CircPHGDH downregulation decreases papillary thyroid cancer progression through miR-122-5p/PKM2 axis.

BACKGROUND: Although papillary thyroid carcinoma (PTC) has a favorable prognosis, it could affect patient life quality and become a serious threat because of invasion and metastasis. Many investigations have suggested that circular RNAs (circRNAs) are involved in different cancer regulations. Nevertheless, circRNAs role in invasive PTC remains unclear. METHODS: In the present investigation, next-generation sequencing was applied to explore abnormal circRNA expression. The expression of circRNA phosphoglycerate dehydrogenase (circPHGDH) in PTC cell lines and tissues were examined. Then, we investigated regulatory mechanism and circPHGDH downstream targets using bioinformatics analysis and luciferase reporting analysis. Then transwell migration, Cell Counting Kit-8 (CCK8) and 5-ethynyl-2'-deoxyuridine (EdU) assays were used for cells migration and proliferation analysis. In vivo metastasis and tumorigenesis assays were also employed to evaluate the circPHGDH role in PTC. RESULTS: The data showcased that circPHGDH expression increased in both PTC cell lines and tissues, which suggested that circPHGDH functions in PTC progression. circPHGDH downregulation suppressed PTC invasion and proliferation in both in vivo and in vitro experiments. Bioinformatics and luciferase reporter results confirmed that both microRNA (miR)-122-5p and pyruvate kinase M2 subtype (PKM2) were downstream targets of circPHGDH. PKM2 overexpression or miR-122-5p suppression reversed PTC cell invasion and proliferation post silencing circPHGDH by restoring aerobic glycolysis. CONCLUSION: Taken together, our research found that circPHGDH downregulation reduced PTC progression via miR-122-5p/PKM2 axis regulation mediated by aerobic glycolysis.

TCEB3 initiates ovarian cancer apoptosis by mediating ubiquitination and degradation of MCL-1.

Platinum resistance remains a major contributor to the poor prognosis of ovarian cancer. Anti-apoptotic protein myeloid cell leukemia-1 (MCL-1) has emerged as a promising target for overcoming drug resistance, but different cancer cells utilize distinct protein degradation pathways to alter MCL-1 level. We systematically investigated E3 ligases to identify novel candidates that mediate platinum resistance in ovarian cancer. Transcription Elongation Factor B (TCEB3) has been identified as a novel E3 ligase recognition subunit that targets MCL-1 in the cytoplasm during platinum treatment other than its traditional function of targeting the Pol II in the nuclear compartment. TCEB3 expression is downregulated in platinum-resistant cell lines and this low expression is associated with poor prognosis. The ubiquitination of MCL-1 induced by TCEB3 leads to cell death in ovarian cancer. Moreover, platinum treatment increased the cytoplasm proportion of TCEB3, and the cytoplasm localization of TCEB3 is important for its targeting of MCL-1. This study emphasizes the dual function of TCEB3 in homeostasis maintenance and in cell fate determination under different conditions, and provides a new insight into drug resistance in ovarian cancer.

Does the active hydrogen atom in the hydantoin anion affect the physical properties, CO2 capture and conversion of ionic liquids?

Compared to the effect of the active hydrogen atom in the cation in protic ionic liquids (ILs) on their properties and applications, there are very few reports on the role of the active hydrogen atom in the anion. In order to better understand the role of the active hydrogen atom in the anion, the physical properties, CO2 capture and conversion of three hydantoin-based anion-functionalized ILs ([P4442][Hy], [P4442]2[Hy], and [HDBU][Hy]) have been investigated via experiments, spectroscopy, and DFT calculations in this work. The results show that the active hydrogen atom in the anion can form anionic hydrogen bonding networks, which significantly increase the melting point and viscosity and decrease the basicity of the IL, thereby weakening its ability to capture and convert CO2. Interestingly, [P4442][Hy] undergoes a solid/liquid two-phase transition during CO2 absorption/desorption due to the formation of quasi-intramolecular hydrogen bonding between the active hydrogen atom and the O- atom of the absorbed CO2, suggesting that the presence of the active hydrogen atom gives [P4442][Hy] the potential to be an excellent molecular switch. As there is no active hydrogen atom in the anion of [P4442]2[Hy], it shows excellent CO2 capture and conversion performance through the double-site interaction. [HDBU][Hy] shows the weakest catalytic CO2 conversion due to the presence of active hydrogen atoms on both its anion and cation. Therefore, the active hydrogen atom in the anion may play a more important role in the properties and potential applications of ILs than the active hydrogen atom in the cation.

