Association between neutrophil-to-lymphocyte ratio and outcomes in hospitalized patients with left ventricular thrombus.

BACKGROUND: Left ventricular thrombus (LVT) is a severe cardiovascular complication occurring in approximately 10% of patients with acute anterior ST-segment elevation myocardial infarction. This study aimed to evaluate the association between neutrophil-to-lymphocyte ratio (NLR) and in-hospital major adverse cardiovascular and cerebrovascular events (MACCE) in patients with LVT. MATERIAL AND METHODS: This multicenter retrospective study was conducted between January 2000 and June 2022 in hospitalized patients with LVT. The outcome included in-hospital MACCE. The association between NLR and in-hospital MACCE was measured by odds ratios (ORs). The restricted cubic spline model was used for dose-response analysis. RESULTS: A total of 197 LVT patients from four centers were included for analysis in this study. MACCE occurred in 13.7% (27/197) of the patients. After adjusting for estimated glomerular filtration rate (eGFR), D-dimer, and age, the OR for MACCE comparing first to the third tertile of NLR was 13.93 [95% confidence interval: 2.37-81.77, P = 0.004, P-trend = 0.008]. When further adjusting for etiology and heart failure with reduced ejection fraction (HFrEF), the association remained statistically significant. Spline regression models showed an increasing trend in the incidence of MACCEs with NLR both in crude and adjusted models. Subgroup analyses showed that a high NLR may be correlated with poorer outcomes for LVT patients older than 65 years, or with hypertension, dyslipidemia, low ejection fraction, liver, and renal dysfunctions. CONCLUSION: In conclusion, these findings suggested that higher NLR may be associated with an increased risk of in-hospital MACCE in patients with LVT.

Effect of acupuncture on quality of life in patients with chronic prostatitis/chronic pelvic pain syndrome: a randomized controlled trial. / é’ˆåˆºæ²»ç–—å¯¹æ ¢æ€§å‰åˆ—è ºç‚Ž/æ ¢æ€§ç›†è ”ç–¼ç—›ç»¼åˆå¾æ‚£è€ ç”Ÿæ´»è´¨é‡çš„å½±å“ï¼šéšæœºå¯¹ç §è¯•éªŒ.

OBJECTIVES: To observe the effect and safety of acupuncture on quality of life, pain, and prostate symptoms in patients with chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS). METHODS: Seventy patients with CP/CPPS were randomly divided into an acupuncture group (35 cases, 1 case was eliminated) and a sham acupuncture group (35 cases, 3 cases dropped out). The patients in the acupuncture group were treated with routine acupuncture at bilateral Zhongliao (BL 33), Huiyang (BL 35), Shenshu (BL 23) and Sanyinjiao (SP 6), while the patients in the sham acupuncture group were treated with shallow needling at non-meridian and non-acupoint points beside bilateral Zhongliao (BL 33), Huiyang (BL 35), Shenshu (BL 23) and Sanyinjiao (SP 6),without manipulation to induce arrival of qi (deqi). Both groups retained the needles for 30 min, with one session every other day, three times a week, for a total of 8 weeks (24 sessions). Before and after treatment, and at the follow-up of 24 weeks after treatment completion, the scores of MOS 36-item short-form health survey (SF-36, including 8 dimensions of physical function [PF], role physical function [RP], bodily pain [BP], general health status [GH], vitality [VT], social function [SF], role emotional [RE], and mental health [MH], which can be summarized as physical component summary [PCS] and mental component summary [MCS]), pelvic pain visual analogue scale (VAS), National Institutes of Health chronic prostatitis symptom index (NIH-CPSI), and international prostate symptom score (IPSS) were evaluated, and safety of both groups was assessed. RESULTS: After treatment and at the follow-up, the scores of each dimension and PCS, MCS scores of SF-36 in the acupuncture group were higher than those before treatment (P<0.05, P<0.01); compared before treatment, the RP, BP, and SF scores and PCS score in the sham acupuncture group were increased after treatment (P<0.05, P<0.01). After treatment, the acupuncture group had higher scores in RP, BP, GH, MH and PCS, MCS than those in the sham acupuncture group (P<0.05, P<0.01); at the follow-up, except for PF and RE dimensions, the scores in each dimension and PCS, MCS scores in the acupuncture group were higher than those in the sham acupuncture group (P<0.05, P<0.01). After treatment and at the follow-up, pelvic pain VAS, NIH-CPSI, IPSS scores in the acupuncture group were lower than those before treatment (P<0.01); in the sham acupuncture group, pelvic pain VAS, NIH-CPSI scores were lower after treatment, and NIH-CPSI score at the follow-up was lower compared with those before treatment (P<0.01). After treatment and at the follow-up, pelvic pain VAS, NIH-CPSI, IPSS scores in the acupuncture group were lower than those in the sham acupuncture group (P<0.01, P<0.05). No significant adverse reactions were observed in both groups, and the incidence rates of adverse reactions had no significant difference (P>0.05). CONCLUSIONS: Acupuncture could effectively improve the quality of life, reduce pain levels, alleviate prostate symptoms, and shows favorable long-term efficacy in patients with CP/CPPS.

