Construction and Validation of a Prognostic Model Based on Mitochondrial Genes in Prostate Cancer.

This study attempted to build a prostate cancer (PC) prognostic risk model with mitochondrial feature genes. PC-related MTGs were screened for Cox regression analyses, followed by establishing a prognostic model. Model validity was analyzed via survival analysis and receiver operating characteristic (ROC) curves, and model accuracy was validated in the GEO dataset. Combining risk score with clinical factors, the independence of the risk score was verified by using Cox analysis, followed by generating a nomogram. The Gleason score, microsatellite instability (MSI), immune microenvironment, and tumor mutation burden were analyzed in two risk groups. Finally, the prognostic feature genes were verified through a q-PCR test. Ten PC-associated MTGs were screened, and a prognostic model was built. Survival analysis and ROC curves illustrated that the model was a good predictor for the risk of PC. Cox regression analysis revealed that risk score acted as an independent prognostic factor. The Gleason score and MSI in the high-risk group were substantially higher than in the low-risk group. Levels of ESTIMATE Score, Immune Score, Stromal Score, immune cells, immune function, immune checkpoint, and immunopheno score of partial immune checkpoints in the high-risk group were significantly lower than in the low-risk group. Genes with the highest mutation frequencies in the two groups were SPOP, TTN, and TP53. The q-PCR results of the feature genes were consistent with the gene expression results in the database. The 10-gene model based on MTGs could accurately predict the prognosis of PC patients and their responses to immunotherapy.

Non-intestinal-type adenocarcinoma of the nasal cavity and paranasal sinuses: an analysis of clinical characteristics and prognosis.

BACKGROUND: Non­intestinal adenocarcinoma of the nasal cavity and paranasal sinuses (non­ITAC) is a heterogeneous tumour that has rarely been reported in previous studies. We compared and analysed the symptoms, radiographic and pathological features, treatment methods, and prognosis of patients with low-grade (G1) and high-grade (G3) tumours. METHODS: This was a retrospective study included 22 patients with pathologically confirmed non-ITAC of the nasal cavity and paranasal sinuses who were treated between January 2008 and December 2021 at a single centre. Of these, 11 patients had G1 tumours, and 11 patients had G3 tumours. Clinicopathological features, treatment methods, and survival outcomes were analysed. RESULTS: The median follow-up period was 48.5 months. Nasal congestion was the most common initial symptom, and the nasal cavity was the most frequently involved site. For G1 tumours, the main treatment was simple surgery, 1 and 3­year overall survival (OS) rates were 100 and 88.9%, while the 1 and 3­year local control (LC) rates were 100 and 100%, respectively. For G3 tumours, the main treatments were surgery combined with radiotherapy and/or chemotherapy,1 and 3­year OS rates were 72.7 and 72.7%, while the 1 and 3­year LC rates were 100 and 90.91%, respectively. G3 tumours was associated with significantly shorter overall survival than G1 tumours (P = 0.035). Patients with stage III-IV showed shorter overall survival compared to stage I-II patients (P = 0.035). CONCLUSIONS: Non-ITAC of the nasal cavity and paranasal sinuses may frequently occur in the nasal cavity. The main treatment modality is surgery, supplemented by radiotherapy and chemotherapy. Pathological grade and tumour stage were poor prognostic factors for the disease.

Predictive effect of estimated glomerular filtrate rate by creatinine or cystatin C on mortality in patients with coronary artery disease.