The masking phenomenon of microplastics additives on oxidative stress responses in freshwater food chains.

The variability and intrinsic mechanisms of oxidative stress induced by microplastics at different trophic levels in freshwater food chains are not well understood. To comprehensively assess the oxidative stress induced by polystyrene microplastics (PS-MPs) in freshwater food chains, the present study first quantified the oxidative stress induced by PS-MPs in organisms at different trophic levels using factorial experimental design and molecular dynamics methods. Then focuses on analyzing the variability of these responses across different trophic levels using mathematical statistical analysis. Notably, higher trophic level organisms exhibit diminished responses under PS-MPs exposure. Furthermore, the coexistence of multiple additives was found to mask these responses, with antioxidant plastic additives significantly influencing oxidative stress responses. Mechanism analysis using computational chemistry simulation determines that protein structure and amino acid characteristics are key factors driving PS-MPs induced oxidative stress variation in freshwater organisms at different nutrient levels. Increased hydrophobic additives induce protein helicalization and amino acid residue aggregation. This study systematically reveals the variability of biological oxidative stress response under different nutrient levels, emphasizing the pivotal role of chemical additives. Overall, this study offers crucial insights into PS-MPs' impact on oxidative stress responses in freshwater ecosystems, informing future environmental risk assessment.

Flavonoid extracted from Epimedium attenuate cGAS-STING-mediated diseases by targeting the formation of functional STING signalosome.

Hyperactivation of the cyclic-GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signalling pathway has been shown to be associated with the development of a variety of inflammatory diseases, and the discovery of an inhibitor of the cGAS-STING signalling pathway holds great promise in the therapeutic interventions. Epimedium flavonoid (EF), a major active ingredient isolated from the medicinal plant Epimedium, has been reported to have good anti-inflammatory activity, but its exact mechanism of action remains unclear. In the present study, we found that EF in mouse bone marrow-derived macrophages (BMDMs), THP-1 (Tohoku Hospital Pediatrics-1) as well as in human peripheral blood mononuclear cells (hPBMC) inhibited the activation of the cGAS-STING signalling pathway, which subsequently led to a decrease in the expression of type I interferon (IFN-ß, CXCL10 and ISG15) and pro-inflammatory cytokines (IL-6 and TNF-α). Mechanistically, EF does not affect STING oligomerization, but inhibits the formation of functional STING signalosome by attenuating the interaction of interferon regulatory factor 3 (IRF3) with STING and TANK-binding kinase 1 (TBK1). Importantly, in vivo experiments, EF has shown promising therapeutic effects on inflammatory diseases mediated by the cGAS-STING pathway, which include the agonist model induced by DMXAA stimulation, the autoimmune inflammatory disease model induced by three prime repair exonuclease 1 (Trex1) deficiency, and the non-alcoholic steatohepatitis (NASH) model induced by a pathogenic amino acid and choline deficiency diet (MCD). To summarize, our study suggests that EF is a potent potential inhibitor component of the cGAS-STING signalling pathway for the treatment of inflammatory diseases mediated by the cGAS-STING signalling pathway.

Improved microalgae carbon fixation and microplastic sedimentation in the lake through in silico method.