Blood leukocytes as a non-invasive diagnostic tool for thyroid nodules: a prospective cohort study.

BACKGROUND: Thyroid nodule (TN) patients in China are subject to overdiagnosis and overtreatment. The implementation of existing technologies such as thyroid ultrasonography has indeed contributed to the improved diagnostic accuracy of TNs. However, a significant issue persists, where many patients undergo unnecessary biopsies, and patients with malignant thyroid nodules (MTNs) are advised to undergo surgery therapy. METHODS: This study included a total of 293 patients diagnosed with TNs. Differential methylation haplotype blocks (MHBs) in blood leukocytes between MTNs and benign thyroid nodules (BTNs) were detected using reduced representation bisulfite sequencing (RRBS). Subsequently, an artificial intelligence blood leukocyte DNA methylation (BLDM) model was designed to optimize the management and treatment of patients with TNs for more effective outcomes. RESULTS: The DNA methylation profiles of peripheral blood leukocytes exhibited distinctions between MTNs and BTNs. The BLDM model we developed for diagnosing TNs achieved an area under the curve (AUC) of 0.858 in the validation cohort and 0.863 in the independent test cohort. Its specificity reached 90.91% and 88.68% in the validation and independent test cohorts, respectively, outperforming the specificity of ultrasonography (43.64% in the validation cohort and 47.17% in the independent test cohort), albeit with a slightly lower sensitivity (83.33% in the validation cohort and 82.86% in the independent test cohort) compared to ultrasonography (97.62% in the validation cohort and 100.00% in the independent test cohort). The BLDM model could correctly identify 89.83% patients whose nodules were suspected malignant by ultrasonography but finally histological benign. In micronodules, the model displayed higher specificity (93.33% in the validation cohort and 92.00% in the independent test cohort) and accuracy (88.24% in the validation cohort and 87.50% in the independent test cohort) for diagnosing TNs. This performance surpassed the specificity and accuracy observed with ultrasonography. A TN diagnostic and treatment framework that prioritizes patients is provided, with fine-needle aspiration (FNA) biopsy performed only on patients with indications of MTNs in both BLDM and ultrasonography results, thus avoiding unnecessary biopsies. CONCLUSIONS: This is the first study to demonstrate the potential of non-invasive blood leukocytes in diagnosing TNs, thereby making TN diagnosis and treatment more efficient in China.

Association of atopic dermatitis and headache disorder: a systematic review and meta-analyses.

Background: Growing evidence suggests that headache disorders and atopic dermatitis share similar pathological mechanisms and risk factors. The aim of this study was to assess the risk for headache disorders in patients with atopic dermatitis. Methods: We systematically searched the PubMed and Embase databases from inception to December 1, 2023, for observational studies that examined risk of migraine in subjects with atopic dermatitis. Risk estimates from individual studies were pooled using random-effects models. Results: Ten studies with 12,717,747 subjects were included in the meta-analysis. Our results showed that patients with atopic dermatitis were associated with a higher risk of headache disorder (OR, 1.46, 95% CI = 1.36-1.56; P < 0.001; I2 = 98%) or migraine (OR, 1.32, 95% CI = 1.18-1.47; P < 0.001; I2 = 98.9%). Most of the results of the subgroup analyses were consistent with the overall results. Conclusion: The findings of this meta-analysis suggest that atopic dermatitis is a potential risk indicator for headache disorder or migraine. Further studies are still needed to verify our findings due to the substantial heterogeneity in our analyses.