BACKGROUND: Renal dysfunction leads to poor prognosis of patients with coronary artery disease (CAD). Current studies have reported the prognosis or mortality of various diseases using different estimated glomerular filtrate rate (eGFR) formulas, while the performance of these equations is unclear in CAD patients. We aim to evaluate the predict effect of creatinine-based eGFR (eGFRcr), cystatin C-based eGFR (eGFRcys), and both creatinine and cystatin C-based eGFR (eGFRcr-cys) in CAD patients. METHODS: A total of 23,178 patients with CAD were included from CIN-II cohort study. The association of eGFRcr, eGFRcys and eGFRcr-cys with cardiovascular and all-cause mortality was detected by Cox regression analysis. The predictive effect of eGFRcr, eGFRcys and eGFRcr-cys on mortality was assessed. RESULTS: During a median follow up of 4.3 years, totally 2051 patients (8.8%) experience all-cause mortality, of which 1427 patients (6.2%) died of cardiovascular disease. For the detection of cardiovascular mortality among CAD patients, eGFRcr-cys had high discriminatory capacity with area under the curve (AUC) in receiver operator characteristic analysis of 0.730, which was significantly better than eGFRcr (AUC = 0.707, p < 0.001) and eGFRcys (AUC = 0.719, p < 0.001). Similar results were observed in all-cause mortality. Restricted cubic spline showed a U-shaped association between eGFRcr and all outcomes in patients with both reduced and supranormal eGFR levels, while a L-shaped association in eGFRcys and eGFRcr-cys. CONCLUSIONS: Estimated GFR based on both creatinine and cystatin C has highest predictive effect for cardiovascular and all-cause mortality among CAD patients. Meanwhile, supranormal eGFRcr may indicate a higher risk of mortality.

Forecasting carbon prices in China's pilot carbon market: A multi-source information approach with conditional generative adversarial networks.

In recent years, the Chinese government has actively pursued the implementation of its 'dual-carbon' strategy, concurrently establishing a national carbon emissions trading market. Accurate carbon price forecasts have become essential for policymakers and investors involved in related initiatives. Nevertheless, influenced by the interaction of various information sources, carbon trading prices exhibit non-linear and non-stationary characteristics, posing challenges for accurate prediction. Current research, centered around deep learning models, predominantly emphasizes intricate network structures, optimisation algorithms, and data decomposition. However, these models face a developmental bottleneck in extracting carbon price features and efficiently leveraging multi-source information. Consequently, novel ideas and methodologies are imperative. This study focuses on the Hubei and Guangdong regional carbon markets as research subjects. It develops a prediction framework based on a generative adversarial network model to capture the time-series change characteristics of carbon trading prices and the condition matrix. First, a generator prediction model is used to obtain the input matrix features and extract the time series features through a complex network to predict the carbon price data at the next moment using a fully connected layer. Second, a discriminator is utilised to distinguish between the actual values and the predicted values. The generator and the discriminator undergo continuous iterative training and alternate optimisation. This process aims to bring the generated prediction distributions closer to the actual sample data, resulting in more accurate final predictions. The empirical results convincingly show that the proposed model achieves unparalleled forecasting precision in both markets. The proposed model demonstrates the lowest MAE (0.804 and 0.839), lowest MAPE (0.023 and 0.018), lowest RMSE (1.174 and 1.383), and highest R2 (0.971 and 0.989) across both markets, indicating superior predictive accuracy. Additionally, the proposed model consistently outshines traditional forecasting approaches across one-step, five-step, and ten-step forecasts, affirming its robustness and universal applicability in modelling carbon trading price series. The findings suggest that this study can aid policymakers in optimizing the carbon pricing system. Furthermore, it offers a reference for policymakers to comprehensively leverage external factors, such as regulating traditional energy prices, leveraging international carbon market experiences, and monitoring economic dynamics. This comprehensive strategy can streamline the exploration and management of carbon price fluctuations, ultimately strengthening the carbon market's risk control system.

Impact of stapler versus manual closure techniques on pharyngocutaneous fistula development post-total laryngectomy: A systematic review and meta-analysis.

Pharyngocutaneous fistula (PCF) is a major complication after total laryngectomy, with significant morbidity and mortality. Whether mechanical stapler closure of the pharynx reduces fistula rates compared to hand-sewn techniques remains unclear. We conducted an updated systematic review and meta-analysis to clarify this question. Five databases were systematically searched from inception through November 2023 for studies comparing stapler versus suture closure for fistula outcomes after laryngectomy. Odds ratios (OR) were pooled using random-effects models and fixed-effects models. Subgroup and sensitivity analyses were performed. Risk of bias was appraised using NHLBI tools. Nine studies with 803 patients were included. Mechanical closure significantly reduced fistula incidence versus suture closure (OR = 0.57, 95% CI 0.34-0.95, p = 0.03). Subgroup analysis found that stapling's protective effect varied by patient age, country/region, linear stapler size and female percentage. Stapling reduced fistula odds by 80% in the Turkey subgroup (OR = 0.20, 95% CI 0.09-0.50) but showed no benefit in other regions. Patients <60 years showed an 84% fistula reduction with stapling (OR = 0.17, 95% CI 0.06-0.45), whereas older subgroups did not. Linear stapler size of 60 mm significantly reduced fistula occurrence while 75 mm did not. There was no evidence that low female percentage mitigated stapling benefits. Mechanical stapler closure after total laryngectomy meaningfully reduces the likelihood of postoperative PCF formation compared to hand-sewn closure, especially for patients younger than 60 years old. The absolute risk reduction supports its utility to prevent this complication.

