In vitro and in silico analyses reveal the toxicity of metolachlor to grass carp hepatocytes and the antagonism of melatonin.

Due to the widespread use of metolachlor (MET), the accumulation of MET and its metabolites in the environment has brought serious health problems to aquatic organisms. At present, the toxicity of MET on the physiological metabolism of aquatic animals mainly focused on the role of enzymes. There is still a lack of research on the molecular mechanisms of MET hepatotoxicity, especially on antagonizing MET toxicity. Therefore, this study focuses on grass carp hepatocytes (L8824 cells) closely related to toxin accumulation. By establishing a MET exposed L8824 cells model, it is determined that MET exposure induces pyrolytic inflammation of L8824 cells. Subsequent mechanistic studies found that MET exposure induces pyroptosis in L8824 cells through mitochondrial dysfunction, and siCaspase-1 inhibits the MET induced ROS production, suggesting a regulation of ROS-NLRP3- Caspase-1 pyroptotic inflammation cycling center in MET induced injury to L8824 cells. Molecular docking revealed a strong binding energy between melatonin (MT) and Caspase-1. Finally, a model of L8824 cells with MT intervention in MET exposure was established. MT can antagonize the pyroptosis induced by MET exposure in L8824 cells by targeting Caspase-1, thereby restoring mitochondrial function and inhibiting the ROS-pyroptosis cycle. This study discovered targets and mechanisms of MT regulating pyroptosis in MET exposed-L8824 cells, and the results are helpful to provide new targets for the design of MET antidotes.

Weekly versus triweekly cisplatin treatment in patients with locally advanced nasopharyngeal cancer during concurrent chemoradiotherapy.

BACKGROUND: For patients with locally advanced nasopharyngeal cancer (LA-NPC), concurrent chemoradiotherapy (CCRT) is the standardized treatment. However, whether a weekly or triweekly cisplatin regimen should be used during CCRT is controversial. Therefore, we conducted this meta-analysis to explore differences in the effects and toxicities of the two regimens. METHODS: We searched PubMed, Embase, and the Cochrane Library (until June 10, 2022). We evaluated overall survival (OS), distant metastasis-free survival (DMFS), locoregional recurrence-free survival (LRFS), disease-free survival (DFS) and grade ≥ 3 adverse events. The effect indices were hazard ratios (HRs) and odds ratios (ORs), and Review Manager software 5.4 (RevMan 5.4) was used for computations. RESULTS: We identified 7 studies in our analysis. There was no significant difference in OS (HR = 1.00, 95% CI 0.73-1.38, P = 0.99), DMFS (HR = 0.84, 95% CI 0.58-1.22, P = 0.36), LRFS (HR = 0.91, 95% CI 0.63-1.32, P = 0.62) or DFS (HR = 0.93, 95% CI 0.56-1.56; P = 0.78) between the weekly and triweekly cisplatin regimens. We found that the weekly cisplatin regimen was more likely to cause grade ≥ 3 hematological toxicity events than the triweekly cisplatin regimen. In addition, subgroup analyses revealed that patients undergoing CCRT and CCRT plus adjuvant chemotherapy (AC) had similar OS or DFS. CONCLUSION: Weekly and triweekly cisplatin regimens had similar efficacy for LA-NPC. The triweekly regimen may replace the weekly regimen for LA-NPC because of lower toxicity. Larger data accumulation and more multicenter clinical trials may be needed to verify these results.

Inflammatory mediators and immune function in different stages of systemic lupus erythematosus.

