Causal relationship of genetically predicted particulate matter 2.5 level with Alzheimer's disease and the mediating effect of dehydroepiandrosterone sulphate.

BACKGROUND: The causal association between particulate matter 2.5 (PM2.5) and Alzheimer's disease (AD) remains inconclusive, and the mediators of the association have yet to be explored. AIMS: We aimed to assess the potential causal relationship between PM2.5 and AD, and to investigate the mediating role of dehydroepiandrosterone sulphate (DHEAS). SUBJECTS AND METHODS: We implemented a two-sample Mendelian randomisation (MR) study to examine the genetic predisposition to PM2.5 exposure and its association with AD. The inverse-variance weighted (IVW) method served as the primary analytical tool to estimate the odds ratio (OR) and 95% confidence interval (95% CI). RESULTS: There were 6 and 4 genetic variants associated with DHEAS and PM2.5, respectively. Based on the multivariable MR analysis, we found that after adjusting for DHEAS, each standard deviation increase in PM2.5 was associated with the risk of AD (OR: 2.96, 95% CI: 1.33, 6.58, p = 0.00769). The MR Egger intercept test did not detect horizontal pleiotropy for PM2.5 (P-pleiotropy = 0.879) and DHEAS(P-pleiotropy = 0.941). According to the results of the mediation analysis, DHEAS accounted for 18.3% of the association between PM2.5 and AD. CONCLUSION: Our findings affirm a significant causal association between PM2.5 exposure and AD, with DHEAS playing a mediating role in this relationship.

Structural insights into human organic cation transporter 1 transport and inhibition.

The human organic cation transporter 1 (hOCT1), also known as SLC22A1, is integral to hepatic uptake of structurally diversified endogenous and exogenous organic cations, influencing both metabolism and drug pharmacokinetics. hOCT1 has been implicated in the therapeutic dynamics of many drugs, making interactions with hOCT1 a key consideration in novel drug development and drug-drug interactions. Notably, metformin, the frontline medication for type 2 diabetes, is a prominent hOCT1 substrate. Conversely, hOCT1 can be inhibited by agents such as spironolactone, a steroid analog inhibitor of the aldosterone receptor, necessitating a deep understanding of hOCT1-drug interactions in the development of new pharmacological treatments. Despite extensive study, specifics of hOCT1 transport and inhibition mechanisms remain elusive at the molecular level. Here, we present cryo-electron microscopy structures of the hOCT1-metformin complex in three distinct conformational states - outward open, outward occluded, and inward occluded as well as substrate-free hOCT1 in both partially and fully open states. We also present hOCT1 in complex with spironolactone in both outward and inward facing conformations. These structures provide atomic-level insights into the dynamic metformin transfer process via hOCT1 and the mechanism by which spironolactone inhibits it. Additionally, we identify a 'YER' motif critical for the conformational flexibility of hOCT1 and likely other SLC22 family transporters. Our findings significantly advance the understanding of hOCT1 molecular function and offer a foundational framework for the design of new therapeutic agents targeting this transporter.

Siglec9 + tumor-associated macrophages predict prognosis and therapeutic vulnerability in patients with colon cancer.

BACKGROUND: Siglec9 has been identified as an immune checkpoint molecule on tumor-associated macrophages (TAMs). Nevertheless, the expression profile and clinical significance of Siglec9 + TAMs in colon cancer (CC) are still not fully understood. METHODS: Two clinical cohorts from distinct medical centers were retrospectively enrolled. Immunohistochemistry and immunofluorescence were conducted to evaluate the infiltration of immune cells. Single-cell RNA sequencing and flow cytometry were utilized to identify the impact of Siglec9 + TAMs on the tumor immune environment, which was subsequently validated through bioinformatics analysis of the TCGA database. Prognosis and the benefit of adjuvant chemotherapy (ACT) were also evaluated using Cox regression analysis and the Kaplan-Meier method. RESULTS: High infiltration of Siglec9 + TAMs was associated with worse prognosis and better benefit from 6-month ACT. Siglec9 + TAMs contributed to immunoevasion by promoting the infiltration of immunosuppressive cells and the dysfunction process of CD8 + T cells. Additionally, high infiltration of Siglec9 + TAMs was associated with the mesenchymal-featured subtype and overexpression of the VEGF signaling pathway, which was validated by the strongest communication between Siglec9 + TAMs and vascular endothelial cells. CONCLUSIONS: Siglec9 + TAMs may serve as a biomarker for prognosis and response to ACT in CC. Furthermore, the immunoevasive contexture and angiogenesis stimulated by Siglec9 + TAMs suggest potential treatment combinations for CC patients.

