DNA nanomachine with endogenous apurinic/apyrimidinic endonuclease 1 (APE1) as a driving force for one-step imaging of telomerase in living cells. The DNA nanomachine is designed by rational engineering of substrate probes and reporter probes embedded with an enzyme-activatable site (i.e., AP site) and their subsequent assembly on a gold nanoparticle (AuNP). Upon recognition and cleavage of the AP site in the substrate probe by APE1, the loop of the substrate probe unfolds, exposing telomeric primer (TP) with the 3'-OH end. Subsequently, the TP is elongated by telomerase at the 3'-OH end to generate a long telomeric product. The resultant telomeric product acts as a swing arm that can hybridize with a reporter probe to initiate the APE1-powered walking reaction, ultimately generating a significantly enhanced fluorescence signal. Notably, endogenous APE1 is used as the driving force of the DNA nanomachine, avoiding the introduction of exogenous auxiliary cofactors into the cellular microenvironment. Owing to the high kinetics and high amplification efficiency of the APE1-powered DNA nanomachine, this strategy enables one-step sensitive sensing of telomerase in vitro and in vivo. It can successfully discriminate telomerase activity between cancer cells and normal cells, screen telomerase inhibitors, and monitor the variations of telomerase activity in living cells, offering a prospective platform for molecular diagnostics and drug discovery.

Novel methyltransferase G9a inhibitor induces ferroptosis in multiple myeloma through Nrf2/HO-1 pathway.

Multiple myeloma (MM) is a common malignant hematologic neoplasm, and the involvement of epigenetic modifications in its development and drug resistance has received widespread attention. Ferroptosis, a new ferroptosis-dependent programmed death mode, is closely associated with the development of MM. The novel methyltransferase inhibitor DCG066 has higher cell activity, but its mechanism of action in MM has not been clarified. Here, we found that DCG066 (5µM) inhibited the proliferation and induced ferroptosis in MM cells; the intracellular levels of ROS, iron, and MDA were significantly elevated, and the level of GSH was reduced after the treatment of DCG066; The protein expression levels of SLC7A11, GPX4, Nrf2 and HO-1 were significantly reduced, and these phenomena could be reversed by ferroptosis inhibitor Ferrostatin-1 (Fer-1) and Nrf2 activator Tert-butyl hydroquinone (TBHQ). Meanwhile, the protein expression levels of Keap1 was increased, and heat shock proteins (HSP70, HSP90 and HSPB1) were reduced after DCG066 treatment. In conclusion, this study confirmed that DCG066 inhibits MM proliferation and induces ferroptosis via the Nrf2/HO-1 pathway.

Perioperative and Post-Hospital Whole-Course nutrition management in patients with pancreatoduodenectomy - a Single-Center prospective randomized controlled trial.

OBJECTIVE: Whole-course nutrition management (WNM) has been proven to improve outcomes and reduce complications. We conducted this randomized controlled trial to validate its effectiveness in patients undergoing pancreatoduodenectomy. METHODS: From December 1, 2020, to November 30, 2023, this single-center randomized clinical trial was conducted at the Department of Hepatobiliopancreatic Surgery in a major hospital in Beijing, China. Participants who were undergoing pancreatoduodenectomy were enrolled and randomly allocated to either the WNM group or the control group. The primary outcome was the incidence of postoperative complications. Subgroup analysis in patients who were at nutritional risk was performed. Finally, a six-month follow-up was conducted and the economic benefit was evaluated using an incremental cost-effectiveness ratio (ICER). RESULTS: A total of 84 patients were randomly assigned (1:1) into the WNM group and the control group. The incidences of total complications (47.6% vs. 69.0%, P=0.046), total infections (14.3% vs. 33.3%, P= 0.040) and abdominal infection (11.9% vs. 31.0%, P= 0.033) were significantly lower in the WNM group. In the subgroup analysis of patients at nutritional risk, 66 cases were included (35 cases in the WNM group and 31 cases in the control group). The rate of abdominal infection (11.4% vs. 32.3%, P= 0.039) and postoperative length of stay (23.1±10.3 vs. 30.4±17.2, P= 0.046) were statistically different between the two subgroups. In the six-month follow-up, more patients reached the energy target in the WNM group (97.0% vs. 79.4%, P=0.049) and got a higher daily energy intake (1761.3±339.5 vs. 1599.6±321.5, P=0.045). The ICER suggested that WNM saved 31,511 Chinese Yuan (CNY) while reducing the rate of total infections by 1% in the ITT population and saved 117,490 CNY in patients at nutritional risk, while WNM saved 31,511 CNY while reducing the rate of abdominal infections by 1% in the ITT population and saved 101,359 CNY in patients at nutritional risk. CONCLUSION: In this trial, whole-course nutrition management was associated with fewer total postoperative complications, total and abdominal infections, and was cost-effective, especially in patients at nutritional risk. It seems to be a favorable strategy for patients undergoing PD.