The impact of microplastics in lake water environments on microalgae carbon fixation and microplastic sedimentation has attracted global attention. The molecular dynamic simulation method was used to design microplastic additive proportioning schemes for improving microalgae carbon fixation and microplastic sedimentation. Results showed that the harm of microplastics can be effectively alleviated by adjusting the proportioning scheme of plastic additives. Besides, the decabromodiphenyl oxide (DBDPO) was identified as the main additive that affect the microalgae carbon fixation and microplastic sedimentation. Thus, a molecular modification based on CiteSpace visual analysis was firstly used and 12 DBDPO derivatives were designed. After the screening, DBDPO-2 and DBDPO-5 became the environmentally friendly DBDPO alternatives, with the highest microalgae carbon fixation and microplastic sedimentation ability enhancement of over 25 %. Compared to DBDPO, DBDPO derivatives were found easier to stimulate the adsorption and binding ability of surrounding hotspot amino acids to CO2 and ribulose-5-phosphate, increasing the solvent-accessible surface area of microplastics, thus improving the microalgae carbon fixation and microplastic sedimentation ability. This study provides theoretical support for simultaneously promoting the microalgae carbon fixation and microplastic sedimentation in the lake water environment and provides scientific basis for the protection and sustainable development of lake water ecosystem.

Bacterial antigens and asthma: a comparative study of common respiratory pathogenic bacteria.

Objective: In a previous study we have shown that, in the presence of interleukin (IL)-33, repeated, per-nasal challenge of murine airways with Streptococcus pneumoniae (S. pneumoniae) organisms induces human asthma-like airways inflammation. It is not clear, however, whether this effect is unique or manifest in response to other common respiratory pathogens.Methods: To explore this, airways of BALB/c mice were repeatedly challenged per-nasally with formaldehyde-inactivated bacterial bodies in the presence or absence of murine recombinant IL-33. Serum concentrations of S.pneumoniae, Moraxella catarrhalis (M.catarrhalis) and Haemophilus influenzae (H.influenzae) lysates-specific IgE were measured in patients with asthma and control subjects.Results: We showed that in the presence of IL-33, repeated, per-nasal airways exposure to the bodies of these bacteria induced airways hyperresponsiveness (AHR) in the experimental mice. This was accompanied by cellular infiltration into bronchoalveolar lavage fluid (BALF), eosinophilic infiltration and mucous hypertrophy of the lung tissue, with elevated local expression of some type 2 cytokines and elevated, specific IgG and IgE in the serum. The precise characteristics of the inflammation evoked by exposure to each bacterial species were distinguishable.Conclusions: These results suggest that in the certain circumstances, inhaled or commensal bacterial body antigens of both Gram-positive (S. pneumoniae) and Gram-negative (M. catarrhalis and H. influenzae) respiratory tract bacteria may initiate type 2 inflammation typical of asthma in the airways. In addition, we demonstrated that human asthmatic patients manifest elevated serum concentrations of M.catarrhalis- and H.influenzae-specific IgE.

Comparison of the medial midline and the anterolateral portal in ankle arthroscopy for the treatment of osteochondral lesions of the medial talus.

PURPOSE: To compare the clinical efficacy and complication rates between the medial midline and anterolateral portals in ankle arthroscopy for treating medial osteochondral lesions of the talus (OLTs). METHODS: We retrospectively analyzed patients with medial OLTs who underwent either a dual medial approach (via the medial midline and anteromedial portal) or a traditional approach (via the anterolateral and anteromedial portal) between June 2017 and January 2023. The degree of injury was evaluated by radiographs, computed tomography, and magnetic resonance imaging. Clinical outcomes were assessed using the visual analog scale (VAS), the American Orthopaedic Foot and Ankle Society (AOFAS) score, and the Magnetic Resonance Observation of Cartilage Repair Tissue (MOCART) scoring system. The incidence of postoperative complications, including superficial peroneal nerve (SPN) injury, was evaluated in all patients. RESULTS: There were 39 patients in total; 16 patients underwent the dual medial approach, and 23 patients underwent the traditional approach. The mean age was 39.4 ± 9.0 years, and the mean follow-up duration was 18.7 ± 6.4 months. The clinical outcomes improved significantly in both groups (*P < 0.05), but there was no significant difference between the two groups (P > 0.05). Postoperative complications were mainly SPN injury. The incidence of SPN injury was 13.0% in the traditional approach group and 0% in the dual medial approach group, with no significant difference between the two groups (P > 0.05), but a trend of reduction in SPN injury was observed in the dual medial approach group. CONCLUSION: The dual medial approach can also treat medial OLTs well, providing clear visualization and more convenient operation and reducing the possibility of injury to the SPN compared with the traditional approach. Therefore, we consider that the MM portal would be a good alternative to the anterolateral portal in treating medial OLTs.