Analysis of the impact of immunotherapy efficacy and safety in patients with gastric cancer and liver metastasis.

BACKGROUND: Gastric cancer (GC) is the fifth most common type of cancer and has the fourth highest death rate among all cancers. There is a lack of studies examining the impact of liver metastases on the effectiveness of immunotherapy in individuals diagnosed with GC. AIM: To investigate the influence of liver metastases on the effectiveness and safety of immunotherapy in patients with advanced GC. METHODS: This retrospective investigation collected clinical data of patients with advanced stomach cancer who had immunotherapy at our hospital from February 2021 to January 2023. The baseline attributes were compared using either the Chi-square test or the Fisher exact probability method. The chi-square test and Kaplan-Meier survival analysis were employed to assess the therapeutic efficacy and survival duration in GC patients with and without liver metastases. RESULTS: The analysis comprised 48 patients diagnosed with advanced GC, who were categorized into two groups: A liver metastasis cohort (n = 20) and a non-liver metastatic cohort (n = 28). Patients with liver metastasis exhibited a more deteriorated physical condition compared to those without liver metastasis. The objective response rates in the cohort with metastasis and the cohort without metastasis were 15.0% and 35.7% (P > 0.05), respectively. Similarly, the disease control rates in these two cohorts were 65.0% and 82.1% (P > 0.05), respectively. The median progression-free survival was 5.0 months in one group and 11.2 months in the other group, with a hazard ratio of 0.40 and a significance level (P) less than 0.05. The median overall survival was 12.0 months in one group and 19.0 months in the other group, with a significance level (P) greater than 0.05. CONCLUSION: Immunotherapy is less effective in GC patients with liver metastases compared to those without liver metastasis.

Engineered Exosomes with Growth Differentiation Factor-15 Overexpression Enhance Cardiac Repair After Myocardial Injury.

Background: Cardiac repair remains a thorny issue for survivors of acute myocardial infarction (AMI), due to the regenerative inertia of myocardial cells. Cell-free therapies, such as exosome transplantation, have become a potential strategy for myocardial injury. The aim of this study was to investigate the role of engineered exosomes in overexpressing Growth Differentiation Factor-15 (GDF-15) (GDF15-EVs) after myocardial injury, and their molecular mechanisms in cardiac repair. Methods: H9C2 cells were transfected with GDF-15 lentivirus or negative control. The exosomes secreted from H9C2 cells were collected and identified. The cellular apoptosis and autophagy of H2O2-injured H9C2 cells were assessed by Western blotting, TUNEL assay, electron microscopy, CCK-8 and caspase 3/7 assay. A rat model of AMI was constructed by ligating the left anterior descending artery. The anti-apoptotic, pro-angiogenic effects of GDF15-EVs treatment, as well as ensuing functional and histological recovery were evaluated. Then, mRNA sequencing was performed to identify the differentially expressed mRNAs after GDF15-EVs treatment. Results: GDF15-EVs inhibited apoptosis and promoted autophagy in H2O2 injured H9C2 cells. GDF15-EVs effectively decreased the infarct area and enhanced the cardiac function in rats with AMI. Moreover, GDF15-EVs hindered inflammatory cell infiltration, inhibited cell apoptosis, and promoted cardiac angiogenesis in rats with AMI. RNA sequence showed that telomerase reverse transcriptase (TERT) mRNA was upregulated in GDF15-EVs-treated H9C2 cells. AMPK signaling was activated after GDF15-EVs. Silencing TERT impaired the protective effects of GDF15-EVs on H2O2-injured H9C2 cells. Conclusion: GDF15-EVs could fulfil their protective effects against myocardial injury by upregulating the expression of TERT and activating the AMPK signaling pathway. GDF15-EVs might be exploited to design new therapies for AMI.