Risk factors for anastomotic leak and postoperative morbidity after right hemicolectomy for colon cancer: results from a prospective, multi-centre, snapshot study in China.

BACKGROUND: Right hemicolectomy is the standard treatment for right-sided colon cancer. There is variation in the technical aspects of performing right hemicolectomy as well as in short-term outcomes. It is therefore necessary to explore best clinical practice following right hemicolectomy in expert centres. METHODS: This snapshot study of right hemicolectomy for colon cancer in China was a prospective, multicentre cohort study in which 52 tertiary hospitals participated. Eligible patients with stage I-III right-sided colon cancer who underwent elective right hemicolectomy were consecutively enrolled in all centres over 10 months. The primary endpoint was the incidence of postoperative 30-day anastomotic leak. RESULTS: Of the 1854 patients, 89.9 per cent underwent laparoscopic surgery and 52.3 per cent underwent D3 lymph node dissection. The overall 30-day morbidity and mortality were 11.7 and 0.2 per cent, respectively. The 30-day anastomotic leak rate was 1.4 per cent. In multivariate analysis, ASA grade > II (P < 0.001), intraoperative blood loss > 50 ml (P = 0.044) and D3 lymph node dissection (P = 0.008) were identified as independent risk factors for postoperative morbidity. Extracorporeal side-to-side anastomosis (P = 0.031), intraoperative blood loss > 50 ml (P = 0.004) and neoadjuvant chemotherapy (P = 0.004) were identified as independent risk factors for anastomotic leak. CONCLUSION: In high-volume expert centres in China, laparoscopic resection with D3 lymph node dissection was performed in most patients with right-sided colon cancer, and overall postoperative morbidity and mortality was low. Further studies are needed to explore the optimal technique for right hemicolectomy in order to improve outcomes further.

Robotic versus open surgery for simultaneous resection of rectal cancer and liver metastases: a randomized controlled trial.

OBJECTIVE: This study aimed to compare the short-term and long-term outcomes between robotic-assisted simultaneous resection and open surgery in patients with rectal cancer and liver metastases. BACKGROUND: Open simultaneous resection of colorectal cancer and synchronous liver metastases is widely performed and the potential cure for eligible patients. However, the feasibility of robotic simultaneous resection of primary and secondary liver lesions has not been established as a treatment option for metastatic rectal cancer. PATIENTS AND METHODS: A single-center randomized controlled trial was conducted at a hospital in China. Enrolling patients were aged from 18 to 75 years and diagnosed with surgically resectable metastatic rectal cancer (distal extension to ≤15 cm from the anal margin). Patients selected for simultaneous resection were randomly assigned to have robotic or open surgery at a 1:1 ratio. The primary endpoint was the incidence rate of complications within 30 days after surgery. Secondary endpoints were bladder, sexual function, 3-year disease-free survival, and overall survival. RESULTS: A total of 171 patients were enrolled in this trial with 86 in the robotic group and 85 in the open group. As a result, patients in the robotic group demonstrated fewer complications within 30 days after surgery than those in the open group (31.4 vs. 57.6%, P =0.014) and no mortality seen in either group. Patients in the robotic group had less blood loss [mean (SD), 125.5 (38.3) vs. 211.6 (68.7) ml; P <0.001], faster bowel function recovery [mean (SD), 63.7 (27.4) vs. 93.8 (33.5) h P <0.001] and shorter hospital stay [mean (SD), 8.0 (2.2) vs. 10.7 (5.4) days; P <0.001] compared with those in the open group. The robotic group had a faster recovery of bladder and sexual function at 3 months after surgery than that of the open group. The 3-year disease-free survival rate (39.5 vs. 35.3%, P =0.739) and the 3-year overall survival rate (76.7 vs. 72.9%, P =0.712) were not statistically significant between the two groups. CONCLUSIONS: In our randomized clinical trial, robotic simultaneous resection treatment of patients with rectal cancer and liver metastases resulted in fewer surgical complications, and a faster recovery to those of open surgery. Oncological outcomes showed no significant difference between the two groups.

