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After consultation with external experts, the authors acknowledged discrepancies in the classification of certain Berberis samples discussed in the article. Berberis is one of the most complex plant genera, and identifications are very hard, limited to only a handful of experts due to rampant hybridizations and other issues of reticulate evolution. This article has therefore been withdrawn at the request of the authors and with the consent of the editor until the species identification issue has been resolved. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/policies/article-withdrawal.
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INTRODUCTION: Increasing evidence implicates retinal vascular occlusions as a susceptibility factor for cardiovascular diseases (CVDs), whereas inconsistent results on the relationship were reported in previous observational studies. This research using a bidirectional two-sample Mendelian randomization (MR) analysis aimed to investigate the potential association between genetically determined central/branch retinal artery and retinal vein occlusions (CRAO/BRAO/RVO) and the risk of CVD. METHODS: Summary statistics of retinal vascular occlusions from the largest available genome-wide association study of European descent were used to investigate their relationship with CVDs, and vice versa. Primary analyses were conducted using the common inverse-variance weighted approach. Several complementary sensitivity analyses were performed to verify the reliability of our results. RESULTS: Inverse variance weighted method showed suggestive effects of genetically determined RVO on ischemic stroke (IS) (odds ratio [OR] = 1.021, 95% confidence [CI] = 1.004-1.037, p = 0.012), a genetic liability to CRAO increased the risk of myocardial infarction (MI) (OR = 1.014, 95% CI = 1.006-1.023, p = 7.0 × 10-4). In addition, genetic predisposition to BRAO had a positive effect on stroke (OR = 1.008, 95% CI = 1.002-1.013, p = 0.011), IS (OR = 1.007, 95% CI = 1.001-1.014, p = 0.022), and cardioembolic stroke (CES) (OR = 1.018, 95% CI = 1.006-1.031, p = 0.004). The point estimates from sensitivity analyses were in the same direction. Reverse MR analyses found no significant evidence for the effect of CVDs on retinal vascular occlusions. CONCLUSION: Our MR study provides potential evidence that retinal vascular occlusions are causally linked to increased risk of CVDs including IS, MI, stroke, and CES. This supports the need for clinical CVD screening in individuals with retinal vascular occlusions. Further investigations are warranted to clarify the effects of CVDs on ocular comorbidities.
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Cardiovascular Diseases , Genetic Predisposition to Disease , Genome-Wide Association Study , Mendelian Randomization Analysis , Retinal Vein Occlusion , Humans , Retinal Vein Occlusion/genetics , Cardiovascular Diseases/genetics , Risk Factors , Polymorphism, Single Nucleotide , Retinal Artery Occlusion/geneticsABSTRACT
OBJECTIVE: The aim of the study was to investigate the characteristics and prognosis of patients with immune-mediated necrotizing myopathy (IMNM) based on clinical, serological and pathological classification. METHODS: A total of 138 patients with IMNM who met the 2018 European Neuromuscular Center criteria for IMNM including 62 anti-SRP, 32 anti-HMGCR-positive and 44 myositis specific antibody-negative were involved in the study. All patients were followed up and evaluated remission and relapse. Clustering analysis based on clinical, serological, and pathological parameters was used to define subgroups. RESULTS: Clustering analysis classified IMNM into three clusters. Cluster 1 patients (n = 35) had the highest CK levels, the shortest disease course, severe muscle weakness, and more inflammation infiltration in muscle biopsy. Cluster 2 patients (n = 79) had the lowest CK level and moderate inflammation infiltrate. Cluster 3 patients (n = 24) had the youngest age of onset, the longest disease course and the least frequency of inflammatory infiltration. Patients in cluster 3 had the longest time-to-remission (median survival time: 61[18.3, 103.7] vs 20.5[16.2, 24.9] and 27[19.6, 34.3] months) and shortest relapse-free time than those in cluster 1 and 2 (median remission time 95%CI: 34[19.9, 48.0] vs 73[49.0, 68.7] and 73[48.4, 97.6] months). Patients with age of onset >55 years, more regeneration of muscle fibers, more CD4+T infiltration, and MAC deposition had more favorable outcomes regarding time to achieving remission. CONCLUSIONS: Stratification combining clinical, serological, and pathological features could distinguish phenotypes and prognosis of IMNM. The pathological characteristics may impact the long-term prognosis of patients with IMNM.