Calcitonin Inhibits Phenotypic Switching of Aortic Smooth Muscle Cells and Neointimal Hyperplasia through the AMP-Activated Protein Kinase/Mechanistic Target of Rapamycin Pathway.

Calcitonin (CT) is a peptide hormone secreted by the parafollicular C cells of the thyroid gland, salmon calcitonin was originally extracted from the hind cheek of salmon. Neointimal hyperplasia refers to the excessive proliferation and migration of vascular smooth muscle cells (VSMCs). In this study, a rat model of restenosis was employed to explore the impact of calcitonin on neointima proliferation. Calcitonin was administered via continuous injections for a duration of 14 days postsurgery, and the expression of proteins associated with proliferation, migration, and phenotypic switching was assessed using the vascular smooth muscle cells. Additionally, metabolomic analyses were conducted to shed light on the mechanisms that underlie the role of calcitonin in the development of cardiovascular disease. In our study, we found that calcitonin possesses the capability to dispute the proliferation, migration, and phenotypic transformation of VSMCs induced by platelet-derived growth factor-BB (PDGF-BB) and 15% fetal bovine serum in vitro. Calcitonin has demonstrated a favorable impact on smooth muscle cells, both in vitro and in vivo. More specifically, it has been observed to mitigate phenotypic switching, proliferation, and migration of these cells. Moreover, calcitonin has been identified as a protective factor against phenotypic switching and the formation of neointima, operating through the AMP-activated protein kinase/mechanistic target of rapamycin (mTOR) pathway.

The combination of Schisandrin C and Luteolin synergistically attenuates hepatitis B virus infection via repressing HBV replication and promoting cGAS-STING pathway activation in macrophages.

BACKGROUND: HBV infection can result in severe liver diseases and is one of the primary causes of liver cell carcinoma-related mortality. Liuwei Wuling tablet (LWWL) is a traditional Chinese medicine formula, with a protecting liver and decreasing enzyme activity, usually used to treat chronic hepatitis B with NAs in clinic. However, its main active ingredients and mechanism of action have not been fully investigated. Hence, we aimed to screen the active ingredient and effective ingredient combinations from Liuwei Wuling tablet to explore the anti-herpatitis B virus activity and mechanism. METHODS: Analysis and screening of effective antiviral components in LWWL by network pharmacology, luteolin (Lut) may be a compound with significant antiviral activity. The mechanism of antiviral action of Lut was also found by real-time PCR detection and western blotting. Meanwhile, we established a co-culture model to investigate the antiviral mechanism of Schisandrin C (SC), one of the main active components of Schisandra chinensis fructus (the sovereign drug of LWWL). Next, HBV-infected mice were established by tail vein injection of pAAV-HBV1.2 plasmid and administered continuously for 20 days. And their antiviral capacity was evaluated by checking serum levels of HBsAg, HBeAg, levels of HBV DNA, and liver levels of HBcAg. RESULTS: In this study, we conducted network pharmacology analysis on LWWL, and through in vitro experimental validation and data analysis, we found that luteolin (Lut) possessed obviously anti-HBV activity, inhibiting HBV replication by downregulating hepatocyte nuclear factor 4α (HNF4α) via the ERK pathway. Additionally, we established a co-culture system and proved that SC promoted activation of cGAS-STINIG pathway and IFN-ß production in THP-1 cells to inhibit HBV replication in HepG2.2.15 cells. Moreover, we found the combination of SC and Lut shows a greater effect in inhibiting HBV compared to SC or Lut alone in HBV-infected mice. CONCLUSION: Taken together, our study suggests that combination of SC and Lut may be potential candidate drug for the prevention and treatment of chronic hepatitis B.