Associations of maternal serum concentration of iron-related indicators with birth outcomes in Chinese: a pilot prospective cohort study.

BACKGROUND: Previous studies of maternal iron and birth outcomes have been limited to single indicators that do not reflect the comprehensive relationship with birth outcomes. We aimed to investigate the relationship between maternal iron metabolism and neonatal anthropometric indicators using comprehensive iron-related indicators. METHODS: A total of 914 Chinese mother-child dyads were enrolled in this prospective study. Subjects' blood samples were collected at ≤ 14 weeks of gestation. Serum concentrations of iron-related indicators were measured by enzyme-linked immunosorbent assay (ELISA). Femur length was measured by B-ultrasound nearest delivery. Neonatal anthropometric indicators were collected from medical records. RESULTS: After adjustment for potential covariates, higher iron (per one standard deviation, SD increase) was detrimentally associated with - 0.22 mm lower femur length, whereas higher transferrin (per one SD increase) was associated with 0.20 mm higher femur length. Compared with normal subjects (10th-90th percentiles), subjects with extremely high (> 90th percentile) iron concentration were detrimentally associated with lower femur length, birth weight, and chest circumference, and a higher risk of low birth weight, LBW (HR: 3.92, 95%CI: 1.28, 12.0). Subjects with high concentration of soluble transferrin receptor, sTFR and transferrin (> 90th percentile) were associated with higher femur length. Subjects with low concentration of iron and ferritin concentrations (< 10th percentile) were associated with a higher risk of LBW (HR: 4.10, 95%CI: 1.17, 14.3) and macrosomia (HR: 2.79, 95%CI: 1.06, 7.35), respectively. CONCLUSIONS: Maternal iron overload in early pregnancy may be detrimentally associated with neonatal anthropometric indicators and adverse birth outcomes.

Safety and efficacy of ultrasound-guided superior hypogastric plexus block combined with conscious sedation in ambulatory patients undergoing percutaneous microwave ablation of uterine myomas: Study protocol for a single-center, double-blinded, randomized controlled trial.

Background: Pain is a major challenge in performing ultrasound-guided percutaneous microwave ablation (PMWA) of uterine myomas. Inadequate analgesia by local anesthetics hinders the possibility of conducting PMWA of uterine myomas in the Ambulatory Surgery Center (ASC) of the Department of Ultrasound. Objective: The superior hypogastric plexus (SHP) forms a suitable target for pain relief through the blockade, as it contains nociceptive afferent fibers from pelvic organs such as the uterus, rectum, and bladder. Superior hypogastric plexus block (SHPB) has demonstrated promise as an alternative treatment option for alleviating pelvic pain, reducing opioid consumption, and improving quality of life. This study aims to evaluate the efficacy of ultrasound-guided SHPB combined with conscious sedation as an alternative anesthesia option for ambulatory patients receiving ultrasound-guided PMWA of uterine myomas. Methods and analysis: This randomized controlled trial (RCT) will be carried out at the Department of Ultrasound, The First Affiliated Hospital of Xiamen University. Women scheduled for ultrasound-guided PMWA of uterine myomas will be eligible. 86 patients will be recruited and randomly assigned to either the intervention or control groups in a 1:1 ratio. The intervention group will undergo ultrasound-guided superior hypogastric plexus block (SHPB) combined with conscious sedation, while the control group will receive local anesthesia combined with conscious sedation. The primary outcome is the success rate of anesthesia, secondary outcomes include vasoactive drug consumption, acetaminophen consumption, sleep quality, sonographer satisfaction score, patient satisfaction score, the detained time in hospital, and adverse events. Discussions: This RCT represents the inaugural effort to specifically evaluate the safety and efficacy of ultrasound-guided SHPB combined with conscious sedation in patients undergoing ultrasound-guided PMWA of uterine myomas and will provide valuable evidence and insight into the analgesic management of this ambulatory surgery. Ethics and dissemination: This study has been approved by the Ethics Committee of the First Affiliated Hospital of Xiamen University (Scientific Research Ethics Review 2023, No. 139). The results will be submitted for publication in peer-reviewed journals.

