Crocin improves the renal autophagy in rat experimental membranous nephropathy via regulating the SIRT1/Nrf2/HO-1 signaling pathway.

Membranous nephropathy (MN) is a glomerular disease. Crocin is isolated from saffron and gardenia. Its antioxidant, anti-inflammatory, anti-hyperlipidemic, anti-atherosclerotic, anti-tumor, free-radical scavenging and neuroprotective activities have been well established. We investigated the biological functions of crocin and its related mechanisms in MN. We established an experimental passive Heymann nephritis (PHN) rat model induced by anti-Fx1A antiserum. The rats were divided into sham, sham + crocin, PHN, PHN + crocin, and PHN + enalapril groups. Blood samples and kidneys of rats were collected for estimation of biochemical parameters in serum and oxidative stress indicators in kidney tissues. Histopathological changes of renal tissues were evaluated by hematoxylin and eosin, periodic acid-Schiff (PAS) and Masson staining. The podocyte number was estimated by immunohistochemistry staining of Wilms tumor type 1 (WT1). The deposition of rat anti-rabbit IgG antibodies, complement C3 and C5b-9 was detected by immunofluorescence staining. Western blotting was performed to measure the levels of Sirtuin 1 (Sirt1), nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase 1 (HO-1) and apoptosis-related proteins. The total cholesterol, triglycerides, creatinine, blood urea nitrogen, urine volume and urine albumin of PMN rats were significantly reduced by crocin. Additionally, crocin attenuated the renal histopathological changes. Moreover, the oxidative stress damage and podocyte loss and immune injury were relieved by crocin in PHN rats. Mechanistically, crocin administration activated the Sirt1/Nrf2/HO-1 pathways. The results provide a scientific basis that crocin could alleviate MN by inhibiting immune injury and podocyte damage through activating the Sirt1/Nrf2/HO-1 pathways.

Influence of green biomass composition on the urban thermal environment in hot summer and warm winter regions: The example of Fuzhou residential area.

The aim of this study was to investigate the relationship between green biomass composition and thermal environment, as well as their optimal composition pattern. We decomposed total green biomass in a certain spatial range into two categories: trees and shrubs-grasses, with urban residential areas as sampling sites and based on aerial photography and field research data of green biomass and optimized green biomass measurement method. We analyzed the correlation between the green biomass composition indicators (shrub and grass biomass, tree canopy biomass, green biomass, mean tree canopy biomass, number of trees) and ambient temperature and humidity in different spatial ranges. The results showed that the most significant cooling and humidifying effect of different green biomass composition indicators was at 50 m below the building scale. The mean tree canopy biomass and tree canopy biomass were the key factors affecting ambient temperature and humidity, respectively, in different time periods during the day. With an average canopy biomass of about 211 m3 and 62 trees in a 50 m space, the regulation effects of trees on ambient temperature and humidity were closer to the thermal comfort requirements of human body.

Biomaterial-based scaffolds in promotion of cartilage regeneration: Recent advances and emerging applications.

Osteoarthritis (OA) poses a significant burden for countless individuals, inflicting relentless pain and impairing their quality of life. Although traditional treatments for OA focus on pain management and surgical interventions, they often fall short of addressing the underlying cause of the disease. Fortunately, emerging biomaterial-based scaffolds offer hope for OA therapy, providing immense promise for cartilage regeneration in OA. These innovative scaffolds are ingeniously designed to provide support and mimic the intricate structure of the natural extracellular matrix, thus stimulating the regeneration of damaged cartilage. In this comprehensive review, we summarize and discuss current landscape of biomaterial-based scaffolds for cartilage regeneration in OA. Furthermore, we delve into the diverse range of biomaterials employed in their construction and explore the cutting-edge techniques utilized in their fabrication. By examining both preclinical and clinical studies, we aim to illuminate the remarkable versatility and untapped potential of biomaterial-based scaffolds in the context of OA. Thetranslational potential of this article: By thoroughly examining the current state of research and clinical studies, this review provides valuable insights that bridge the gap between scientific knowledge and practical application. This knowledge is crucial for clinicians and researchers who strive to develop innovative treatments that go beyond symptom management and directly target the underlying cause of OA. Through the comprehensive analysis and multidisciplinary approach, the review paves the way for the translation of scientific knowledge into practical applications, ultimately improving the lives of individuals suffering from OA and shaping the future of orthopedic medicine.