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OBJECTIVE: To investigate the association of serum anti-Jo-1 antibody levels with the disease activity and prognosis in anti-Jo-1-positive patients with antisynthetase syndrome (ASS). METHODS: This study included 115 anti-Jo-1-positive patients with ASS who were admitted to China-Japan Friendship Hospital between 2009 and 2019. Anti-Jo-1 antibody serum levels at initial admission and follow-up were determined by enzyme-linked immunosorbent assay (ELISA). Global and organ disease activity was assessed at baseline and follow-up according to the International Myositis Assessment and Clinical Studies guidelines. RESULTS: Among enrolled patients, 70 (60.9%) patients initially presented with interstitial lung disease (ILD), and 46 (40%) patients presented with with muscle weakness at initial admission. At baseline, patients with ILD had lower levels of anti-Jo-1 antibodies than those without ILD (p = 0.012). Baseline anti-Jo-1 antibody levels were higher in patients with muscle weakness, skin involvement, and arthritis (all p < 0.05) compared to those without these manifestations. Baseline anti-Jo-1 antibody levels were positively correlated with skin visual analogue scale (VAS) scores (r = 0.25, p = 0.006), but not with disease activity in other organs. However, changes in anti-Jo-1 antibody levels were significantly positively correlated with the changes in PGA (ß = 0.002, p = 0.001), muscle (ß = 0.003, p < 0.0001), and pulmonary (ß = 0.002, p = 0.013) VAS scores, but not with skin and joint VAS scores. Older age of onset (hazard ratio [HR] 1.069, 95% confidence interval [CI]:1.010-1.133, p = 0.022) and higher C-reactive protein (CRP) levels (HR 1.333, 95% CI: 1.035-1.717, p = 0.026) were risk factors for death. CONCLUSION: Anti-Jo-1 titers appear to correlate more with disease activity changes over time rather than with organ involvement at baseline, which provides better clinical guidance for assessing the disease course using anti-Jo-1 levels.
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Antibodies, Antinuclear , Myositis , Humans , Myositis/blood , Myositis/immunology , Myositis/diagnosis , Male , Female , Middle Aged , Prognosis , Adult , Antibodies, Antinuclear/blood , Follow-Up Studies , Aged , Retrospective Studies , Biomarkers/blood , Lung Diseases, Interstitial/immunology , Lung Diseases, Interstitial/blood , Lung Diseases, Interstitial/diagnosisABSTRACT
BACKGROUND: Cardiolipin (CL) plays a critical role in maintaining mitochondrial membrane integrity and overall mitochondrial homeostasis. Recent studies have suggested that mitochondrial damage resulting from abnormal cardiolipin remodelling is associated with the pathogenesis of diabetic kidney disease (DKD). Acyl-coenzyme A:lyso-cardiolipin acyltransferase-1 (ALCAT1) was confirmed to be involved in the progression of Parkinson's disease, diet-induced obesity and other ageing-related diseases by regulating pathological cardiolipin remodelling. Thus, the purpose of this investigation was to determine the role of ALCAT1-mediated CL remodelling in DKD and to explore the potential underlying mechanism. METHODS: In vivo study, the mitochondrial structure was examined by transmission electron microscopy (TEM). The colocalization of ALCAT1 and synaptopodin was evaluated by double immunolabelling. Western blotting (WB) was performed to assess ALCAT1 expression in glomeruli. Lipidomics analysis was conducted to evaluate the composition of reconstructed cardiolipins. In vitro study, the lipidomics, TEM and WB analyses were similar to those in vivo. Mitochondrial function was evaluated by measuring the mitochondrial membrane potential (MMP) and the production of ATP and ROS. RESULTS: Here, we showed that increased oxidized cardiolipin (ox-CL) and significant mitochondrial damage were accompanied by increased ALCAT1 expression in the glomeruli of patients with DKD. Similar results were found in db/db mouse kidneys and in cultured podocytes stimulated with high glucose (HG). ALCAT1 deficiency effectively prevented HG-induced ox-CL production and mitochondrial damage in podocytes. In contrast, ALCAT1 upregulation enhanced ox-CL levels and podocyte mitochondrial dysfunction. Moreover, treatment with the cardiolipin antioxidant SS-31 markedly inhibited mitochondrial dysfunction and cell injury, and SS-31 treatment partly reversed the damage mediated by ALCAT1 overexpression. We further found that ALCAT1 could mediate the key regulators of mitochondrial dynamics and mitophagy through the AMPK pathway. CONCLUSIONS: Collectively, our studies demonstrated that ALCAT1-mediated cardiolipin remodelling played a crucial role in DKD, which might provide new insights for DKD treatment. Video Abstract.
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Diabetes Mellitus , Diabetic Nephropathies , Mitochondrial Diseases , Podocytes , Animals , Humans , Mice , Cardiolipins , MitochondriaABSTRACT
Chronic interstitial fibrosis presents a significant challenge to the long-term survival of transplanted kidneys. Our research has shown that reduced expression of acyl-coenzyme A oxidase 1 (ACOX1), which is the rate-limiting enzyme in the peroxisomal fatty acid ß-oxidation pathway, contributes to the development of fibrosis in renal allografts. ACOX1 deficiency leads to lipid accumulation and excessive oxidation of polyunsaturated fatty acids (PUFAs), which mediate epithelial-mesenchymal transition (EMT) and extracellular matrix (ECM) reorganization respectively, thus causing fibrosis in renal allografts. Furthermore, activation of Toll-like receptor 4 (TLR4)-nuclear factor kappa-B (NF-κB) signaling induced ACOX1 downregulation in a DNA methyltransferase 1 (DNMT1)-dependent manner. Overconsumption of PUFA resulted in endoplasmic reticulum (ER) stress, which played a vital role in facilitating ECM reorganization. Supplementation with PUFAs contributed to delayed fibrosis in a rat model of renal transplantation. The study provides a novel therapeutic approach that can delay chronic interstitial fibrosis in renal allografts by targeting the disorder of lipid metabolism.