TRIM64 promotes ox-LDL-induced foam cell formation, pyroptosis, and inflammation in THP-1-derived macrophages by activating a feedback loop with NF-κB via IκBα ubiquitination.

Atherosclerosis is a chronic inflammatory disease and the main pathology behind most cardiovascular diseases and the overactivation of macrophages initiates the development of atherosclerosis. However, the specific functions of oxidized low-density lipoprotein (ox-LDL) in macrophages remain elusive. Macrophages derived from monocyte (THP-1) were treated with ox-LDL and were used to generate atherosclerosis in an in vitro model. NLRP3 inflammasome markers were examined using quantitative RT-PCR and Western blotting. Cytokines were measured using ELISA. Chromatin immunoprecipitation (ChIP) was utilized to detect nuclear factor kappa B (NF-κB) and TRIM64 interactions. A fat-rich diet was applied to ApoE-/- mice for in vivo studies. ox-LDL promoted TRIM64 expression in a time-dependent manner. According to loss- and gain-of-function analyses, TRIM64 enhanced the activation of NLRP3 inflammasomes and the expression of downstream molecules. TRIM64 directly interacted with IκBα and promoted IκBα ubiquitination at K67 to activate NF-κB signaling. We detected direct binding between NF-κB and the TRIM64 promoter, as well as enhanced TRIM64 expression. Our study revealed an interaction between TRIM64 and NF-κB in the development of atherosclerosis. TRIM64 and NF-κB formed a positive feedback to activate NF-κB pathway. ox-LDL induces foam cell formation and TRIM64 expression TRIM64 regulates ox-LDL-induced foam cell formation, pyroptosis and inflammation via the NF-κB signaling TRIM64 activates NF-κB signaling by ubiquitination of IκBα NF-κB inhibition attenuates atherosclerosis in HFD-induced ApoE (-/-) mice.

Four thermostatic steps: A novel CRISPR-Cas12-based system for the rapid at-home detection of respiratory pathogens.

The outbreak of coronavirus disease 2019 (COVID-19) in 2019 has severely damaged the world's economy and public health and made people pay more attention to respiratory infectious diseases. However, traditional quantitative real-time polymerase chain reaction (qRT-PCR) nucleic acid detection kits require RNA extraction, reverse transcription, and amplification, as well as the support of large-scale equipment to enrich and purify nucleic acids and precise temperature control. Therefore, novel, fast, convenient, sensitive and specific detection methods are urgently being developed and moving to proof of concept test. In this study, we developed a new nucleic acid detection system, referred to as 4 Thermostatic steps (4TS), which innovatively allows all the detection processes to be completed in a constant temperature device, which performs extraction, amplification, cutting of targets, and detection within 40 min. The assay can specifically and sensitively detect five respiratory pathogens, namely SARS-CoV-2, Mycoplasma felis (MF), Chlamydia felis (CF), Feline calicivirus (FCV), and Feline herpes virus (FHV). In addition, a cost-effective and practical small-scale reaction device was designed and developed to maintain stable reaction conditions. The results of the detection of the five viruses show that the sensitivity of the system is greater than 94%, and specificity is 100%. The 4TS system does not require complex equipment, which makes it convenient and fast to operate, and allows immediate testing for suspected infectious agents at home or in small clinics. Therefore, the assay system has diagnostic value and significant potential for further reducing the cost of early screening of infectious diseases and expanding its application. KEY POINTS: • The 4TS system enables the accurate and specific detection of nucleic acid of pathogens at 37 °C in four simple steps, and the whole process only takes 40 min. •A simple alkali solution can be used to extract nucleic acid. • A small portable device simple to operate is developed for home diagnosis and detection of respiratory pathogens.