Erratum: Zinc-α2-glycoprotein 1 promotes EMT in colorectal cancer by filamin A mediated focal adhesion pathway: Erratum.

[This corrects the article DOI: 10.7150/jca.35380.].

MicroRNA-29b-3p promotes intestinal permeability in IBS-D via targeting TRAF3 to regulate the NF-κB-MLCK signaling pathway.

Irritable bowel syndrome with predominant diarrhea (IBS-D) is characterized by increased intestinal permeability. Previous studies have shown that the microRNA-29 gene is involved in the regulation of intestinal permeability in patients with IBS-D. NF-κB was proved to play a key role in inflammatory response of intestine and resultant disruption of tight junction integrity, whose activity could be inhibited by TNF Receptor-Associated Factor 3 (TRAF3). However, the exact mechanism that induces increased intestinal permeability in IBS-D patients has not been clarified. In this study, we found that microRNA-29b­3p (miR-29b-3p) was significantly upregulated, while TRAF3 was decreased and the NF-κB-MLCK pathway was activated within the colonic tissue of IBS-D patients. Subsequently, we confirmed the targeting relationship between miR-29b-3p and TRAF3 through a double-luciferase reporter assay. Lentivirus transfection of NCM460 cells with miR-29b-3p-overexpressing and -silencing vectors demonstrated that the expression of TRAF3 was negatively correlated with the level of miR-29b-3p. The NF-κB/MLCK pathway was activated in the miR-29b-3p-overexpressing group and inhibited to some extent in the miR-29b-3p-silencing group. Results in WT and miR-29 knockout mice showed that miR-29b-3p levels were increased, TRAF3 levels were decreased, and the NF-κB/MLCK signaling was activated in the WT IBS-D group as compared with the WT control group. The protein levels of TRAF3 and TJs in the miR-29b-/- IBS-D group were partially recovered and NF-κB/MLCK pathway indicators were, to a certain extent, decreased as compared with the WT IBS-D group. These results suggested that miR-29b-3p deletion enhances the TRAF3 level in IBS-D mice and alleviates the high intestinal permeability. In brief, through the analysis of intestinal tissue samples from IBS-D patients and miR-29b-/- IBS-D mice, we showed that miR-29b-3p is involved in the pathogenesis of intestinal hyperpermeability in IBS-D via targeting TRAF3 to regulate the NF-κB-MLCK signaling pathway.

Preoperative chemotherapy prior to primary tumour resection for asymptomatic synchronous unresectable colorectal liver-limited metastases: The RECUT multicenter randomised controlled trial.

PURPOSE: Primary tumour resection (PTR) is still a selection for patients with low tumour burden and good condition, especially with conversion therapy purpose for colorectal liver-limited metastases (CRLMs). The objective was to evaluate whether pre-PTR chemotherapy could improve progression-free survival (PFS) for patients with asymptomatic synchronous unresectable CRLMs. PATIENTS AND METHODS: Patients with asymptomatic synchronous unresectable CRLMs were randomly assigned to receive pre-PTR chemotherapy (arm A) or upfront PTR (arm B). Chemotherapy regimens of mFOLFOX6 plus cetuximab, mFOLFOX6 plus bevacizumab or mFOLFOX6 alone were chosen according to the RAS genotype. The primary end-point was PFS; secondary end-points included overall survival (OS), tumour response, disease control rate (DCR), liver metastases resection rate, surgical complications and chemotherapy toxicity. RESULTS: Three hundred and twenty patients were randomly assigned to arm A (160 patients) and arm B (160 patients). Patients in arm A had significantly improved the median PFS compared with arm B (10.5 versus 9.1 months; P = 0.013). Patients in arm A also had significantly better DCR (84.4% versus 75.0%; P = 0.037). The median OS (29.4 versus 27.2 months; P = 0.058), objective response rate (ORR) (53.1% versus 45.0%; P = 0.146) and liver metastases resection rate (21.9% versus 18.1%; P = 0.402) were not significantly different. The Clavien-Dindo 3-4 complications post PTR (4.5% versus 3.8%, P = 0.759) and the incidence of grade 3/4 chemotherapy events (42.2% versus 40.4%, P = 0.744) reached no statistical significance. CONCLUSIONS: For asymptomatic synchronous unresectable CRLMs, Pre-PTR chemotherapy improved the PFS compared with upfront PTR.