Association between triglyceride glucose and acute kidney injury in patients with acute myocardial infarction: a propensity score­matched analysis.

BACKGROUND: Acute kidney injury (AKI) in patients with acute myocardial infarction (AMI) often indicates a poor prognosis. OBJECTIVE: This study aimed to investigate the association between the TyG index and the risk of AKI in patients with AMI. METHODS: Data were taken from the Medical Information Mart for Intensive Care (MIMIC) database. A 1:3 propensity score (PS) was set to match patients in the AKI and non-AKI groups. Multivariate logistic regression analysis, restricted cubic spline (RCS) regression and subgroup analysis were performed to assess the association between TyG index and AKI. RESULTS: Totally, 1831 AMI patients were included, of which 302 (15.6%) had AKI. The TyG level was higher in AKI patients than in non-AKI patients (9.30 ± 0.71 mg/mL vs. 9.03 ± 0.73 mg/mL, P < 0.001). Compared to the lowest quartile of TyG levels, quartiles 3 or 4 had a higher risk of AKI, respectively (Odds Ratiomodel 4 = 2.139, 95% Confidence Interval: 1.382-3.310, for quartile 4 vs. quartile 1, Ptrend < 0.001). The risk of AKI increased by 34.4% when the TyG level increased by 1 S.D. (OR: 1.344, 95% CI: 1.150-1.570, P < 0.001). The TyG level was non-linearly associated with the risk of AKI in the population within a specified range. After 1:3 propensity score matching, the results were similar and the TyG level remained a risk factor for AKI in patients with AMI. CONCLUSION: High levels of TyG increase the risk of AKI in AMI patients. The TyG level is a predictor of AKI risk in AMI patients, and can be used for clinical management.

The role of the CXCR6/CXCL16 axis in the pathogenesis of fibrotic disease.

CXC chemokine receptor 6 (CXCR6), a seven-transmembrane domain G-protein-coupled receptor, plays a pivotal regulatory role in inflammation and tissue damage through its interaction with CXC chemokine ligand 16 (CXCL16). This axis is implicated in the pathogenesis of various fibrotic diseases and correlates with clinical parameters that indicate disease severity, activity, and prognosis in organ fibrosis, including afflictions of the liver, kidney, lung, cardiovascular system, skin, and intestines. Soluble CXCL16 (sCXCL16) serves as a chemokine, facilitating the migration and recruitment of CXCR6-expressing cells, while membrane-bound CXCL16 (mCXCL16) functions as a transmembrane protein with adhesion properties, facilitating intercellular interactions by binding to CXCR6. The CXCR6/CXCL16 axis is established to regulate the cycle of damage and repair during chronic inflammation, either through modulating immune cell-mediated intercellular communication or by independently influencing fibroblast homing, proliferation, and activation, with each pathway potentially culminating in the onset and progression of fibrotic diseases. However, clinically exploiting the targeting of the CXCR6/CXCL16 axis requires further elucidation of the intricate chemokine interactions within fibrosis pathogenesis. This review explores the biology of CXCR6/CXCL16, its multifaceted effects contributing to fibrosis in various organs, and the prospective clinical implications of these insights.

Neutrophil Percentage as a Potential Biomarker of Acute Kidney Injury Risk and Short-Term Prognosis in Patients with Acute Myocardial Infarction in the Elderly.