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Acyl-CoA Oxidase , Kidney Transplantation , Kidney , Metabolic Diseases , Animals , Rats , Acyl-CoA Oxidase/metabolism , Allografts , Fibrosis , Kidney/pathology , LipidsABSTRACT
OBJECTIVES: To investigate the prevalence and characteristics of typical polymyositis (PM) in Chinese patients with idiopathic inflammatory myopathy (IIM). METHODS: Patients diagnosed with IIM according to the 2017 EULAR/ACR criteria were included. Serological aspects including myositis-specific antibodies (MSA) and pathological data were re-evaluated. The diagnosis of typical PM was strictly done using the pathological criteria, while excluding other IIM subtypes such as dermatomyositis (DM), immune-mediated necrotising myopathies (IMNM), anti-synthetase syndrome (ASS), and sporadic inclusion body myositis (sIBM), based on their respective diagnostic criteria. RESULTS: A total of 544 IIM patients with muscle biopsy were involved, and 129 of them were diagnosed with initial PM according to the 2017 EULAR/ACR criteria. Only 6 (1.1%, 6/544) patients met the strict definition of typical PM after re-evaluation. Patients with typical PM were MSA-negative (100% vs. 35.7%, p=0.003) and had CD8+ T cells surrounding or invading non-necrotic muscle fibres in muscle biopsies (100% vs. 7.8%, p<0.001) compared to the initially diagnosed PM patients. All typical PM patients achieved clinical remission at the second-year follow-up. Typical PM patients had a favourable prognosis compared to MSA-negative IMNM and unspecific myositis patients. CONCLUSIONS: Strictly defined typical PM is a rare clinical subtype in Chinese IIM patients. Typical PM patients with classical pathology were MSA-negative and responded well to treatment and had a favourable prognosis. It is crucial for clinicians to combine clinical, serological, and pathological features to properly distinguish PM from other IIM subtypes.
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Autoimmune Diseases , Myositis, Inclusion Body , Myositis , Polymyositis , Humans , Myositis/diagnosis , Myositis/epidemiology , Myositis/therapy , Polymyositis/diagnosis , Polymyositis/epidemiology , Antibodies , China/epidemiology , AutoantibodiesABSTRACT
INTRODUCTION: Coptidis Rhizoma (CR) is one of the most frequently used herbs to treat ulcerative colitis (UC) and is often processed before usage. However, the composition changes and therapeutic effects of CR before and after processing in the treatment of UC are still unclear. OBJECTIVE: The purpose of the study is to explore the chemical components and therapeutic effects of crude and processed CR. MATERIAL AND METHODS: CR was processed according to the 2020 version of the Chinese Pharmacopoeia. The liquid chromatography-mass spectrometry (LC-MS) and multivariate statistical analysis were used to screen the different compounds before and after processing. The network pharmacological prediction was carried out. The mechanism and therapeutic effects between crude and processed CR were verified by using dextran sulphate sodium-induced UC mice assay. RESULTS: Ten compounds distinguish crude and processed CR based on multivariate statistical analysis. Network pharmacology predicts that the 10 compounds mainly play a role through TNF-α and IL-6 targets and PI3K/Akt and HIF-1 signalling pathways, and these results are verified by molecular biology experiments. For IL-6, IL-10 and TNF-α inflammatory factors, CR is not effective, while CR stir-fried with Evodiae Fructus (CRFE) and ginger juice (CRGJ) are. For PI3K/p-Akt, Cleaved caspase3, NF- κBp65 and HIF-1α signalling pathways, CR has therapeutic effects, while CRFE and CRGJ are significant. CONCLUSION: Overall, CRFE and CRGJ show better effects in treating UC. The chemical changes of processing and the efficacy of processed CR are correlated, which provides a scientific basis for the clinical use of crude and processed CR.