Overcoming cold tumors: a combination strategy of immune checkpoint inhibitors.

Immune Checkpoint Inhibitors (ICIs) therapy has advanced significantly in treating malignant tumors, though most 'cold' tumors show no response. This resistance mainly arises from the varied immune evasion mechanisms. Hence, understanding the transformation from 'cold' to 'hot' tumors is essential in developing effective cancer treatments. Furthermore, tumor immune profiling is critical, requiring a range of diagnostic techniques and biomarkers for evaluation. The success of immunotherapy relies on T cells' ability to recognize and eliminate tumor cells. In 'cold' tumors, the absence of T cell infiltration leads to the ineffectiveness of ICI therapy. Addressing these challenges, especially the impairment in T cell activation and homing, is crucial to enhance ICI therapy's efficacy. Concurrently, strategies to convert 'cold' tumors into 'hot' ones, including boosting T cell infiltration and adoptive therapies such as T cell-recruiting bispecific antibodies and Chimeric Antigen Receptor (CAR) T cells, are under extensive exploration. Thus, identifying key factors that impact tumor T cell infiltration is vital for creating effective treatments targeting 'cold' tumors.

Circulating 25-hydroxyvitamin D and survival outcomes of colorectal cancer: evidence from population-based prospective cohorts and Mendelian randomisation.

BACKGROUND: To investigate the association between circulating 25-hydroxyvitamin D (25-OHD) and colorectal cancer (CRC) survival outcomes. METHODS: We conducted analyses among the Study of Colorectal Cancer in Scotland (SOCCS) and the UK Biobank (UKBB). Both cancer-specific survival (CSS) and overall survival (OS) outcomes were examined. The 25-OHD levels were categorised into three groups, and multi-variable Cox-proportional hazard models were applied to estimate hazard ratios (HRs). We performed individual-level Mendelian randomisation (MR) through the generated polygenic risk scores (PRS) of 25-OHD and summary-level MR using the inverse-variance weighted (IVW) method. RESULTS: We observed significantly poorer CSS (HR = 0.65,95%CI = 0.55-0.76,P = 1.03 × 10-7) and OS (HR = 0.66,95%CI = 0.58-0.75,P = 8.15 × 10-11) in patients with the lowest compared to those with the highest 25-OHD after adjusting for covariates. These associations remained across patients with varied tumour sites and stages. However, we found no significant association between 25-OHD PRS and either CSS (HR = 0.98,95%CI = 0.80-1.19,P = 0.83) or OS (HR = 1.07,95%CI = 0.91-1.25,P = 0.42). Furthermore, we found no evidence for causal effects by conducting summary-level MR analysis for either CSS (IVW:HR = 1.04,95%CI = 0.85-1.28,P = 0.70) or OS (IVW:HR = 1.10,95%CI = 0.93-1.31,P = 0.25). CONCLUSION: This study supports the observed association between lower circulating 25-OHD and poorer survival outcomes for CRC patients. Whilst the genotype-specific association between better outcomes and higher 25-OHD is intriguing, we found no support for causality using MR approaches.