Profilin1 Promotes Renal Tubular Epithelial Cell Apoptosis in Diabetic Nephropathy Through the Hedgehog Signaling Pathway.

Background: Profilin-1 (PFN1) regulates the dynamic balance of actin and plays an important role in cell functions as a hub protein in signaling molecule interaction networks. Dysregulation of PFN1 is related to pathologic kidney diseases. Diabetic nephropathy (DN) was recently reported as an inflammatory disorder, however, the molecular mechanisms of PFN1 in DN remain unclear. Therefore, the present study was conducted to explore the molecular and bioinformatic characteristics of PFN1 in DN. Methods: Bioinformatics analyses were performed on the chip of database in DN kidney tissues. A cellular model of DN was established in human renal tubular epithelial cells (HK-2) induced by high glucose. The PFN1 gene was overexpressed or knocked-down to investigate its function in DN. Flow cytometry was used to detect cell proliferation and apoptosis. PFN1 and proteins in the related signaling pathways were evaluated by Western blotting. Results: The expression of PFN1 was significantly increased in DN kidney tissues (P < 0.001) and was correlated with a high apoptosis-associated score (Pearson's correlation = 0.664) and cellular senescence-associated score (Pearson's correlation = 0.703). PFN1 protein was mainly located in cytoplasm. Overexpression of PFN1 promoted apoptosis and blocked the proliferation of HK-2 cells treated with high levels of glucose. Knockdown of PFN1 led to the opposite effects. Additionally, we found that PFN1 was correlated with the inactivation of the Hedgehog signaling pathway in HK-2 cells treated with high levels of glucose. Conclusion: PFN1 might play an integral role in the regulation of cell proliferation and apoptosis during DN development by activating the Hedgehog signaling pathway. This study provided molecular and bioinformatic characterizations of PFN1, and contributed to the understanding of the molecular mechanisms leading to DN.

The association of lead exposure with blood pressure and hypertension: a mediation analyses of estimated glomerular filtration rate.

The link between lead and blood pressure was debatable, and whether it was mediated by renal function was unknown. The purpose was to investigate the relationship between blood lead concentrations and blood pressure and hypertension, as well as the mediating role of estimated glomerular filtration rate (eGFR) in this relationship. Participants aged 18 were recruited from the National Health and Nutrition Examination Survey (1999-2014) and provided with lead and blood pressure data. Multivariate linear and logistic regression, stratification, interaction tests, and a restricted cubic spline curve were used to assess the association of blood lead with systolic/diastolic blood pressure (SBP/DBP) and hypertension, and mediation effect analysis was used to investigate the role of eGFR in this relationship. A total of 20,073 subjects were enrolled, and among them, 9837 (49.01%) were male and 7800 (38.86%) were hypertensive patients. Multivariate linear and logistic regression analysis showed that blood lead levels were significantly associated with SBP (ß = 3.14, 95%CI: 2.03, 4.25; P < 0.001), DBP (ß = 3.50, 95%CI: 2.69, 4.30; P < 0.001), and hypertension (OR = 1.29, 95%CI: 1.09, 1.52; P = 0.0026). In comparison to the lowest blood lead quartile, the highest lead group was significantly associated with SBP (= 2.55, 95%CI: 1.66, 3.44; P = 0.0001), DBP (= 2.60, 95%CI: 1.95, 3.24; P = 0.0001), and hypertension (OR = 1.26, 95%CI: 1.10, 1.45; P = 0.0007). Mediation analysis showed that the proportion of blood lead mediated for SBP, DBP, and hypertension was 3.56% (95%CI: 0.42%, 7.96%; P = 0.0320), 6.21% (95%CI: 4.02%, 9.32%; P < 0.0001), and 17.39% (95%CI: 9.34%, 42.71%; P < 0.0001), respectively. Adjusted restricted cubic spline curves presented a non-linear correlation of blood lead levels with DBP (P-non-linearity < 0.001), linear with SBP (P-non-linearity = 0.203), and hypertension (P-non-linearity = 0.763). Our findings demonstrated that blood lead levels were non-linear with DBP, but linear with SBP and hypertension, and this relationship was mediated by eGFR.