New Local Composition Model for Correlating of the Molar Conductivity of Ionic Liquid-Solvent Systems over the Whole Concentration Range.

Considering that traditional electrolyte models are limited to use in the solvent-rich region, the development of new models to describe the molar conductivity (Λm) over the whole concentration range of ionic liquid (IL)-solvent systems is a meaningful study. Based on the idea of local composition and the law of independent ion migration, a new model is proposed in this study and used to successfully correlate the relationship between Λm and composition over the whole concentration range for 18 IL-solvent systems with satisfactory fitting accuracy. Meanwhile, the electrical conductivity (κ) of the systems is estimated using the calculated Λm. Moreover, the strength of anion-cation, anion-solvent, and cation-solvent interactions in the systems is explored by the obtained energy parameters, and the effect of the solvent on the interactions is investigated. The proposed model provides a new method to accurately describe the conductivity property of IL-solvent systems over the whole concentration range.

Four new glycosides isolated from Gerbera delavayi Franch.

Phytochemical investigation of the whole plant of Gerbera delavayi afforded four new glycosides including three coumarin glycosides, Gerbelavinside A (1), Gerbelavinside B (2) and Gerbelavinside C (3) and one acetophenone glycoside, Gerbelavinside F (4). The structures of isolated compounds were elucidated by analysis of 1D and 2D NMR, HR-ESI-MS, acid hydrolysis, as well as comparing with the literature. The isolated compounds were examined the effects of nitric oxide (NO) production inhibition in lipopolysaccharide (LPS)-induced RAW264.7 macrophage cells, and Gerbelavinside C presented a certain inhibitory activity.

An original strategy and evaluation of a reaction mechanism for recovering valuable metals from zinc oxide dust containing intractable germanide.

A novel leaching-roasting-leaching strategy was used to recover valuable metals from zinc oxide dust containing intractable germanide. In the ultrasonic enhanced oxidation leaching stage, potassium permanganate and ultrasonication were introduced to strengthen the dissolution of sulphide. During the roasting stage, sodium carbonate and magnesium nitrate were added to promote the reaction between the insoluble tetrahedral germanium dioxide and complex forms of germanium-containing compounds. Simultaneously, the sulphur produced in the ultrasonic enhanced oxidation leaching stage was used to change the phases of tin dioxide and zinc ferrite, thereby releasing germanium into its lattice. Finally, the germanium in the roasting slag was recovered by conventional leaching, and the grades of lead and tin in the residue were enriched to 35.21% and 11.31%, respectively. Compared with the conventional acid leaching process of enterprise, the total reaction time of this method was shortened to 80 min, and the recovery rates of zinc and germanium increased by approximately 10% and 40%, respectively. The entire process is clean and environmentally friendly and does not cause adverse effects on the recovery of lead and tin. Overall, this study provides new insights into the design of valuable metal recovery methods for zinc oxide dust containing intractable germanide.

Suramin inhibits phenotypic transformation of vascular smooth muscle cells and neointima hyperplasia by suppressing transforming growth factor beta receptor 1 /Smad2/3 pathway activation.

Vascular smooth muscle cells (VSMCs) contribute to neointimal hyperplasia (NIH) after vascular injury, a common feature of vascular remodelling disorders. Suramin is known to exert antitumour effects by inhibiting the proliferation of various tumour cells; however, its effects and mechanism on VSMCs remain unclear. This study investigated the effects of suramin on human aortic smooth muscle cells (HASMCs), rat aortic smooth muscle cells (RASMCs) and NIH to examine its suitability for the prevention of vascular remodelling disorders. In vitro, suramin administration reduced platelet-derived growth factor type BB (PDGF-BB)-stimulated proliferation, migration, and dedifferentiation of VSMCs through a transforming growth factor beta receptor 1 (TGFBR1)/Smad2/3-dependent pathway. Suramin dramatically inhibited NIH ligation in the left common carotid artery (LCCA) vivo. Therefore, our results indicate that suramin protects against the development of pathological vascular remodelling by attenuating VSMCs proliferation, migration, and phenotypic transformation and may be used as a potential medicine for the treatment of NIH.