Subject(s)
Colitis, Ulcerative , Drugs, Chinese Herbal , Mice , Animals , Colitis, Ulcerative/drug therapy , Colitis, Ulcerative/chemically induced , Drugs, Chinese Herbal/pharmacology , Drugs, Chinese Herbal/therapeutic use , Drugs, Chinese Herbal/chemistry , Network Pharmacology , Tumor Necrosis Factor-alpha , Interleukin-6 , Phosphatidylinositol 3-Kinases/therapeutic use , Proto-Oncogene Proteins c-akt/therapeutic useABSTRACT
Objective: To explore the clinical features of thymoma with and without myasthenia gravis (MG). Methods: This was a retrospective study. Two hundred and thirty-three patients with mediastinal masses who were initially diagnosed in People's Hospital of Shijiazhuang, China, between January 2014 and June 2022 and had complete clinical data and underwent surgical treatment at People's Hospital of Shijiazhuang were retrospectively analyzed. Result: The age of patients with thymoma alone was significantly older than that of thymoma patients complicated with MG. The number of female patients was slightly more than males for both groups. Proportions of type A, AB, B1, B2, and B3 thymomas in Group-A were 0.77, 11.54, 11.51, 33.85, and 31.54%, respectively, and the proportions in Group-B were 9.68, 22.58, 12.90, 32.26, and 22.58%. The size of tumors in patients with thymoma alone was larger than that of patients with thymoma complicated with MG. The proportion of patients with tumor size of more than 10 cm in the thymoma alone group was significantly higher than that in the MG group. There were no relapses in patients with type A disease and relapses were noted in a few patients with type B1, B2 and B3 diseases. The same survival rates were reported for the two groups. Conclusion: MG rarely occurs in type A and type C diseases. The prognosis of thymoma with MG is similar to that of thymoma alone. The main causes of death may be myasthenia crisis in thymoma patients with MG and advanced tumor stage in patients with thymoma alone.
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BACKGROUND: Immune checkpoint inhibitors targeting PD-1 or CTLA-4 individually have shown substantial clinical benefits in the treatment of malignancies. We aimed to assess the safety and antitumour activity of cadonilimab monotherapy, a bispecific PD-1/CTLA-4 antibody, in patients with advanced solid tumours. METHODS: This multicentre, open-label, phase 1b/2 trial was conducted across 30 hospitals in China. Patients aged 18 years or older with histologically or cytologically confirmed, unresectable advanced solid tumours, unsuccessful completion of at least one previous systemic therapy, and an Eastern Cooperative Oncology Group performance status of 0 or 1 were eligible for inclusion. Patients who had previously received anti-PD-1, anti-PD-L1, or anti-CTLA-4 treatment were not eligible for inclusion. In the dose escalation phase of phase 1b, patients received intravenous cadonilimab at 6 mg/kg and 10 mg/kg every 2 weeks. In the dose expansion phase of phase 1b, cadonilimab at 6 mg/kg and a fixed dose of 450âmg were given intravenously every 2 weeks. In phase 2, cadonilimab at 6 mg/kg was administered intravenously every 2 weeks in three cohorts: patients with cervical cancer, oesophageal squamous cell carcinoma, and hepatocellular carcinoma. The primary endpoints were the safety of cadonilimab in phase 1b and objective response rate in phase 2, based on the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. The safety analysis was done in all patients who received at least one dose of cadonilimab. Antitumour activity was assessed in the full analysis set for the cervical cancer cohort, and in all patients with measurable disease at baseline and who received at least one dose of cadonilimab in the oesophageal squamous cell carcinoma and hepatocellular carcinoma cohorts. The study is registered on ClinicalTrial.gov, NCT03852251, and closed to new participants; follow-up has been completed. FINDINGS: Between Jan 18, 2019, and Jan 8, 2021, 240 patients (83 [43 male and 40 female] in phase 1b and 157 in phase 2) were enrolled. Phase 2 enrolled 111 female patients with cervical cancer, 22 patients with oesophageal squamous cell carcinoma (15 male and seven female), and 24 patients with hepatocellular carcinoma (17 male and seven female). During dose escalation, no dose-limiting toxicities occurred. Grade 3-4 treatment-related adverse events occurred in 67 (28%) of 240 patients; the most frequent grade 3 or worse treatment-related adverse events were anaemia (seven [3%]), increased lipase (four [2%]), decreased bodyweight (three [1%]), decreased appetite (four [2%]), decreased neutrophil count (three [1%]), and infusion-related reaction (two [1%]). 17 (7%) patients discontinued treatment due to treatment-related adverse events. 54 (23%) of 240 patients reported serious treatment-related adverse events, including five patients who died (one due to myocardial infarction; cause unknown for four). In phase 2, in the cervical cancer cohort, with a median follow-up of 14·6 months (IQR 13·1-17·5), the objective response rate was 32·3% (32 of 99; 95% CI 23·3-42·5). In the oesophageal squamous cell carcinoma cohort, with a median follow-up of 17·9 months (IQR 4·0-15·1), the objective response rate was 18·2% (four of 22; 95% CI 5·2-40·3). In the hepatocellular carcinoma cohort, with a median follow-up of 19·6 months (IQR 8·7-19·8), the objective response rate was 16·7% (four of 24; 95% CI 4·7-37·4). INTERPRETATION: Cadonilimab showed an encouraging tumour response rate, with a manageable safety profile, suggesting the potential of cadonilimab for the treatment of advanced solid tumours. FUNDING: Akeso Biopharma. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.