Apolipoprotein L3 enhances CD8+ T cell antitumor immunity of colorectal cancer by promoting LDHA-mediated ferroptosis.

Aim: Colorectal cancer (CRC) is the leading cause of cancer associated death worldwide and immune checkpoint blockade therapy only benefit a small set of CRC patients. Tumor ferroptosis of CRC reflected immune-activation in our previous findings. Understanding the mechanisms underlying how to bolster CD8+ T cells function through ferroptosis in CRC tumor microenvironment (TME) will greatly benefit cancer immunotherapy. Methods: Genes between ferroptosis and CD8+ T cell function in CRC were screened through Cox, WGCNA and differential expression analysis. Immunohistochemistry and Immunofluorescence analysis were performed. Co-immunoprecipitation were performed to determine protein-protein interaction, mRNA level was determined by qRT-PCR. RSL3 was used to induce ferroptosis, and ferroptosis levels were evaluated by measuring Transmission Electron Microscope analysis, MDA, Fe2+level and cell viability. Results: We screened APOL3 as the significant modulator for ferroptosis-related CD8+ infiltration in CRC. Next, by in vitro and in vivo, we found that increased APOL3 expression was positively correlated with sensitivity to ferroptosis and antitumor ability of CD8+ T cells. Next, we demonstrated that APOL3 can binds LDHA and promote its ubiquitylation-related degradation. Then, based on in vivo analysis and tumor specimen, we discovered the APOL3-LDHA axis can facilitate the tumor ferroptosis and cytotoxic ability of CD8+ T cells through increased IFNγ and decreased lactic acid concentration. Conclusion: The present study demonstrated that APOL3 promotes ferroptosis and immunotherapy in colorectal cancer cells. The present work provides us with a novel target to overcome drug resistance to ferroptosis and immunotherapy.

Efficacy and influencing factors of Insect Compound Particle combined with chemotherapy for mismatch repair-related locally advanced stage III CRC who had undergone surgery and achieved R0 resection: a multicenter, double-blind, randomized, placebo-controlled clinical trial protocol.

Background: Colorectal cancer (CRC) is an insidious malignancy and the occurrence of chemotherapy resistance and toxicity seriously limits its clinical efficacy. Insect Compound Particle [Chong Yao Fu Fang (CYFF)] is a traditional Chinese medicine (TCM) compound based on the concepts of "invigorating spleen for strengthening vital qi" and "collateral disease theory". In long-term clinical application, it can reduce the toxicity of CRC chemotherapy and improve the anti-tumor effect. However, there is currently a lack of high-quality clinical evidence to prove the clinical efficacy and safety of CYFF in the treatment of CRC. Methods: We plan to include 262 patients with locally advanced stage III CRC who had undergone surgery and achieved R0 resection. These patients will be randomized into a CYFF group (treated with CYFF combined with chemotherapy) and a control group (treated with placebo plus chemotherapy) at a 1:1 ratio. The patients were routinely followed-up every 2 weeks within 2 months and every 4 weeks after 2 months after the treatment, every 3 months within 1 year, and every 6 months after 1 year. The primary endpoint is disease-free survival (DFS), defined as the time from random assignment to recurrence of primary CRC or death from any cause. The secondary endpoints include overall survival (OS) (defined as the time from randomization to death from any cause), safety [any adverse events (AEs)], and the Colorectal Cancer-Specific Quality of Life Questionnaire (QLQ-CR38) score. Conclusions: Compared with previous studies, our current study applies CYFF plus basic adjuvant chemotherapy, which is expected to achieve better efficacy and longer survival than standard chemotherapy, and reduce the toxic and side effects of chemotherapy, improve the safety of clinical treatment. In addition, our present study is the first clinical study to evaluate the safety and efficacy of CYFF in combination with chemotherapy in the treatment of stage III CRC after R0 resection. Trial Registration: This clinical trial has been registered in the Chinese Clinical Trial Registry (ChiCTR) (registration No. ChiCTR2000037568; August 28, 2020).