Research progress of CTC, ctDNA, and EVs in cancer liquid biopsy.

Circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), and extracellular vehicles (EVs) have received significant attention in recent times as emerging biomarkers and subjects of transformational studies. The three main branches of liquid biopsy have evolved from the three primary tumor liquid biopsy detection targets-CTC, ctDNA, and EVs-each with distinct benefits. CTCs are derived from circulating cancer cells from the original tumor or metastases and may display global features of the tumor. ctDNA has been extensively analyzed and has been used to aid in the diagnosis, treatment, and prognosis of neoplastic diseases. EVs contain tumor-derived material such as DNA, RNA, proteins, lipids, sugar structures, and metabolites. The three provide different detection contents but have strong complementarity to a certain extent. Even though they have already been employed in several clinical trials, the clinical utility of three biomarkers is still being studied, with promising initial findings. This review thoroughly overviews established and emerging technologies for the isolation, characterization, and content detection of CTC, ctDNA, and EVs. Also discussed were the most recent developments in the study of potential liquid biopsy biomarkers for cancer diagnosis, therapeutic monitoring, and prognosis prediction. These included CTC, ctDNA, and EVs. Finally, the potential and challenges of employing liquid biopsy based on CTC, ctDNA, and EVs for precision medicine were evaluated.

Pirfenidone alleviates chronic pancreatitis via suppressing the activation of pancreatic stellate cells and the M1 polarization of macrophages.

In the realm of fibroinflammatory conditions, chronic pancreatitis (CP) stands out as a particularly challenging ailment, lacking a dedicated, approved treatment. The potential of Pirfenidone (PFD), a drug originally used for treating idiopathic pulmonary fibrosis (IPF), in addressing CP's fibrotic aspects has sparked new interest. This investigation focused on the role of PFD in diminishing fibrosis and immune response in CP, using a mouse model induced by caerulein. The research extended to in vitro studies examining the influence of PFD on pancreatic stellate cells' (PSCs) behavior and the polarization of macrophages into M1 and M2 types. Advanced techniques like RNA sequencing and comprehensive data analyses were employed to decode the molecular interactions of PFD with PSCs. Supplementary experiments using techniques such as quantitative real-time PCR, western blotting, and immunofluorescence were also implemented. Results showed a notable reduction in pancreatic damage in PFD-treated mice, manifested through decreased acinar cell atrophy, lower collagen deposition, and a reduction in macrophage presence. Further investigation revealed PFD's capacity to hinder PSCs' migration, growth, and activation, alongside a reduction in the production and secretion of extracellular matrix proteins. This effect is primarily achieved by interfering with signaling pathways such as TGF-ß/Smad, Wnt/ß-catenin, and JAK/STAT. Additionally, PFD selectively hampers M1 macrophage polarization through the STAT3 pathway, without impacting M2 polarization. These outcomes highlight PFD's dual mechanism in moderating PSC activity and M1 macrophage polarization, positioning it as a promising candidate for CP therapy.

Microplastics exposure causes the senescence of human lung epithelial cells and mouse lungs by inducing ROS signaling.

Microplastics (MPs) are environmental pollutants and can be inhaled by humans to threaten health. The lung tissue, responsible for the gas exchange between the body and the environment, is vulnerable to MPs exposure. However, from the perspective of cellular senescence, the effect of MPs on lung cells and tissues has not yet been deeply dissected. In this study, we reported that all the four typical MPs exhibited the significant biological effects in term of inducing senescence of human lung derived cells A549 and BEAS-2B in vitro. We further found that polyvinyl chloride (PVC) increased the reactive oxygen species (ROS) level in A549 cells and that PVC-induced senescent characteristics could be largely reversed by antioxidant treatment. Importantly, intratracheal instillation of PVC MPs in mice could effectively impair their physical function, induce the increased systemic inflammation level, cause the accumulation of senescent cells. Our study demonstrates that MPs induce senescence in human lung epithelial cells and mouse lungs by activating ROS signaling, and provides new insight into the potential pathogenesis of MPs on lung diseases.