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Antineoplastic Agents, Immunological , Carcinoma, Hepatocellular , Esophageal Neoplasms , Esophageal Squamous Cell Carcinoma , Liver Neoplasms , Uterine Cervical Neoplasms , Humans , Male , Female , Carcinoma, Hepatocellular/drug therapy , Esophageal Squamous Cell Carcinoma/drug therapy , Uterine Cervical Neoplasms/drug therapy , CTLA-4 Antigen , Programmed Cell Death 1 Receptor , Empathy , Antibodies, Monoclonal, Humanized , Antineoplastic Agents, Immunological/adverse effects , Esophageal Neoplasms/drug therapy , Esophageal Neoplasms/chemically induced , Liver Neoplasms/drug therapy , Antineoplastic Combined Chemotherapy Protocols/therapeutic useABSTRACT
Activation of the renin-angiotensin system is associated with podocyte injury and has been well demonstrated as a pivotal factor in the progression of chronic kidney disease. Podocyte energy metabolism is crucial for maintaining their physiological functions. However, whether renin-angiotensin system activation promotes chronic kidney disease progression by disturbing the energy metabolism of podocytes has not been elucidated. Angiotensin II, the main active molecule of the renin-angiotensin system, plays a crucial role in chronic kidney disease initiation and progression, but its impact on podocyte metabolism remains unclear. Here, we demonstrate a rapid decrease in the expression of pyruvate kinase M2, a key glycolytic enzyme, and reduced glycolytic flux in podocytes exposed to angiotensin II in vivo and in vitro. Podocyte-specific deletion of pyruvate kinase M2 in mice aggravated angiotensin II-induced glomerular and podocyte injury with foot process effacement and proteinuria. The inhibition of glycolysis was accompanied by adenosine triphosphate deficiency, cytoskeletal remodeling and podocyte apoptosis. Mechanistically, we found that angiotensin II-induced glycolysis impairment contributed to an insufficient energy supply to the foot process, leading to podocyte injury. Additionally, pyruvate kinase M2 expression was found to be reduced in podocytes from kidney biopsies of patients with hypertensive nephropathy and diabetic kidney disease. Thus, our findings suggest that glycolysis activation is a potential therapeutic strategy for podocyte injury.
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Diabetic Nephropathies , Podocytes , Renal Insufficiency, Chronic , Mice , Animals , Podocytes/pathology , Angiotensin II/metabolism , Anaerobiosis , Pyruvate Kinase/genetics , Pyruvate Kinase/metabolism , Diabetic Nephropathies/pathology , Renal Insufficiency, Chronic/pathology , GlycolysisABSTRACT
OBJECTIVE: To explore the role of peripheral lymphocyte count in phenotyping and prognosis prediction in dermatomyositis (DM) patients with anti-MDA5 antibodies. METHODS: In total, 1669 patients with idiopathic inflammatory myopathy (IIM) were retrospectively enrolled. Clinical characteristics and prognosis of patients with anti-MDA5+ DM were analyzed in association with peripheral lymphocyte counts and clusters determined by unsupervised machine learning. RESULTS: The peripheral lymphocyte count was significantly lower in the anti-MDA5+ DM group (N = 421) than in the other IIM serotype groups. The anti-MDA5+ DM patients were divided into three groups; the severe lymphopenia group had skin ulcers and rapidly progressive interstitial lung disease (RP-ILD); patients with a normal lymphocyte count had a younger age of onset, more frequent arthritis, and normal serum ferritin levels, whereas mild lymphopenia group showed a moderate increase of serum ferritin and intermediate incidence of RP-ILD. Survival analysis revealed that the 3- and 6-month mortality rates were significantly higher in the severe lymphopenia group (29.0% and 42.1%, respectively) than in the mild lymphopenia group and normal lymphocyte count group (p value <0.001). Consistently, unsupervised machine learning identified three similar groups; the arthritis cluster shows the highest lymphocyte counts and best prognosis; the RP-ILD cluster presents the lowest peripheral lymphocyte, high incidence of RP-ILD, and poor prognosis; the typical DM rash cluster had a moderate peripheral lymphocyte count and an intermediate prognosis. CONCLUSIONS: Lymphopenia is a unique manifestation of anti-MDA5+ DM. Peripheral lymphocyte count can define clinical phenotypes and predict prognosis in anti-MDA5+ DM.
Subject(s)
Dermatomyositis , Lung Diseases, Interstitial , Lymphopenia , Humans , Dermatomyositis/complications , Dermatomyositis/diagnosis , Disease Progression , Retrospective Studies , Lung Diseases, Interstitial/complications , Lung Diseases, Interstitial/diagnosis , Interferon-Induced Helicase, IFIH1 , Autoantibodies , Prognosis , Phenotype , Lymphocyte Count , Lymphocytes , FerritinsABSTRACT
Galacturonosyltransferase (GalAT) is required for the synthesis of pectin, an important component of plant cell walls that is also involved in signal transduction. Here, we describe the rice (Oryza sativa) male-sterile mutant O. sativa pectin-defective tapetum1 (ospdt1), in which GalAT is mutated. The ospdt1 mutant exhibited premature programmed cell death (PCD) of the tapetum and disordered pollen walls, resulting in aborted pollen grains. Pectin distribution in the anther sac was comparable between the mutant and the wild-type, suggesting that the structural pectin was not dramatically affected in ospdt1. Wall-associated kinases are necessary for the signal transduction of pectin, and the intracellular distribution of O. sativa indica WALL-ASSOCIATED KINASE1 (OsiWAK1), which binds pectic polysaccharides to its extracellular domain, was affected in ospdt1. OsiWAK1 RNA interference lines exhibited earlier tapetal PCD, similar to ospdt1. Furthermore, overexpression of OsiWAK1 in ospdt1 lines partially rescued the defects observed in ospdt1, suggesting that OsiWAK1 plays pivotal roles in the function of OsPDT1. These results suggest that the mutation of OsPDT1 does not dramatically affect structural pectin but affects components of the pectin-mediated signaling pathway, such as OsiWAK1, and causes male sterility.