Objective: This study aimed to explore the association of preoperative neutrophil percentage (NEUT%) with the risk of acute kidney injury (AKI) in patients with acute myocardial infarction (AMI) having undergone coronary interventional therapy. Methods: A single-center, retrospective and observational study was conducted. From December 2012 to June 2021, patients with AMI were enrolled and divided into AKI group and non-AKI group. The NEUT% in the two groups was compared. The association between NEUT% with the risk of post-AMI AKI was analyzed by univariate and multivariable logistic regression. Kaplan-Meier survival curve was drawn to evaluate the prognostic ability of NEUT% for short-term all-cause death following AMI. Results: A total of 3001 consecutive patients were enrolled with an average age of 64.38 years. AKI occurred in 327 (10.9%) patients. The NEUT% was higher in the AKI group than in the non-AKI group ([76.65±11.43]% versus [73.22±11.83]%, P<0.001). NEUT% was also identified as an independent risk factor for AKI in AMI patients after adjustment (OR=1.021, 95% CI: 1.010-1.033, P < 0.001). Compared with those at the lowest quartile of NEUT%, the patients at quartiles 2-4 had a higher risk of AKI (P for trend = 0.003). The odds of AKI increased by 29.0% as NEUT% increased by 1 standard deviation (OR=1.290, 95% CI: 1.087-1.531, P = 0.004). After a median of 35 days follow-up, 93 patients died. Patients with a higher NEUT% presented a higher risk of all-cause death after AMI (Log rank: χ2 =24.753, P<0.001). Conclusion: In AMI patients, the peripheral blood NEUT% was positively associated with the odds of AKI and short-term all-cause mortality. NEUT% may provide physicians with more information about disease development and prognosis.

The Nexus of Innovation: Electrochemically Synthesizing H2O2 and Its Integration with Downstream Reactions.

Hydrogen peroxide (H2O2) represents a chemically significant oxidant that is prized for its diverse applicability across various industrial domains. Recent innovations have shed light on the electrosynthesis of H2O2 through two-electron oxygen reduction reactions (2e- ORR) or two-electron water oxidation reactions (2e- WOR), processes that underscore the attractive possibility for the on-site production of this indispensable oxidizing agent. However, the translation of these methods into practical utilization within chemical manufacturing industries remains an aspiration rather than a realized goal. This Perspective intends to furnish a comprehensive overview of the latest advancements in the domain of coupled chemical reactions with H2O2, critically examining emergent strategies that may pave the way for the development of new reaction pathways. These pathways could enable applications that hinge on the availability and reactivity of H2O2, including, but not limited to the chemical synthesis coupled with H2O2 and waste water treatment byFenton-like reactions. Concurrently, the Perspective acknowledges and elucidates some of the salient challenges and opportunities inherent in the coupling of electrochemically generated H2O2, thereby providing a scholarly analysis that might guide future research.

Comparing clinical outcomes of hybrid coronary revascularization with open coronary artery bypass in patients with multi-vessels lesions.

OBJECTIVES: Hybrid coronary revascularization (HCR) involves the use of minimally invasive direct coronary artery bypass grafting (CABG) to treat the left anterior descending artery (LAD), and percutaneous coronary intervention to treat non-LAD vessels. We reported the results of a comparative analysis between HCR and off-pump CABG via sternotomy (OPCABG). METHODS: Data were retrospectively collated from patients who underwent HCR or OPCABG for multivessel coronary artery disease between 2011 and 2022. Propensity score-based matching was performed to reduce the selection bias. The Comparisons of cardiac-related death, major adverse cardiac and cerebrovascular events (MACCE), and repeat revascularization were performed by Kaplan-Meier analysis or the Fine-Gray test. RESULTS: After matching, the baseline characteristics were well-balanced between the two groups with 91 patients per group. There was no significant difference in operative mortality rate (1.1% for HCR vs2.2% for OPCABG, p = 1.000). However, patients undergoing HCR required a significantly lower rate of blood product transfusions (p < .001) and experienced significantly fewer pulmonary complications than OPCABG patients (p < .001). At 10 years, the incidences of cardiac-related death, MACCE and repeat revascularization did not differ significantly between the two groups (9.5% vs11.5%, p = .277; 4.7% vs12.3%, p = .361; 1.2% vs2.5%, p = .914, respectively). CONCLUSIONS: For patients with multi-vessel lesions, HCR was comparable to OPCABG in long-term outcomes such as cardiac-related death, MACCE, and the durability of grafts. Additionally, HCR was better than OPCABG in perioperative outcomes. HCR may be an alternative therapy for OPCABG in patients with multi-vessel coronary artery disease.

RV1+RV3 Index to Differentiate Idiopathic Ventricular Arrhythmias Arising From Right Ventricular Outflow Tract and Aortic Sinus of Valsalva: A Multicenter Study.