This study aimed to study the relationship between the expression levels of inflammatory mediators IL-36ß and IL-36R and disease symptoms, laboratory indices and somatic immune function in Systemic Lupus Erythematosus (SLE) of different stages. In this research 70 patients with SLE who were treated in public hospitals from February 2020 to December 2021 were randomly divided into the stable group (n=35) and active group (n=35), and serum IL-36 was measured in the two groups ß and IL-36R concentration with the standard curve of Enzyme-Linked Immunosorbent Assay (ELISA) to analyze IL-36ß and IL-36R concentrations. 36ß and IL-36R concentrations were analyzed in relation to the Disease activity score of systemic lupus erythematosus (SLEDAI), disease duration, typical symptoms of SLE and experimental characteristics. Results showed that the differences in IL-36ß and IL-36R concentrations between the stable and active groups overall and for each disease duration group were tiny. There was no significant correlation between serum IL-36ß and IL-36R concentrations and SLEDAI scores in stable and active patients, and a negative correlation between them and disease duration. Serum inflammatory mediator IL-36R concentrations were significantly higher in patients with mucosal ulcers and the difference was statistically significant. differences in IL-36ß concentrations were statistically significant only for indicators of decreased erythrocyte count and IL-36R concentrations were statistically significant for indicators of decreased erythrocyte count, decreased haemoglobin and decreased lymphocytes The differences were huge and tiny in C4 decline, anti-dsDNA, and urinary routine protein. There was a significant positive correlation between IL-36ß and IL-36R concentrations in patients with stable and active SLE, with correlation coefficients of 0.448 and 0.452 respectively. The differences in IL-36ß and IL-36R concentrations between the stable and active groups were tiny for patients in the stable and active groups as a whole and for all disease groups. The differences in the number of each inflammatory mediator positive cells in the epidermal stratum corneum and superficial dermis between patients in the stable and active groups were tiny. In conclusion, IL-36ß and IL-36R proteins in SLE patients are expressed in immune cells as well as epithelial cells of patients, indicating that these two inflammatory mediators may be one of the early signals that activate the immune system of SLE patients and trigger the immune response of patients; the onset of SLE may be associated with the inflammatory response induced by IL-36ß and IL-36R.

Concurrent chemoradiotherapy versus radiotherapy alone for stage II nasopharyngeal carcinoma in the era of intensity-modulated radiotherapy.

BACKGROUND: Concurrent chemoradiotherapy has long been a standardized therapy for localized advanced nasopharyngeal cancer. It is widely used in clinical applications. In contrast, NCCN guidelines highlight that the efficacy of concurrent chemoradiotherapy for stage II nasopharyngeal cancer in the new era of intensity-modulated radiotherapy has not been defined. Thus, we systematically reviewed the significance of concurrent chemoradiotherapy for stage II nasopharyngeal cancer. METHODS: We searched the relevant literature in PubMed, EMBASE, and Cochrane, extracting relevant data from the searched literature. The main items extracted were hazard ratios (HRs), risk ratios (RRs) and 95% confidence intervals (CIs). When the HR could not be extracted from the literature, we used Engauge Digitizer software for extraction. Data analysis was accomplished using the Review Manager 5.4 tool. RESULTS: Our study included seven articles involving 1633 cases of stage II nasopharyngeal cancer. The survival outcomes were overall survival (OS) (HR = 1.03, 95% CI (0.71-1.49), P = 0.87), progression-free survival (PFS) (HR = 0.91, 95% CI (0.59-1.39), P = 0.66), distant metastasis-free survival (DMFS) (HR = 1.05, 95% CI (0.57-1.93), P = 0.87), local recurrence-free survival (LRFS) (HR = 0.87, 95% CI (0.41-1.84), P = 0.71, P > 0.05), and locoregional failure-free survival (LFFS) (HR = 1.18, 95% CI (0.52-2.70), P = 0.69). CONCLUSIONS: In the era of intensity-modulated radiotherapy, concurrent chemoradiotherapy and radiotherapy alone have the same survival benefits, and concurrent chemoradiotherapy increases acute hematological toxicity. Subgroup analysis showed that for people with N1 nasopharyngeal cancer at risk of distant metastases, concurrent chemoradiotherapy and radiotherapy alone also had equal survival benefits.

A Novel Prognostic Prediction Model for Colorectal Cancer Based on Nine Autophagy-Related Long Noncoding RNAs.