Cryo-EM structure of orphan G protein-coupled receptor GPR21.

GPR21 belongs to class A orphan G protein-coupled receptor (GPCR). The endogenous ligands for human GPR21 remain unidentified. GPR21 expression is associated with developing type 2 diabetes (T2DM), a multifactorial metabolic disease caused by pancreatic ß-cell dysfunction, decreasing insulin production, insulin resistance, and obesity. Animal studies suggested that GPR21 is a potential therapeutic target for T2DM treatment. The underlying mechanisms leading to GPR21 self-activation remain unknown. In our co-expression analysis, we noted that GPR21 could also form a stable complex with an unreported Gα protein subtype, Gαs. To gain further insights into the structural mechanisms of GPR21 activation, we employed cryo-electron microscopy (cryo-EM) and single-particle analysis to resolve the high-resolution structure of GPR21-Gαs complexes. The clear electron density map of the GPR21-Gαs provided direct evidence that GPR21 could couple to Gαs protein at physiological conditions. Thus, GPR21 might mediate previously unexplored pathways in normal or pathological conditions, which warrants further investigation. Structure-guided mutagenesis and biochemical analysis revealed that extracellular loop 2 (ECL2) of GPR21 is essential for the receptor transducing intracellular signal via cAMP. Together, the new structure data reveal a novel signaling cascade of human GPR21 mediated by ECL2 and provide fundamental information for future structure-based drug development.

Carvedilol Reduces the Neuronal Apoptosis after Ischemic Stroke by Modulating Activator of Transcription 3 Expression in vitro.

Cerebral ischemia is divided into local cerebral ischemia and diffuse cerebral ischemia. The etiology of localized cerebral ischemia includes middle cerebral artery embolism; stenosis, occlusion, or thrombosis of extracranial internal carotid artery or vertebral artery; and cerebral artery spasm. The causes of diffuse cerebral ischemia include cardiac arrest, hypotension, anemia, and hypoglycemia. However, the underlying mechanism is still unclear. In this study, we demonstrated that activator of transcription 3 (ATF3) is a hubgene in IS by bioinformatics analysis. The expression of ATF3 was increased in PC12 cells with oxygen-glucose deprivation/reoxygenation (OGD/R) treatment. ATF3 deficiency inhibited cell viability and induced cell apoptosis, whereas ATF3 overexpression showed the opposite role in cell viability and cell apoptosis. Moreover, Carvedilol as a compound targeting ATF3 also facilitated cell viability and reduced cell apoptosis. ATF3 deficiency retarded the increase in cell viability and inhibition of cell apoptosis in OGD/R-PC12 cells with Carvedilol treatment. Additionally, the decreased Bax and cleaved caspase-3 were released in OGD/R-PC12 cells with Carvedilol and siATF3 treatment, while Bcl-2 expression was inhibited in OGD/R-PC12 cells with Carvedilol and siATF3 treatment. In conclusion, Carvedilol may be a key compound targeting ATF3 in OGD/R-PC12 cells. Graphical Abstract: Carvedilol positively regulated cell viability and negatively regulated cell apoptosis in OGD/R-PC12 cells by inhibition of ATF3.

Low ferroptosis score predicts chemotherapy responsiveness and immune-activation in colorectal cancer.