Daytime sleepiness is associated with increased coronary plaque burden among patients with obstructive sleep apnea.

PURPOSE: To investigate the cross-sectional associations of daytime sleepiness with coronary plaque volume and composition in patients with obstructive sleep apnea (OSA), and whether or not these associations are modified by age, gender, and obesity. METHODS: Patients who were confirmed with OSA through respiratory polygraphy and also underwent coronary CTA at a tertiary hospital were consecutively enrolled. The interval between the sleep monitoring and coronary CTA scan was < 3 months. Every patient completed the Epworth sleepiness scale (ESS) to assess daytime sleepiness, and an ESS score of ≥ 11 was recognized as excessive daytime sleepiness (EDS). Coronary plaque volume and composition were measured using semi-automatic software. RESULTS: Of the 394 patients with OSA (median [IQR] age, 56.0 [49.0-64.0] years; median [IQR] body mass index, 27.9 [25.5-30.2] kg/m2; median [IQR] apnea-hypopnea index, 21.3 [11.7, 36.3] events/h), a total of 200 patients had EDS. In the overall participants, a significant dose-response relationship between ESS scores and low-attenuation plaque volume was found in the fully adjusted model (P = 0.019). Further analysis demonstrated that there was a significant interactive effect of ESS levels and obesity on coronary plaque volume (all P values for interaction analysis < 0.05). Specifically, ESS levels were associated with total plaque volume, volumes of noncalcified, low-attenuation, and calcified plaque (P = 0.008, 0.006, 0.005, and 0.043 respectively) in obese patients with OSA. CONCLUSION: Daytime sleepiness is significantly correlated with increased coronary plaque burden among patients with OSA. Thus, clinicians should recognize that patients with OSA reporting high ESS scores, especially those with obesity, are more prone to experience adverse coronary events.

Clinical correlation analysis of HPV infection in adult laryngeal papilloma and adverse events.

OBJECT: To explore the factors affecting dysplasia and carcinogenesis in adult patients with laryngeal papilloma, and the clinical differences between human papillomavirus (HPV)-positive and HPV-negative patients. METHODS: Clinical data of 80 adult patients with laryngeal papilloma and associated adverse events were collected retrospectively. They had undergone surgery in the Department of Otolaryngology Head and Neck, Beijing Tongren Hospital, Capital Medical University between January 2010 and December 2020. HPV infection was detected using RNA in situ hybridization. RESULTS: Regression analysis showed that multiple lesions and high Ki-67 expression were independent factors affecting the occurrence of adverse events. Differences between the HPV-positive and HPV-negative groups were compared. The age and Ki-67 expression in the HPV-negative group were significantly higher than those in the HPV-positive group. In the severe dysplasia to carcinogenesis subgroup, the proportion of HPV-negative patients was significantly higher than that in the mild to moderate dysplasia subgroup. There was a high correlation between positive p16 immunohistochemistry (IHC) and positive HPV. CONCLUSIONS: Multiple lesions and high Ki-67 expression are independent factors that are linked with adverse laryngeal papilloma progression. Elderly HPV-negative patients are at an increased risk of severe dysplasia and carcinogenesis. Positive p16 IHC was very accurate in detecting HPV infection.

Relationship between dysphagia and surgical treatment for supraglottic laryngeal carcinoma: A meta-analysis.

OBJECTIVE: To systematically evaluate differences in swallowing disorder-related manifestations in patients with supraglottic laryngeal cancer, who underwent traditional open partial horizontal laryngectomy (OPHL) and endoscopic supraglottic laryngectomy (ESL). METHODS: A systematic review of the literature and a meta-analysis were performed. The CNKI, Wan Fang, PubMed, EMBASE, Cochrane Library, Web of Science, and Clinical Trials databases for clinical studies data sources were investigated. The efficiency of recovery, postoperative swallowing function, and complications related to dysphagia were investigated to compare the effects of surgical procedures. RESULTS: The meta-analysis included 8 studies with 281 patients. ESL surgery played a positive role in the recovery of patients. Preservation of the anterior epiglottic space, ventricular band, and arytenoid cartilage without destroying the external framework of the larynx can effectively reduce the risk of aspiration pneumonia in patients. CONCLUSIONS: ESL has advantages in postoperative recovery and retention of swallowing function in patients with supraglottic laryngeal cancer.