Subject(s)
Oryza , Flowers , Gene Expression Regulation, Plant , Oryza/metabolism , Pectins/metabolism , Plant Proteins/genetics , Plant Proteins/metabolism , Signal TransductionABSTRACT
BACKGROUND: The potential predictive significance of atherogenic index of plasma (AIP) for cardiovascular outcomes in patients with acute coronary syndrome (ACS) and who have undergone percutaneous coronary intervention (PCI), with low-density lipoprotein-cholesterol (LDL-C) below 1.8mmol/L, has not been well explored. METHODS: The retrospective cohort analysis included 1,133 patients with ACS and LDL-C levels below 1.8mmol/L who underwent PCI. AIP is calculated as log (triglyceride/high-density lipoprotein-cholesterol). Patients were divided into two groups according to the median value of AIP. The primary endpoint was major adverse cardiovascular and cerebrovascular events (MACCEs), a composite of all-cause death, nonfatal myocardial infarction, ischemic stroke or unplanned repeat revascularization. The association between AIP and the prevalence of MACCE was evaluated using multivariable Cox proportional hazard models. RESULTS: Over a median follow-up of 26 months, the incidence of MACCE was higher in the high AIP group compared to the low AIP group (9.6% vs. 6.0%, P log-rank = 0.020), and the difference was mainly derived from an increased risk of unplanned repeat revascularization (7.6% vs. 4.6%, P log-rank = 0.028). After adjusting for multiple variables, elevated AIP was independently associated with an increased risk of MACCE, regardless of whether AIP was considered a nominal or continuous variable (hazard ratio [HR] 1.62, 95% confidence interval [CI] 1.04-2.53 or HR 2.01, 95% CI 1.09-3.73). CONCLUSIONS: The present study demonstrates that AIP is a significant predictor of adverse outcomes in ACS patients undergoing PCI with LDL-C < 1.8mmol/L. These results suggest that AIP may offer supplementary prognostic information for ACS patients with optimally managed LDL-C levels.
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Acute Coronary Syndrome , Atherosclerosis , Percutaneous Coronary Intervention , Humans , Acute Coronary Syndrome/diagnosis , Acute Coronary Syndrome/therapy , Cholesterol, LDL , Percutaneous Coronary Intervention/adverse effects , Percutaneous Coronary Intervention/methods , Retrospective Studies , Risk Factors , Treatment OutcomeABSTRACT
BACKGROUND: Chronic interstitial fibrosis is the primary barrier against the long-term survival of transplanted kidneys. Extending the lifespan of allografts is vital for ensuring the long-term health of patients undergoing kidney transplants. However, few targets and their clinical applications have been identified. Moreover, whether dyslipidemia facilitates fibrosis in renal allograft remains unclear. METHODS: Blood samples were collected from patients who underwent kidney transplantation. Correlation analyses were conducted between the Banff score and body mass index, and serum levels of triacylglycerol, total cholesterol, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol. A rat model of renal transplantation was treated with the lipid-lowering drug, fenofibrate, and kidney fibrosis levels were determined by histochemical staining. Targeted metabolomic detection was conducted in blood samples from patients who underwent kidney transplantation and were divided into fibrotic and non-fibrotic groups. Rats undergoing renal transplantation were fed either an n-3 or n-6 polyunsaturated fatty acid (PUFA)-enriched diet. Immunohistochemical and Masson's trichrome staining were used to determine the degree of fibrosis. RESULTS: Hyperlipidemia was associated with fibrosis development. Treatment with fenofibrate contributed to improve fibrosis in a rat model of renal transplantation. Moreover, n-3 PUFAs from fibrotic group showed significant downregulation compared to patients without fibrotic renal allografts, and n-3 PUFAs-enriched diet contributed to delayed fibrosis in a rat model of renal transplantation. CONCLUSIONS: This study suggests that hyperlipidemia facilitates fibrosis of renal allografts. Importantly, a new therapeutic approach was provided that may delay chronic interstitial fibrosis in transplanted kidneys by augmenting the n-3 PUFA content in the diet.