BACKGROUND: Existing studies for ferroptosis and prognosis in colorectal cancer (CRC) were limited. In this study, we aim to investigate the prognostic role of ferroptosis markers in patients with CRC and exploration of its micro-environmental distributions. METHODS: Immunohistochemical staining was performed for CRC patients' tissue microarray. Selection and prognostic validation of markers were based on mRNA data from the cancer genome atlas (TCGA) database. Gene Set Enrichment Analysis (GSEA) was performed to indicate relative immune landmarks and hallmarks. Ferroptosis and immune contexture were examined by CIBERSORT. Survival outcomes were analyzed by Kaplan-Meier analysis and cox analysis. RESULTS: A panel of 42 genes was selected. Through mRNA expression difference and prognosis analysis, GPX4, NOX1 and ACSL4 were selected as candidate markers. By IHC, increased GPX4, decreased NOX1 and decreased FACL4 indicate poor prognosis and worse clinical characteristics. Ferroptosis score based on GPX4, NOX1 and ACSL4 was constructed and validated with high C-index. Low ferroptosis score can also demonstrate the better progression free survival and better adjuvant chemotherapy (ACT) responsiveness. Moreover, tumor with low ferroptosis score tend to be infiltrated with more CD4+ T cells, CD8+ T cells and less M1 macrophage. Finally, we found that IFN-γ was potentially the central molecule at the crossroad between ferroptosis and onco-immune response. CONCLUSION: Ferroptosis plays important role on CRC tumor progression, ACT response and prognosis. Ferroptosis contributes to immune-supportive responses and IFN-γ was the central molecule for this process.

Preoperative transarterial chemoembolization with drug-eluting beads (DEB-TACE) in patients undergoing conversional hepatectomy: a propensity-score matching analysis.

OBJECTIVES: Patients with colorectal liver metastases (CRLM) who underwent hepatic resection after conversion therapy had a high recurrence rate of nearly 90%. Preoperative DEB-TACE has the potential to prevent postoperative recurrence which has not been elucidated. The objective of this study was to evaluate the safety and efficacy of preoperative DEB-TACE. MATERIALS AND METHODS: Patients with CRLM who underwent liver resection from June 1, 2016, to June 30, 2021, were collected and those who received conversional hepatectomy were included in this study. Patients with preoperative DEB-TACE were propensity-score matched in a 1:1 ratio to patients without preoperative DEB-TACE. Short-term outcomes and recurrence-free survival (RFS) were compared between the two groups. RESULTS: After PSM, 44 patients were included in each group. The toxicities of DEB-TACE were mild and could be managed by conservative treatment. Overall response rate (ORR) of conversion therapy (75.0% vs. 81.2%, p = 0.437) and postoperative complication of hepatic resection (27.3% vs. 20.5%, p = 0.453) were similar between the two groups. The median RFS of the DEB-TACE group (10.7 months, 95%CI: 6.6-14.8 months) was significantly longer than that of the control group (8.1 months, 95%CI: 3.4-12.8 months) (HR: 0.60, 95%CI: 0.37-0.95, p = 0.027). CONCLUSIONS: In patients who became resectable after conversion therapy, preoperative DEB-TACE might be a safe option to achieve longer RFS. KEY POINTS: • This is a propensity-score matching study comparing patients who underwent conversional hepatectomy with or without preoperative DEB-TACE. • The preoperative DEB-TACE was safe and with mild toxicities (without toxicities more than CTCAE grade 3). • The preoperative DEB-TACE significantly prolonged the RFS of those patients who underwent conversional hepatectomy (10.7 vs. 8.1 months, p = 0.027).

Expression Profiles and Functional Analysis of Plasma Exosomal Circular RNAs in Acute Myocardial Infarction.

Acute myocardial infarction (AMI) is a common cardiovascular disease with high rates of morbidity and mortality globally. The dysregulation of circular RNAs (circRNAs) has been shown to be closely related to various pathological aspects of AMI. However, the function of exosomal circRNAs in AMI has yet to be investigated. The purpose of this study was to investigate the expression profiles of plasma exosomal circRNAs in AMI and explore their potential functionality. The expression profiles of plasma exosomal circRNAs in patients with AMI, stable coronary heart atherosclerotic disease (CAD), and healthy controls were obtained from a GEO expression dataset (GSE159657). We also analyzed bioinformatics functionality, potential pathways, and interaction networks related to the microRNAs associated with the differentially expressed circRNAs. A total of 253 exosomal circRNAs (184 up- and 69 down-regulated) and 182 exosomal circRNAs (94 up- and 88 down-regulated) were identified as being differentially expressed between the control group and the AMI and CAD patients, respectively. Compared with the CAD group, 231 different exosomal circRNAs (177 up- and 54 down-regulated) were identified in the AMI group. Functional analysis suggested that the parental genes of exosomal has_circ_0061776 were significantly enriched in the biological process of lysine degradation. Pathway interaction network analysis further indicated that exosomal has_circ_0061776 was associated with has-miR-133a, has-miR-214, has-miR-423, and has-miR-217 and may play a role in the pathogenesis of AMI through the MAPK signaling pathway. This study identified the differential expression and functionality of exosomal circRNAs in AMI and provided further understanding of the potential pathogenesis of an exosomal circRNA-related competing endogenous RNA (ceRNA) network in AMI.