BACKGROUND: This study aimed to investigate the predictive value of parameters of every precordial lead and their combinations in differentiating between idiopathic ventricular arrhythmias (IVAs) from the right ventricular outflow tract and aortic sinus of Valsalva (ASV). METHODS AND RESULTS: Between March 1, 2018, and December 1, 2021, consecutive patients receiving successful ablation of right ventricular outflow tract or ASV IVAs were enrolled. The amplitude and duration of the R wave and S wave were measured in every precordial lead during IVAs. These parameters were either summed, subtracted, multiplied, or divided to create different indexes. The index with the highest area under the curve to predict ASV IVAs was developed, compared with established indexes, and validated in an independent prospective multicenter cohort. A total of 150 patients (60 men; mean age, 45.3±16.4 years) were included in the derivation cohort. The RV1+RV3 index (summed R-wave amplitude in leads V1 and V3) had the highest area under the curve (0.942) among the established indexes. An RV1+RV3 index >1.3 mV could predict ASV IVAs with a sensitivity of 95% and a specificity of 83%. Its predictive performance was maintained in the validation cohort (N=109). In patients with V3 R/S transition, an RV1+RV3 index >1.3 mV could predict ASV IVAs, with an area under the curve of 0.892, 93% sensitivity, and 75% specificity. CONCLUSIONS: The RV1+RV3 index is a simple and novel criterion that accurately differentiates between right ventricular outflow tract and ASV IVAs. Its performance outperformed established indexes, making it a valuable tool in clinical practice.

Nanoarchitectonics of Bimetallic Cu-/Co-Doped Nitrogen-Carbon Nanozyme-Functionalized Hydrogel with NIR-Responsive Phototherapy for Synergistic Mitigation of Drug-Resistant Bacterial Infections.

Superbug infections and transmission have become major challenges in the contemporary medical field. The development of novel antibacterial strategies to efficiently treat bacterial infections and conquer the problem of antimicrobial resistance (AMR) is extremely important. In this paper, a bimetallic CuCo-doped nitrogen-carbon nanozyme-functionalized hydrogel (CuCo/NC-HG) has been successfully constructed. It exhibits photoresponsive-enhanced enzymatic effects under near-infrared (NIR) irradiation (808 nm) with strong peroxidase (POD)-like and oxidase (OXD)-like activities. Upon NIR irradiation, CuCo/NC-HG possesses photodynamic activity for producing singlet oxygen(1O2), and it also has a high photothermal conversion effect, which not only facilitates the elimination of bacteria but also improves the efficiency of reactive oxygen species (ROS) production and accelerates the consumption of GSH. CuCo/NC-HG shows a lower hemolytic rate and better cytocompatibility than CuCo/NC and possesses a positive charge and macroporous skeleton for restricting negatively charged bacteria in the range of ROS destruction, strengthening the antibacterial efficiency. Comparatively, CuCo/NC and CuCo/NC-HG have stronger bactericidal ability against methicillin-resistant Staphylococcus aureus (MRSA) and ampicillin-resistant Escherichia coli (AmprE. coli) through destroying the cell membranes with a negligible occurrence of AMR. More importantly, CuCo/NC-HG plus NIR irradiation can exhibit satisfactory bactericidal performance in the absence of H2O2, avoiding the toxicity from high-concentration H2O2. In vivo evaluation has been conducted using a mouse wound infection model and histological analyses, and the results show that CuCo/NC-HG upon NIR irradiation can efficiently suppress bacterial infections and promote wound healing, without causing inflammation and tissue adhesions.

A turn-on fluorescence probe for imaging tyrosinase at the wound site in broken tail of zebrafish.

Tyrosinase (TYR) is a copper-containing oxidase that affects the synthesis of melanin in the human body, which is regulate to the pigmentation of the skin. Nevertheless, abnormal expression of TYR can lead to albinism, vitiligo and other skin diseases. Excessive accumulation of TYR is a marker of melanoma cancer and an important factor leading to pigmentation during wound healing, freckles and browning of fruits and vegetables. Efficient tracking of TYR is of significance for studying its pathophysiological mechanism. Herein, we synthesized a benzindole-based fluorescent probe Pro-OH to detect TYR in living cells and zebrafish. The probe displayed a high selectivity and sensitivity in distinguishing TYR from other analytes with the low detection limit of 1.024 U/mL. Importantly, Pro-OH was successfully used to imagine TYR at the wound site of broken tail of zebrafish.