Predictors and prognosis of early neurological outcomes on patients with Vertebrobasilar artery occlusion undergoing endovascular treatment.

BACKGROUND: This research explored the factors influencing early neurological outcomes (ENO) in patients who had vertebrobasilar artery occlusion (VBAO) and received endovascular treatment (EVT), as well as examining the causal influence of ENO on the prognosis of VBAO patients. METHODS: A retrospective review was carried out on patients from 65 Chinese stroke centers, all within 24 hours of the estimated occlusion time. ENO includes early neurological improvement (ENI) and early neurological deterioration (END), defined as a decrease or an increase of at least 4 points in NIHSS score between baseline and 24 hours after EVT. Death within 24 hours after EVT also consider as END. END was further divided into explainable END and unexplainable END (unEND). Independent predictors of ENO and the association between ENO and outcomes in patients with VBAO were determined using center-adjusted analyses. The study developed a multivariate logistic regression model to examine the comparative risk of unEND versus explainable END on the clinical outcomes in VBAO patients. RESULTS: A total of 2257 patients were included. Glasgow Coma Scale (GCS) (OR 1.16, 95% CI 1.03-1.30) and successful reperfusion (OR 1.15, 95% CI 1.02-1.30) were associated with ENI. Baseline NIHSS (OR 0.60, 95% CI 0.53-0.68), successful reperfusion (OR 0.79, 95% CI 0.71-0.89) and puncture to reperfusion time (OR 1.17, 95% CI 1.03-1.33) were associated with END. When examining three-month prognostic indexes, both END and ENI were found to be linked to the three-month outcomes, but in opposite directions. A subgroup analysis of END suggested that unexplained END typically demonstrated a more favorable prognosis compared to explained END, although the prognosis remained generally unfavorable. CONCLUSIONS: ENO, whether they manifested as early improvement or deterioration, were linked to the prognosis of VBAO patients undergoing EVT. The outcomes after unEND were more favorable than those following explained END.

C-to-G editing generates double-strand breaks causing deletion, transversion and translocation.

Base editors (BEs) introduce base substitutions without double-strand DNA cleavage. Besides precise substitutions, BEs generate low-frequency 'stochastic' byproducts through unclear mechanisms. Here, we performed in-depth outcome profiling and genetic dissection, revealing that C-to-G BEs (CGBEs) generate substantial amounts of intermediate double-strand breaks (DSBs), which are at the centre of several byproducts. Imperfect DSB end-joining leads to small deletions via end-resection, templated insertions or aberrant transversions during end fill-in. Chromosomal translocations were detected between the editing target and off-targets of Cas9/deaminase origin. Genetic screenings of DNA repair factors disclosed a central role of abasic site processing in DSB formation. Shielding of abasic sites by the suicide enzyme HMCES reduced CGBE-initiated DSBs, providing an effective way to minimize DSB-triggered events without affecting substitutions. This work demonstrates that CGBEs can initiate deleterious intermediate DSBs and therefore require careful consideration for therapeutic applications, and that HMCES-aided CGBEs hold promise as safer tools.

Children systemic lupus erythematosus-associated pancreatitis.

OBJECTIVE: To early recognise and improve the prognosis of children systemic lupus erythematosus (cSLE)-associated pancreatitis by summarising and analysing clinical features and prognosis data from 12 cases. METHODS: Retrospective analysis of clinical data from 12 cases of cSLE-associated pancreatitis diagnosed and treated from January 2016 to December 2021 at hospitals such as Children's Hospital of Capital Institute of Paediatrics. RESULTS: The median SLEDAI-2K score for disease activity was 18.00 (range 12.25-21.00) in the case group and 10.00 (range 7.00-18.00) in the control group, with a statistically significant difference (P < 0.05) between the two groups. The case group had a higher proportion of abdominal pain, vomiting, abdominal distension, pleural effusion, Raynaud's phenomenon (RP), splenic infarction, and concurrent macrophage activation syndrome (MAS) than the control group, with a statistically significant difference (P < 0.05). Serum ferritin (SF), alanine transaminase (ALT), aspartate transaminase (AST), lactate dehydrogenase (LDH), amylase, and increased 24-h urine protein levels were statistically different between the two groups (P < 0.05); platelet counts (PLT) reduction was also statistically different (P < 0.05). The case group had a higher proportion of methylprednisolone pulse therapy, cyclophosphamide pulse therapy during remission induction, and therapeutic plasma exchange than the control group, with a statistically significant difference (P < 0.05) between the two. CONCLUSION: CSLE-associated pancreatitis has a high fatality rate. The presence of RP, splenic infarction, pleural effusion, and MAS warrants attention from clinicians regarding the possibility of pancreatitis. Once pancreatitis is detected, the primary disease needs active treatment for better prognosis.