Plasma metabolomics provides new insights into the relationship between metabolites and outcomes and left ventricular remodeling of coronary artery disease.

BACKGROUND: Coronary artery disease (CAD) is a metabolically perturbed pathological condition. However, the knowledge of metabolic signatures on outcomes of CAD and their potential causal effects and impacts on left ventricular remodeling remains limited. We aim to assess the contribution of plasma metabolites to the risk of death and major adverse cardiovascular events (MACE) as well as left ventricular remodeling. RESULTS: In a prospective study with 1606 Chinese patients with CAD, we have identified and validated several independent metabolic signatures through widely-targeted metabolomics. The predictive model respectively integrating four metabolic signatures (dulcitol, ß-pseudouridine, 3,3',5-Triiodo-L-thyronine, and kynurenine) for death (AUC of 83.7% vs. 76.6%, positive IDI of 0.096) and metabolic signatures (kynurenine, lysoPC 20:2, 5-methyluridine, and L-tryptophan) for MACE (AUC of 67.4% vs. 59.8%, IDI of 0.068) yielded better predictive value than trimethylamine N-oxide plus clinical model, which were successfully applied to predict patients with high risks of death (P = 0.0014) and MACE (P = 0.0008) in the multicenter validation cohort. Mendelian randomisation analysis showed that 11 genetically inferred metabolic signatures were significantly associated with risks of death or MACE, such as 4-acetamidobutyric acid, phenylacetyl-L-glutamine, tryptophan metabolites (kynurenine, kynurenic acid), and modified nucleosides (ß-pseudouridine, 2-(dimethylamino) guanosine). Mediation analyses show that the association of these metabolites with the outcomes could be partly explained by their roles in promoting left ventricular dysfunction. CONCLUSIONS: This study provided new insights into the relationship between plasma metabolites and clinical outcomes and its intermediate pathological process left ventricular dysfunction in CAD. The predictive model integrating metabolites can help to improve the risk stratification for death and MACE in CAD. The metabolic signatures appear to increase death or MACE risks partly by promoting adverse left ventricular dysfunction, supporting potential therapeutic targets of CAD for further investigation.

Association of Choline Intake with Blood Pressure and Effects of Its Microbiota-Dependent Metabolite Trimethylamine-N-Oxide on Hypertension.

Background: The association of total choline (TC) intake and its metabolite trimethylamine-N-oxide (TMAO) with hypertension and blood pressure (BP) has not been elucidated. Methods: For the population study, the association of TC intake with hypertension, as well as blood pressure, was determined through logistic along with multiple linear regression analysis from the National Health and Nutrition Examination Survey 2007 to 2018, respectively. For the animal experimental study, spontaneously hypertensive rats (SHRs) were assigned to the water group or water containing 333 mg/L or 1 g/L TMAO group. After 22 weeks treatment of TMAO, blood pressure measurement, echocardiography, and histopathology of the heart and arteries were evaluated. Results: No significant association of TC with hypertension was observed but the trend for ORs of hypertension was decreased with the increased level of TC. Negative association between TC and BP was significant in quintile 4 and quintile 5 range of TC, and the negative trend was significant. The SHR-TMAO groups showed significant higher urine output levels in contrast with the SHR-water group. No difference of diastolic BP was observed, but there was a trend towards lower systolic BP with the increase doses of TMAO in the SHR group. The SHR 1 g/L TMAO rats had a remarkably lower systolic blood pressure than the SHR-water group. Echocardiography showed a diastolic dysfunction alleviating effect in the 1 g/L TMAO group. Conclusion: High TC intake was not linked to elevated risk of hypertension. An inverse relationship of choline intake with systolic BP was observed. The mechanism for the beneficial effect of TC might be associated with the diuretic effect of its metabolite TMAO.