Subject(s)
Fatty Acids, Omega-3 , Fenofibrate , Hyperlipidemias , Kidney Transplantation , Humans , Rats , Animals , Kidney Transplantation/adverse effects , Fenofibrate/pharmacology , Kidney/pathology , Fibrosis , Allografts , Hyperlipidemias/pathology , CholesterolABSTRACT
BACKGROUND: In a world of rapid digital technology development, the lack of digital health literacy (DHL) among older people cannot be ignored. DHL is becoming an essential competency that can facilitate the health status and health management of older adults. DHL interventions that are feasible and appropriate can be implemented on a large scale through the health care system for older people. OBJECTIVE: The purpose of this meta-analysis was to assess the effectiveness of DHL interventions for older adults. METHODS: English publications in PubMed, Web of Science, Embase, and the Cochrane Library were searched from inception to November 20, 2022. Two reviewers independently completed the data extraction and quality assessment. Review Manager (version 5.4; Cochrane Informatics & Technology Services) software was used for all meta-analyses. RESULTS: A total of 7 studies, including 2 randomized controlled trials and 5 quasi-experimental studies, involving 710 older adults were considered eligible. The main outcome was scores on the eHealth Literacy Scale, and secondary outcomes were knowledge, self-efficacy, and skills. Quasi-experimental studies compared baseline and postintervention outcomes, while randomized controlled trials compared pre- and postintervention outcomes in the intervention group. Of the 7 studies, 3 used face-to-face instruction, while 4 adopted web-based interventions. Among them, 4 of the interventions were conducted using theoretical guidance, while 3 were not. Intervention duration varied from 2 to 8 weeks. In addition, the studies included were all conducted in developed countries, mainly in the United States. Pooled analysis presented that DHL interventions had positive effects on eHealth literacy efficacy (standardized mean difference 1.15, 95% CI 0.46 to 1.84; P=.001). Subgroup analysis revealed that DHL interventions that chose face-to-face teaching (standardized mean difference 1.15, 95% CI 0.46 to 1.84; P=.001), were guided by a conceptual framework (standardized mean difference 1.15, 95% CI 0.46 to 1.84; P=.001), and were sustained over 4 weeks (standardized mean difference 1.1, 95% CI 0.46 to 1.84; P=.001) had a more significant effect. Moreover, the outcomes showed considerable gains in knowledge (standardized mean difference 0.93, 95% CI 0.54 to 1.31; P<.001) and self-efficacy (standardized mean difference 0.96, 95% CI 0.16 to 1.77; P=.02). No statistically significant effect was found for skills (standardized mean difference 0.77, 95% CI -0.30 to 1.85; P=.16). The small number of studies, variable study quality, and heterogeneity are some limitations of this review. CONCLUSIONS: DHL interventions have positive effects on the health status and health management of older adults. Practical and effective DHL interventions are crucial for the use of modern digital information technology in managing the health of older people. TRIAL REGISTRATION: PROSPERO International Prospective Register of Systematic Reviews CRD42023410204; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=410204.
Subject(s)
Health Literacy , Telemedicine , Humans , Aged , Systematic Reviews as Topic , Health Status , Self Efficacy , Randomized Controlled Trials as TopicABSTRACT
STATEMENT OF PROBLEM: Race and sex differences in the mathematical proportions of maxillary anterior teeth have been evaluated. However, studies exploring the relationship between the mathematical proportion of maxillary anterior teeth and maxillary dental arch form are lacking. PURPOSE: The purpose of this clinical study was to determine if a correlation exists between the mathematical proportions of maxillary anterior teeth and 3 dental arch forms. MATERIAL AND METHODS: Three hundred young participants were recruited according to predefined criteria, and images and maxillary casts were obtained. The perceived width and length of the maxillary anterior teeth were measured on the images by using a software program, and mathematical proportions, including width ratios and width-to-length ratios, were calculated for each. The casts were used to categorize each specimen into tapered, ovoid, or square groups by using a specific classification method, and the width ratios and width-to-height ratios of the 3 dental arch forms were compared. Statistical analysis was performed by using analysis of variance (ANOVA) or the Kruskal-Wallis H test to compare the mathematical proportions of maxillary anterior teeth among the 3 dental arch forms (α=.05). The intraclass correlation coefficient (ICC) was used to test the reliability of the investigators. RESULTS: Except for the width-to-length ratios of the central incisor, mathematical proportions were affected by the dental arch form. The perceived width ratios of the maxillary lateral incisor-to-central incisor gradually increased from the tapered arch to the ovoid arch and from the ovoid arch to the square arch, with mean ±standard deviation values of 0.71 ±0.04, 0.73 ±0.05, and 0.79 ±0.06, respectively. For the maxillary perceived width ratios of canine-to-lateral incisor, the ovoid arch had the maximum perceived width ratios (0.86 ±0.10), followed by the tapered (0.82 ±0.10) and square arches (0.77 ±0.11). The width-to-length ratios of the central incisor were not affected by the arch form (P=.075), and the width-to-length ratios of the lateral incisor increased as the arch form became flat, with respective values of 0.70 ±0.10, 0.74 ±0.10, and 0.76 ±0.10. For the width-to-length ratios of the canine, the ovoid arch had the maximum perceived width ratios (0.58 ±0.10), followed by the tapered (0.53 ±0.10) and square arches (0.52 ±0.10). CONCLUSIONS: The mathematical proportions varied among the 3 dental arch forms, and the dental arch form should be considered during the prosthodontic design of maxillary anterior teeth.