Analysis of lesion location and disease characteristics of pharyngeal and laryngeal papilloma in adult.

OBJECTIVES: Papilloma is a common benign epithelial tumor of the respiratory tract in adults. Its histological structure and immune environment vary from site to site. This study investigated the disease characteristics and prognostic differences of papillomas at various primary locations. METHODS: Clinical data was collected from patients with adult glossal root and hypopharyngeal papilloma admitted to our tertiary referral center between January 2010 and December 2020, and compared with patients with laryngeal papilloma. Differences in age, sex, smoking, alcohol consumption, single or multiple lesions, surgical methods, immunohistochemical indexes, Ki-67 and p16, were analyzed in patients with different primary papilloma sites. RESULTS: A total of 84 cases of glossal root papilloma, 51 cases of hypopharyngeal papilloma, and 51 cases of laryngeal papilloma were included. Differential analysis between groups showed that there were statistically significant differences in age, sex, smoking, single and multiple lesions, and surgical methods in the different primary sites. Ki-67 expression in laryngeal papilloma was higher than that in glossal root and hypopharyngeal papilloma. There was no significant difference in p16 expression in the three groups. In terms of prognosis, laryngeal papilloma is more likely to relapse than glossal root or hypopharyngeal papilloma, and the recurrence time is shorter. CONCLUSIONS: As the largest clinical study of papilloma in different primary locations, this study found that the clinical characteristics and postoperative recurrence of papilloma of the glossal root and hypopharynx differ from those of papilloma of the larynx. This finding supports the current clinical experience in treating papillomas in different locations and facilitates the development of clinical treatment plans.

Study on low temperature plasma combined with AC/Mn + TiO2-Al2O3 catalytic treatment of sewage-containing polyacrylamide.

With the introduction of tertiary oil recovery technology, polymer oil drive technology has effectively improved the recovery rate of crude oil, but the resulting oilfield wastewater-containing polyacrylamide (PAM) is viscous and complex in composition, which brings difficulties to wastewater treatment. The treatment of this kind of wastewater has become an urgent problem to be solved, and the removal of PAM is the key. In this paper, a dielectric barrier discharge (DBD) co-catalyst was used to treat PAM-containing solutions to investigate the effect of different catalytic reaction systems on the degradation of PAM. The morphological changes of the PAM solution before and after the reaction were also studied by the environmental electron microscope scanner (ESEM), and the information of the functional groups in the solution before and after the reaction was studied by infrared spectroscopy analysis of the PAM solution. The degradation rate rose by 26.3% in comparison to that without discharge when AC/Mn + TiO2 and Al2O3 were combined and catalyzed at a mass ratio of 2:1 and a discharge period of 300 min. The degradation rate rose by 19.3 and 6.8%, respectively, in comparison to AC/Mn + TiO2 and Al2O3-catalyzed alone. It demonstrates that this catalytic system has the optimum catalytic effect.

Washing antimony and arsenic from agricultural soil with eco-friendly organic acids and the relevant bioavailability assessment.

Antimony (Sb) and arsenic (As) contamination in agricultural soil poses human health risks through agricultural products. Soil washing with degradable low molecular weight organic acids (LMWOAs) is an eco-friendly strategy to remediate agricultural soils. In this study, three eco-friendly LMWOAs, oxalic acid (OA), tartaric acid (TA), and citric acid (CA), were used to treat Sb and As co-contaminated agricultural soil from Xikuangshan mine area. The OA, TA, and CA washed out 18.4, 16.8, and 26.6% of Sb and 15.3, 19.9, and 23.8% of As from the agricultural soil, with CA being the most efficient reagent for the soil washing. These organic acids also led to pH decline and macronutrients losses. Fraction analysis using a sequential extraction procedure showed that the three organic acids targeted and decreased the specifically sorbed (F2) (by 19.3-37.6% and 2.41-23.5%), amorphous iron oxide associated (F3) (by 49.1-61.2% and 51.2-70.2%), and crystallized iron oxide associated (F4) (by 12.3-26.0% and 26.1-29.1%) Sb and As. The leachability of Sb and As, as well as their concentrations and bioconcentration factor (BCF) in vegetables reduced due to the soil washing. It demonstrated that the bioavailability of both the elements was decreased by the organic acids washing. The concentrations of Sb and As in typical vegetable species cultivated in CA washed soil were less than the threshold value for consumption safety, while those in OA and TA washed soils were still higher than the value, suggesting that only CA is a potential washing reagent in soil washing for Sb- and As-contaminated agricultural soil.