INTRODUCTION: Colorectal cancer (CRC) is the most common gastrointestinal cancer and has a low overall survival rate. Tumor-node-metastasis staging alone is insufficient to predict patient prognosis. Autophagy and long noncoding RNAs play important roles in regulating the biological behavior of CRC. Therefore, establishing an autophagy-related lncRNA (ARlncRNA)-based bioinformatics model is important for predicting survival and facilitating clinical treatment. METHODS: CRC data were retrieved from The Cancer Genome Atlas. The database was randomly divided into train set and validation set; then, univariate and multivariate Cox regression analyses were performed to screen prognosis-related ARlncRNAs for prediction model construction. Interactive network and Sankey diagrams of ARlncRNAs and messenger RNAs were plotted. We analyzed the survival rate of high- and low-risk patients and plotted survival curves and determined whether the risk score was an independent predictor of CRC. Receiver operating characteristic curves were used to evaluate model sensitivity and specificity. Then, the expression level of lncRNA was detected by quantitative real-time polymerase chain reaction, and the location of lncRNA was observed by fluorescence in situ hybridization. Additionally, the protein expression was detected by Western blot. RESULTS: A prognostic prediction model of CRC was built based on nine ARlncRNAs (NKILA, LINC00174, AC008760.1, LINC02041, PCAT6, AC156455.1, LINC01503, LINC00957, and CD27-AS1). The 5-year overall survival rate was significantly lower in the high-risk group than in the low-risk group among train set, validation set, and all patients (all p < 0.001). The model had high sensitivity and accuracy in predicting the 1-year overall survival rate (area under the curve = 0.717). The prediction model risk score was an independent predictor of CRC. LINC00174 and NKILA were expressed in the nucleus and cytoplasm of normal colonic epithelial cell line NCM460 and colorectal cancer cell lines HT29. Additionally, LINC00174 and NKILA were overexpressed in HT29 compared with NCM460. After autophagy activation, LINCC00174 expression was significantly downregulated both in NCM460 and HT29, while NKILA expression was significantly increased. CONCLUSION: The new ARlncRNA-based model predicts CRC patient prognosis and provides new research ideas regarding potential mechanisms regulating the biological behavior of CRC. ARlncRNAs may play important roles in personalized cancer treatment.

Comparison of Dosimetric Benefits of Three Precise Radiotherapy Techniques in Nasopharyngeal Carcinoma Patients Using a Priority-Classified Plan Optimization Model.

INTRODUCTION: Although intensity-modulated radiotherapy (IMRT), volumetric-modulated arc therapy (VMAT) and tomotherapy (TOMO) are broadly applied for nasopharyngeal carcinoma (NPC), the best technique remains unclear. Therefore, this study was conducted to address this issue. METHODS: The priority-classified plan optimization model was applied to IMRT, VMAT and TOMO plans in forty NPC patients according to the latest international guidelines. And the dosimetric parameters of planning target volumes (PTVs) and organs at risk (OARs) were compared among these three techniques. The Friedman M test in SPSS software was applied to assess significant differences. RESULTS: The median PGTVnx coverage of IMRT was the lowest (93.5%, P < 0.001) for all T categories. VMAT was comparable to TOMO in OARs clarified as priority I and II, and both satisfied the prescribed requirement. IMRT resulted in a relatively high dose for V25 and V30. Interestingly, subgroup analysis showed that the median PTV coverage of the three techniques was no less than 95% in the early T stage. The heterogeneity index (HI) of PGTVnx in VMAT was better than that in IMRT (P = 0.028). Compared to TOMO, VMAT showed a strong ability to protect eyesight and decrease low-dose radiation volumes. In the advanced T stage subgroup, TOMO numerically achieved the highest median PGTVnx coverage volume compared with VMAT and IMRT (93.61%, 91% and 90%, respectively). The best CI and HI of PCTV-1 were observed in TOMO. Furthermore, TOMO was better than VMAT for sparing the brain stem, spinal cord and temporal lobes (all P < 0.05). However, the median V5, V10, V15, V20 and V25 were significantly higher with TOMO than with VMAT (all P < 0.05). CONCLUSION: In the early T stage, VMAT provides a similar dose coverage and protection of OARs to IMRT, and there are no obvious advantages to choosing TOMO for NPC patients in the early T stage. TOMO may be recommended for patients in the advanced T stage due as it provides the largest dose coverage of PGTVnx and the best protection of the brain stem, spinal cord and temporal lobes. Additionally, more randomized clinical trials are needed for further clarification.

Comparison of relapsing polychondritis patients with and without central nervous system involvement: A retrospective study of 181 patients.

The relapsing polychondritis (RP) patients with central nervous system (CNS) involvement were rare. We aimed to determine the clinical characteristics of RP patients with CNS involvement. The clinical data of 181 RP patients, hospitalized at Peking Union Medical College Hospital between December 2005 and February 2019, were collected. The patients were categorized into two subgroups: 25 RP patients with CNS involvement, and 156 RP patients without CNS involvement. The involvement of the ear was more frequent in RP patients with CNS involvement, compared with those of RP patients without CNS involvement (P < 0.01). After controlling sex and the admission age, logistic regression analysis revealed hypertension (odds ratio = 4.308, P = 0.006) and involvement of eye (odds ratio = 5.158, P = 0.001) and heart (odds ratio = 3.216, P = 0.025) were correlated with RP patients with CNS involvement, respectively. In addition, pulmonary infection (odds ratio = 0.170, P = 0.020), tracheal involvement (odds ratio = 0.073, P < 0.01), and involvement of laryngeal (odds ratio = 0.034, P = 0.001), costochondral joint (odds ratio = 0.311, P = 0.013), sternoclavicular joint (odds ratio = 0.163, P = 0.017) and manubriosternal joint (odds ratio = 0.171, P = 0.021) were associated with RP patients without CNS involvement, respectively. In contrast to RP patients without CNS involvement, the incidence of ear involvement was higher in RP patients with CNS involvement. After controlling the potential confounding factor sex and the admission age, hypertension and involvement of eye and heart were related with RP patients with CNS involvement, respectively.