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OBJECTIVE: To investigate the association between the anti-melanoma differentiation associated gene 5 (MDA5) IgG subclasses and prognosis of patients with dermatomyositis (DM)-associated interstitial lung disease (ILD). METHODS: This retrospective study included 122 anti-MDA5 positive DM-ILD patients admitted from October 2017 to October 2020 as training cohort, and additional 68 patients from August 2014 to September 2017 as validation cohort. The levels of anti-MDA5 total IgG and IgG subclasses were measured using in-house enzyme-linked immunosorbent assays, and analysed in association with the patient prognosis. RESULTS: In the training cohort, the concentrations of anti-MDA5 IgG1 and IgG3 in non-survivors were significantly higher than in survivors (P < 0.05), whereas there were no significant differences in the IgG2 and IgG4 levels. Kaplan-Meier survival analysis revealed that the levels of anti-MDA5 total IgG, IgG1 and IgG3 were associated with mortality (P < 0.05). Multivariate analysis revealed anti-MDA5 IgG1 >13 U/ml and anti-MDA5 IgG3 >11 U/ml were independent risk factors for death of DM-ILD patients (P < 0.05). Anti-MDA5 IgG1 was confirmed as an independent risk factor in the validation cohort, while anti-MDA5 IgG3 was not. Anti-MDA5 IgG1 showed greater discriminable power for patient prognosis (Youden index 0.494) than anti-MDA5 total IgG, IgG3, or the combination of IgG1 and IgG3 (Youden index 0.356, 0.32 and 0.447, respectively). CONCLUSION: Anti-MDA5 IgG1 and IgG3 are significantly associated with poor prognosis in DM-ILD patients, and anti-MDA5 IgG1 is more efficient as a prognostic biomarker in DM-ILD patients.
Subject(s)
Dermatomyositis , Lung Diseases, Interstitial , Humans , Prognosis , Dermatomyositis/complications , Retrospective Studies , Interferon-Induced Helicase, IFIH1 , Autoantibodies , Lung Diseases, Interstitial/complicationsABSTRACT
Image reconstruction based on deep learning has become an effective tool in fluorescence microscopy. Most deep learning reconstruction methods ignore the mechanism of the imaging process where a large number of datasets are required. In addition, a lot of time is spent solving the aliasing problem from multi-scaled image pairs for data pre-processing. Here we demonstrate an improved generative adversarial network for image scanning microscopy (ISM) that can be trained by simulation data and has good generalization. Based on physical imaging models, this method can generate matching image pairs from simulation images and uses them as datasets for network training, without capturing a large number of real ISM images and avoiding image alignment preprocessing. Simulation and experimental results show that this simulation data-driven method improves the imaging quality of conventional microscopic images and reduces the cost of experiments. This method provides inspiration for optimizing network generalizability of the deep learning network.
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BACKGROUND: Endometrial cancer (EC) is the most common gynecologic malignancy in developed countries and its prevalence is increasing. As an emerging therapy with a promising efficacy, immunotherapy has been extensively applied in the treatment of solid tumors. In addition, chromatin regulators (CRs), as essential upstream regulators of epigenetics, play a significant role in tumorigenesis and cancer development. METHODS: CRs and immune checkpoint-related genes (ICRGs) were obtained from the previous top research. The Genome Cancer Atlas (TCGA) was utilized to acquire the mRNA expression and clinical information of patients with EC. Correlation analysis was utilized for screen CRs-related ICRGs (CRRICRGs). By Cox regression and least absolute shrinkage and selection operator (LASSO) analysis, prognosis related CRRICRGs were screened out and risk model was constructed. The Kaplan-Meier curve was used to estimate the prognosis between high- and low-risk group. By comparing the IC50 value, the drugs sensitivity difference was explored. We obtained small molecule drugs for the treatment of UCEC patients based on CAMP dataset. RESULTS: We successfully constructed a 9 CRRICRs-based prognostic signature for patients with UCEC and found the riskscore was an independent prognostic factor. The results of functional analysis suggested that CRRICRGs may be involved in immune processes associated with cancer. Immune characteristics analysis provided further evidence that the CRRICRGs-based model was correlated with immune cells infiltration and immune checkpoint. Eight small molecule drugs that may be effective for the treatment of UCEC patients were screened. Effective drugs identified by drug sensitivity profiling in high- and low-risk groups. CONCLUSION: In summary, our study provided novel insights into the function of CRRICRGs in UCEC. We also developed a reliable prognostic panel for the survival of patients with UCEC.