Exploring functional dysconnectivity in schizophrenia: alterations in eigenvector centrality mapping and insights into related genes from transcriptional profiles.

Schizophrenia is a mental health disorder characterized by functional dysconnectivity. Eigenvector centrality mapping (ECM) has been employed to investigate alterations in functional connectivity in schizophrenia, yet the results lack consistency, and the genetic mechanisms underlying these changes remain unclear. In this study, whole-brain voxel-wise ECM analyses were conducted on resting-state functional magnetic resonance imaging data. A cohort of 91 patients with schizophrenia and 91 matched healthy controls were included during the discovery stage. Additionally, in the replication stage, 153 individuals with schizophrenia and 182 healthy individuals participated. Subsequently, a comprehensive analysis was performed using an independent transcriptional database derived from six postmortem healthy adult brains to explore potential genetic factors influencing the observed functional dysconnectivity, and to investigate the roles of identified genes in neural processes and pathways. The results revealed significant and reliable alterations in the ECM across multiple brain regions in schizophrenia. Specifically, there was a significant decrease in ECM in the bilateral superior and middle temporal gyrus, and an increase in the bilateral thalamus in both the discovery and replication stages. Furthermore, transcriptional analysis revealed 420 genes whose expression patterns were related to changes in ECM, and these genes were enriched mainly in biological processes associated with synaptic signaling and transmission. Together, this study enhances our knowledge of the neural processes and pathways involved in schizophrenia, shedding light on the genetic factors that may be linked to functional dysconnectivity in this disorder.

Efficacy of nab­paclitaxel vs. Gemcitabine in combination with S­1 for advanced pancreatic cancer: A multicenter phase II randomized trial.

Patients with advanced pancreatic cancer (PC) need a cost-effective treatment regimen. The present study was designed to compare the efficacy and safety of nab-paclitaxel plus S-1 (AS) and gemcitabine plus S-1 (GS) regimens in patients with chemotherapy-naïve advanced PC. In this open-label, multicenter, randomized study named AvGmPC, eligible patients with chemotherapy-naïve advanced PC were randomly assigned (1:1) to receive AS (125 mg/m2 nab-paclitaxel, days 1 and 8; 80-120 mg S-1, days 1-14) or GS (1,000 mg/m2 gemcitabine, days 1 and 8; 80-120 mg S-1, days 1-14). The treatment was administered every 3 weeks until intolerable toxicity or disease progression occurred. The primary endpoint was progression-free survival (PFS). Between December 2018 and March 2022, 101 of 106 randomized patients were treated and evaluated for analysis (AS, n=49; GS, n=52). As of the data cutoff, the median follow-up time was 11.37 months [95% confidence interval (CI), 9.31-13.24]. The median PFS was 7.16 months (95% CI, 5.19-12.32) for patients treated with AS and 6.41 months (95% CI, 3.72-8.84) for patients treated with GS (HR=0.78; 95% CI, 0.51-1.21; P=0.264). The AS regimen showed a slightly improved overall survival (OS; 13.27 vs. 10.64 months) and a significantly improved ORR (44.90 vs. 15.38%; P=0.001) compared with the GS regimen. In the subgroup analyses, PFS and OS benefits were observed in patients treated with the AS regimen who had KRAS gene mutations and high C-reactive protein (CRP) levels (≥5 mg/l). The most common grade ≥3 adverse events were neutropenia, anemia and alopecia in the two groups. Thrombocytopenia occurred more frequently in the GS group than in the AS group. While the study did not meet the primary endpoint, the response benefit observed for AS may be suggestive of meaningful clinical activity in this population. In particular, promising survival benefits were observed in the subsets of patients with KRAS gene mutations and high CRP levels, which is encouraging and warrants further investigation. This trial was retrospectively registered as ChiCTR1900024588 on July 18, 2019.