Serum uric acid and prognosis of ischemic stroke: Cohort study, meta-analysis and Mendelian randomization study.

INTRODUCTION: The role of serum uric acid (UA) levels in the functional recovery of ischemic stroke remains uncertain. To evaluate whether UA could predict clinical outcomes in patients with ischemic stroke. PATIENTS AND METHODS: A three-stage study design was employed, combining a large-scale prospective cohort study, a meta-analysis and a Mendelian randomization (MR) analysis. Firstly, we conducted a cohort study using data from the Nanjing Stroke Registry Program (NSRP) to assess the association between UA levels and 3-month functional outcomes in ischemic stroke patients. Secondly, the meta-analysis was conducted to integrate currently available cohort evidence. Lastly, MR analysis was utilized to explore whether genetically determined UA had a causal link to the functional outcomes of ischemic stroke using summary data from the CKDGen and GISCOME datasets. RESULTS: In the first stage, the cohort study included 5631 patients and found no significant association between UA levels and functional outcomes at 3 months after ischemic stroke. In the second stage, the meta-analysis, including 10 studies with 14,657 patients, also showed no significant association between UA levels and stroke prognosis. Finally, in the third stage, MR analysis using data from 6165 patients in the GISCOME study revealed no evidence of a causal relationship between genetically determined UA and stroke functional outcomes. DISCUSSION AND CONCLUSION: Our comprehensive triangulation approach found no significant association between UA levels and functional outcomes at 3 months after ischemic stroke.

Lipid metabolism-associated genes serve as potential predictive biomarkers in neoadjuvant chemoradiotherapy combined with immunotherapy in rectal cancer.

BACKGROUND: The aim of this study was to investigate the potential role of lipid metabolism-associated genes (LMAGs) in neoadjuvant chemoradiotherapy (nCRT) and immunotherapy for rectal cancer. METHODS: Differential LMAGs were characterized and functional enrichment analysis was performed. Multiple machine learning algorithms were combined to explore candidate LMAGs. ROC analysis was performed to evaluate the predicting accuracy of candidate LMAGs. The expression patterns, prognostic value, genetic alterations, and immune cell infiltration of the top-ranked LMAGs were investigated. RESULTS: We identified 45 LMAGs that were differentially expressed in tumor samples of nCRT responders and non-responders. These LMAGs were closely associated with lipid metabolism-related biological processes and pathways. ROC analysis revealed that the SREBF2 gene, an important transcription factor in regulating lipid metabolism, was the highest predictor of nCRT in rectal cancer. SREBF2 was highly expressed in rectal cancer tissues and high expression of SREBF2 was associated with favorable prognosis. Multivariate analysis showed that SREBF2 was an independent prognostic factor, and we integrated it with other clinical factors to establish an effective prognostic nomogram. SREBF2 also played a synergistic role with its co-expressed genes in the prognostic process of rectal cancer. Furthermore, SREBF2 was demonstrated to be closely associated with multiple immune infiltrating cells, and immunotherapy-related genes and may be used to predict the response to immunotherapy. CONCLUSION: Our study suggests that LMAGs may serve as promising biomarkers in nCRT combined with immunotherapy for rectal cancer. However, large-scale clinical trials and biological experiments are necessary to demonstrate the efficacy and underlying mechanisms.