Characteristics of Acquired Inhibitors to Factor VIII and Von Willebrand Factor Secondary to Systemic Lupus Erythematosus: Experiences From a Chinese Tertiary Medical Center.

OBJECTIVE: Because acquired hemophilia (AH) is a rare entity in systemic lupus erythematosus (SLE), we aimed to investigate the clinical features of SLE-related AH in Chinese patients. METHODS: This is a medical records review study carried out at a large tertiary care hospital in China from years 1986 to 2018. We searched the case database in Peking Union Medical College Hospital using the International Classification of Diseases. The clinical data on SLE-related AH patients were collected. RESULTS: A total of 9282 SLE patients had been hospitalized. Six female SLE-related AH patients were identified. Four patients had acquired hemophilia A (AHA), and 2 patients had acquired von Willebrand syndrome. Their mean age was 33.67 ± 13.77 years. Five patients had active disease. The mean SLE disease activity index measured at the time of diagnosis of AH was 10.50 ± 5.28. The average level of activated partial thromboplastin time was 86.5 seconds. Coexistence of secondary antiphospholipid syndrome and AHA was found in one case, and pulmonary embolism was observed 3 years later. After immunosuppressive therapy and symptomatic treatment, an overall remission rate of 83.3% was achieved. CONCLUSIONS: The frequency of SLE-related AH was low. The development of AH in SLE patients frequently occurs with active disease. The AH could be the first clinical presentation of SLE. Secondary antiphospholipid syndrome and AHA could appear in the same SLE patient. Early and aggressive treatment contributes to a favorable prognosis.

Patterns of renal pathology in Chinese patients with systemic sclerosis undergoing renal biopsy at a tertiary medical center.

OBJECTIVE: We investigated renal injury characteristics in Chinese patients with systemic sclerosis (SSc) who had undergone renal biopsy. METHODS: We searched the medical records of patients with SSc who were hospitalized at Peking Union Medical College Hospital between January 1990 and August 2019. We analyzed the clinical characteristics and pathological results of these patients. RESULTS: We identified 25 patients who had undergone renal biopsy. Of these patients, 10 had scleroderma renal crisis (SRC); one underwent renal biopsy twice (for diffuse mesangial proliferative glomerulonephritis and for SRC); two had antineutrophil cytoplasmic antibody-associated glomerulonephritis; one had immunoglobulin M nephropathy; one had minimal change nephropathy; seven had lupus nephritis; one had scleroderma renal crisis with comorbid lupus nephritis; and two had drug-related kidney injury (caused by aristolochic acid in one and D-penicillamine in the other). Acute tubular necrosis was observed in the patient taking oral aristolochic acid, while minimal change nephropathy was observed in the patient with D-penicillamine-induced renal injury. CONCLUSIONS: SRC was the most commonly encountered renal damage in patients with SSc. We recommend biopsy for patients undergoing treatment for SRC who have persistent renal injury with proteinuria, regardless of hematuria. Rheumatologists in Eastern countries should be aware of aristolochic acid nephropathy.

Role of tumor necrosis factor-like weak inducer of apoptosis (TWEAK)/fibroblast growth factor-inducible 14 (Fn14) axis in rheumatic diseases.

Tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) is a member of the TNF superfamily of structurally related cytokines and is known to induce proliferation, migration, differentiation, apoptotic cell death, inflammation, and angiogenesis. These physiological processes are induced by the binding of TWEAK to fibroblast growth factor-inducible 14 (Fn14), a highly inducible cell-surface receptor that is linked to several intracellular signaling pathways, including the nuclear factor-κB (NF-κB) pathway. This review discusses the role of the TWEAK-Fn14 axis in several rheumatic diseases and the potential therapeutic benefits of modulation of the TWEAK-Fn14 pathway.