DNA-Directed Assembly of Hierarchical MOF-Cellulose Nanofiber Microbioreactors with "Branch-Fruit" Structures.

Assembling metal-organic frameworks (MOFs) into ordered multidimensional porous superstructures promises the encapsulation of enzymes for heterogeneous biocatalysts. However, the full potential of this approach has been limited by the poor stability of enzymes and the uncontrolled assembly of MOF nanoparticles onto suitable supports. In this study, a novel and exceptionally robust Ni-imidazole-based MOF was synthesized in water at room temperature, enabling in situ enzyme encapsulation. Based on this MOF platform, we developed a DNA-directed assembly strategy to achieve the uniform placement of MOF nanoparticles onto bacterial cellulose nanofibers, resulting in a distinctive "branch-fruit" structure. The resulting hybrid materials demonstrated remarkable versatility across various catalytic systems, accommodating natural enzymes, nanoenzymes, and multienzyme cascades, thus showcasing enormous potential as universal microbioreactors. Furthermore, the hierarchical composites facilitated rapid diffusion of the bulky substrate while maintaining the enzyme stability, with ∼3.5-fold higher relative activity compared to the traditional enzyme@MOF immobilized in bacterial cellulose nanofibers.

Extracellular vesicle mediated targeting delivery of growth differentiation factor-15 improves myocardial repair by reprogramming macrophages post myocardial injury.

OBJECTIVE: Extracellular vesicles (EVs) have garnered considerable attention among researchers as candidates for natural drug delivery systems. This study aimed to investigate whether extracellular vesicle mediated targeting delivery of growth differentiation factor-15 (GDF15) improves myocardial repair by reprogramming macrophages post myocardial injury. METHODS: EVs were isolated from macrophages transfected with GDF15 (EXO-GDF15) and control macrophages (EXO-NC). In vitro and vivo experiments, we compared their reprogram ability of macrophages and regeneration activity. Furthermore, proteomic analysis were employed to determine the specific mechanism by which GDF15 repairs the myocardium. RESULTS: Compared with EXO-NC, EXO-GDF15 significantly regulated macrophage phenotypic shift, inhibited cardiomyocyte apoptosis, and enhanced endothelial cell angiogenesis. Moreover, EXO-GDF15 also significantly regulated macrophage heterogeneity and inflammatory cytokines, reduced fibrotic area, and enhanced cardiac function in infarcted rats. Proteomic analysis revealed a decrease in fatty acid-binding protein 4 (FABP4) protein expression following treatment with EXO-GDF15. Mechanistically, the reprogramming of macrophages by EXO-GDF15 is accomplished through the activation of Smad2/3 phosphorylation, which subsequently inhibits the production of FABP4. CONCLUSIONS: Extracellular vesicle mediated targeting delivery of growth differentiation factor-15 improves myocardial repair by reprogramming macrophages post myocardial injury via down-regulating the expression of FABP4. EXO-GDF15 may serve as a promising approach of immunotherapy.

Isolation and absolute configuration of alkylpyridine alkaloids from the marine sponge Hippospongia lachne.

Marine sponges are well known as prolific producers of structurally diverse molecules with valuable pharmacological potential. As part of our ongoing program to discover bioactive compounds from marine sponges collected from the Xisha Islands in the South China Sea, a chemical study on the specimens of Hippospongia lachne was conducted. As a result, eight undescribed compounds, including four zwitterionic alkylpyridinium salts, hippospondines A-D (1-4), and four 3-alkylpyridine alkaloids, hippospondines E (5), F (6), and (±)-hippospondine G (7), were isolated from the marine sponge H. lachne, together with one known 3-alkylpyridine alkaloid (8). The undescribed structures were elucidated by HRESIMS, NMR, DP4+ and CP3 probability analysis, and the Snatzke's method. Hippospondines A-D (1-4) represent the rare example of inner salt type alkylpyridinium alkaloid with a farnesyl moiety. Compounds 1-3 and 8 were subjected to cytotoxic and lymphocyte proliferation assays. Compound 3 exhibited a weak promotion effect on the ConA-induced T lymphocyte proliferation.