Bifunctional anti-PD-L1/TGF-ßRII agent SHR-1701 in advanced solid tumors: a dose-escalation, dose-expansion, and clinical-expansion phase 1 trial.

BACKGROUND: Dual inhibition of PD-1/PD-L1 and TGF-ß pathways is a rational therapeutic strategy for malignancies. SHR-1701 is a new bifunctional fusion protein composed of a monoclonal antibody against PD-L1 fused with the extracellular domain of TGF-ß receptor II. This first-in-human trial aimed to assess SHR-1701 in pretreated advanced solid tumors and find the population who could benefit from SHR-1701. METHODS: This was a dose-escalation, dose-expansion, and clinical-expansion phase 1 study. Dose escalation was initiated by accelerated titration (1 mg/kg q3w; intravenous infusion) and then switched to a 3+3 scheme (3, 10, 20, and 30 mg/kg q3w and 30 mg/kg q2w), followed by dose expansion at 10, 20, and 30 mg/kg q3w and 30 mg/kg q2w. The primary endpoints of the dose-escalation and dose-expansion parts were the maximum tolerated dose and recommended phase 2 dose. In the clinical-expansion part, selected tumors were enrolled to receive SHR-1701 at the recommended dose, with a primary endpoint of confirmed objective response rate (ORR). RESULTS: In total, 171 patients were enrolled (dose-escalation: n=17; dose-expansion, n=33; clinical-expansion, n=121). In the dose-escalation part, no dose-limiting toxicity was observed, and the maximum tolerated dose was not reached. SHR-1701 showed a linear dose-exposure relationship and the highest ORR at 30 mg/kg every 3 weeks, without obviously aggravated toxicities across doses in the dose-escalation and dose-expansion parts. Combined, 30 mg/kg every 3 weeks was determined as the recommended phase 2 dose. In the clinical-expansion part, SHR-1701 showed the most favorable efficacy in the gastric cancer cohort, with an ORR of 20.0% (7/35; 95% CI, 8.4-36.9) and a 12-month overall survival rate of 54.5% (95% CI, 29.5-73.9). Grade ≥3 treatment-related adverse events occurred in 37 of 171 patients (22%), mainly including increased gamma-glutamyltransferase (4%), increased aspartate aminotransferase (3%), anemia (3%), hyponatremia (3%), and rash (2%). Generally, patients with PD-L1 CPS ≥1 or pSMAD2 histochemical score ≥235 had numerically higher ORR. CONCLUSIONS: SHR-1701 showed an acceptable safety profile and encouraging antitumor activity in pretreated advanced solid tumors, especially in gastric cancer, establishing the foundation for further exploration. TRIAL REGISTRATION: ClinicalTrials.gov , NCT03710265.

Discovery and preclinical profile of sudapyridine (WX-081), a novel anti-tuberculosis agent.

Multidrug resistant tuberculosis (MDR-TB) remains a major human health challenge. Bedaquiline was approved in 2012 by the US FDA, and listed by WHO as a treatment for multidrug-resistant tuberculosis (MDR-TB) in 2018. However, the side effects of bedaquiline including the risk of unexplained mortality, QTc prolongation and hepatotoxicity limit its wide clinical use. Based on bedaquiline, we describe herein discovery and development of a novel diarylpyridine series, which led to identification of WX-081 (sudapyridine, 21l). It displayed excellent anti-mycobacterial activity against M. tuberculosis H37Rv in vitro and in vivo and low cytotoxicity; additionally WX-081 had excellent pharmacokinetic parameters in animals, better lung exposure and lower QTc prolongation potential compared to bedaquiline. WX-081 is currently under clinical phase II development (NCT04608955).

Discovery and preclinical evaluations of JBD0131, a novel nitrodihydro-imidazooxazole anti-tuberculosis agent.

Multidrug-resistant pulmonary tuberculosis (MDR-TB) is a major health problem worldwide. The treatment for MDR-TB requires medications for a long duration (up to 20-24 months) with second-line drugs resulting in unfavorable outcomes. Nitroimidazoles are promising antimycobacterial agents known to inhibit both aerobic and anaerobic mycobacterial activity. Delamanid and pretomanid are two nitroimidazoles approved by the regulatory agencies for MDR-TB treatment. However, both agents possess unsatisfactory absorption and QTc prolongation. In our search for a safer nitroimidazole, we discovered JBD0131 (2). It exhibited excellent anti-mycobacterial activity against M. tuberculosis H37Rv in vitro and in vivo, improved PK and absorption, reduced QT prolongation potential of delamanid. JBD0131 is currently in clinical development in China for pulmonary tuberculosis (CTR20202308).

Monitoring European data with prospective space-time scan statistics: predicting and evaluating emerging clusters of COVID-19 in European countries.

BACKGROUND: Coronavirus disease 2019 (COVID-19) has become a pandemic infectious disease and become a serious public health crisis. As the COVID-19 pandemic continues to spread, it is of vital importance to detect COVID-19 clusters to better distribute resources and optimizing measures. This study helps the surveillance of the COVID-19 pandemic and discovers major space-time clusters of reported cases in European countries. Prospective space-time scan statistics are particularly valuable because it has detected active and emerging COVID-19 clusters. It can prompt public health decision makers when and where to improve targeted interventions, testing locations, and necessary isolation measures, and the allocation of medical resources to reduce further spread. METHODS: Using the daily case data of various countries provided by the European Centers for Disease Control and Prevention, we used SaTScan™ 9.6 to conduct a prospective space-time scan statistics analysis. We detected statistically significant space-time clusters of COVID-19 at the European country level between March 1st to October 2nd, 2020 and March 1st to October 2nd, 2021. Using ArcGIS to draw the spatial distribution map of COVID-19 in Europe, showing the emerging clusters that appeared at the end of our study period detected by Poisson prospective space-time scan statistics. RESULTS: The results show that among the 49 countries studied, the regions with the largest number of reported cases of COVID-19 are Western Europe, Central Europe, and Eastern Europe. Among the 49 countries studied, the country with the largest cumulative number of reported cases is the United Kingdom, followed by Russia, Turkey, France, and Spain. The country (or region) with the lowest cumulative number of reported cases is the Faroe Islands. We discovered 9 emerging clusters, including 21 risky countries. CONCLUSION: This result can provide timely information to national public health decision makers. For example, a country needs to improve the allocation of medical resources and epidemic detection points, or a country needs to strengthen entry and exit testing, or a country needs to strengthen the implementation of protective isolation measures. As the data is updated daily, new data can be re-analyzed to achieve real-time monitoring of COVID-19 in Europe. This study uses Poisson prospective space-time scan statistics to monitor COVID-19 in Europe.

Acute toxicity of eucalyptus leachate tannins to zebrafish and the mitigation effect of Fe3+ on tannin toxicity.

Fish ponds polluted by the black water of eucalyptus forests (formed by the complexation of eucalyptus tannins with Fe3+) have experienced fish deaths. However, the toxicity of the components of black water is still unclear. To study the acute toxicities of eucalyptus leachate tannins to fish, their changes in the presence of Fe3+, and the underlying mechanisms, the static bioassay test method was adopted for acute exposure testing of zebrafish. Zebrafish were exposed to three kinds of tannins, namely, tannic acid (TA), epigallocatechin gallate (EGCG) and tannins from fresh eucalyptus leaf leacheate (TFL), and to solutions of these tannins with different molar ratios of Fe3+, under both no-aeration and aeration conditions. The results showed that the 48 h LC50 values of TA, EGCG and TFL were respectively 92, 47, and 186 mg·L-1, under no aeration, and 171, 86, and 452 mg·L-1 under aeration. When Fe3+ at 2, 1, and 6 times the molar amount of tannin was added to LC100 solutions of TA, EGCG and TFL, zebrafish mortality in 24 h was reduced to 0-33%. Acute fish death in eucalyptus plantation areas is related to high concentrations of eucalyptus tannins in the water. However, with increasing dissolved oxygen and Fe3+ levels, the acute toxicity of tannins to fish can be reduced. Thus, the black water in eucalyptus plantation areas reflects a water quality phenomenon that reduces the acute toxicity of eucalyptus tannins to fish. The mechanism of tannin toxicity to fish may be related to the impairment of oxygen delivery by fish blood, but the mechanism needs further study. These results provide a scientific basis for the prevention and control of fish suffering from acute eucalyptus tannin poisoning in eucalyptus plantation areas and for the protection of water resources.

Fine root densities of grasses and perennial sugarcane significantly reduce stream channel erosion in southern China.

Stream Channel (SC) erosion results in immense soil and nutrient losses and eutrophication of downstream lakes and rivers. Among other factors, the lack of vegetation cover within SCs and on adjacent soils can accelerate soil and nutrient losses. The combined impact of perennial sugarcane plantation and grass cover on increasing SC erosion losses have not been previously studied. Current study determined SC erosion and associated nutrient losses and clarified the effect of grass roots within SCs and the ratooned sugarcane grown on adjacent lands in Nala watershed in southern subtropics of China. Six SCs in two sub-watersheds (SW1 and SW2) surveyed after revegetation during 2019 were compared with initial survey conducted in 2017 and 2018. The SC erosion was significantly (P < 0.05) reduced by 84.2% (5.19 ± 2.16 Mg ha-1) in entire watershed in 2019 compared to 2018 (43.9 ± 15.2 Mg ha-1). It notably decreased by 99.23% and 96.50% in SC-1-3 at SW1 and SC2-3 at SW2, respectively. Total N and P losses decreased by 84.9% and 82.5%, respectively, in entire watershed. The decreases in SC erosion and nutrient losses are attributed to increasing vegetative cover (R2 = 0.7543, P < 0.001), and grass root densities of <1 mm (R2 = 0.7543, P < 0.001), 1-2 mm (R2 = 0.7051, P < 0.001) and >2 mm (R2 = 0.5746, P < 0.001). Principal component regression analysis confirmed that root densities of SC grasses, perennial sugarcane, and organic matter had positive impacts on controlling SC erosion and consequent nutrient losses.

IL-23R in laryngeal cancer: a cancer immunoediting process that facilitates tumor cell proliferation and results in cisplatin resistance.

Oncogenic pathogens can disturb tissue homeostasis and initiate immune responses for oncogenicity clearance and homeostasis restoration, while failed clearance and chronic inflammation may result in tumorigenesis. The primary tumor development will undergo a cancer immunoediting process, including three phases, termed elimination, equilibrium and escape. Importantly, immune-edited tumor cells can not only reduce immunogenic molecular expression but also manipulate cytokines within the tumor environment (TME) for immune evasion and tumor proliferation. Many studies have revealed that IL-23R performed an essential role in mucous inflammation and tumorigenesis, and the role of IL-23R, either in tumor-infiltrating lymphocytes (TILs) or within immune-edited tumor cells, remained largely unknown in laryngeal cancer (LC). Here, we separately analyzed the IL-23R expression in LC TILs and tumor cells and found that high IL-23R expression in tumor cells was associated with moderate and poor tumor differentiation and an unfavorable prognosis. Furthermore, the real-time quantitative polymerase chain reaction analysis revealed that human LC tissues overexpress signal transducers and activators of transcription 3 (STAT3), and the relevance analysis found this STAT3 overexpression had a significant correlation with IL-23R expression. Besides, we isolated and cultured IL-23R+ human tumor cells from the postoperation tumor sample of three LC patients, and found that rhIL-23 could phosphorylate STAT3 (pSTAT3, residue Y705), which resulted in cancer cell proliferation and cisplatin resistance. These results indicate that IL-23R was a Hallmark of cancer immunoediting process, and targeting IL-23 should be considered as a therapeutic option for laryngeal function preservation and survival improvement.