Field observations of C2 and C3 organosulfates and insights into their formation mechanisms at a suburban site in Hong Kong.

Organosulfates (OSs) are formed from volatile organic compounds (VOCs) and their oxidation products in the presence of sulfate particles. While OSs represent an important component in secondary organic aerosol, the knowledge of their formation driving force, mechanisms, and environmental impact remain inadequately understood. In this study, we report ambient observations of C2-3 oxygenated VOCs derived OSs (C2-3 OSs) at a suburban location of Hong Kong during autumn 2016. The C2-3 OSs, including glycolaldehyde sulfate (GS), hydroxyacetone sulfate (HAS), glycolic acid sulfate (GAS), and lactic acid sulfate (LAS), were quantified/semi-quantified using offline liquid chromatography-mass spectrometry analysis of aerosol filter samples. The average sum concentration of C2-3 OSs was 36 ng/m3. Correlation analysis revealed that sulfate, surface area, and liquid water content were important factors influencing C2-3 OS formation. Online measurement with an iodide High-Resolution Time-of-Flight Chemical-Ionization Mass Spectrometer (HR-ToF-CIMS) coupled with the Filter Inlet for Gases and AEROsols (FIGAERO) was also conducted to monitor C2-3 OSs, and their potential oxygenated VOC precursors in both gas- and particle-phase, and aerosol acidity tracer simultaneously. Our measurements support that glycolaldehyde/glyoxal, hydroxyacetone, glycolic acid/glyoxal, and lactic acid/methylglyoxal are likely precursors for GS, HAS, GAS, and LAS, respectively. Additionally, we found strong correlation between C2-3 OSs and H3S2O8-, a marker for aerosol acidity, providing field observational evidence for acid-catalyzed formation of small OSs. Based on both online and offline measurements, acid-catalyzed formation mechanisms in particle/aqueous phase are proposed. Specifically, the unique structure of adjacent carbonyl and hydroxyl groups in the C2-3 oxygenated VOC precursors can facilitate the formation of (1) a five-member ring intermediate via intramolecular hydrogen bond to react with sulfur trioxide through heterogenous reaction or (2) cyclic sulfate intermediate via particle-phase reaction with sulfuric acid to generate C2-3 OSs. These proposed mechanisms provide an alternative pathway for the liquid-phase production of C2-3 OSs.

Current state of interventional procedures to treat pernicious placenta previa accompanied by placenta accreta spectrum: A review.

Pernicious placenta previa (PPP) accompanied by placenta accreta spectrum (PAS) is a life-threatening placental implantation that causes a variety of complications, including antepartum hemorrhage, postpartum hemorrhage, hemorrhagic shock, preterm birth, and neonatal asphyxia. Along with continuous improvements in medical technology, interventional procedures have been widely used to prevent intraoperative hemorrhage associated with PPP. The commonly used interventional procedures include abdominal aorta clamping, prophylactic balloon occlusion of the internal or common iliac arteries, and uterine artery embolization. The above-mentioned interventional procedures have their respective advantages and disadvantages. The best procedure for different situations continues to be debated considering the complex pattern of blood supply to the uterus in patients with PPP. The specific choice of interventional procedure depends on the clinical situation of the patient with PPP. For grade III PAS, the need for uterine artery embolization is assessed based on blood loss and preoperative hemostatic effect following abdominal aorta clamping. Repair or hysterectomy may be performed following uterine artery embolization if there is a hybrid operating room for grade III PAS patients with extensive sub-serosal penetration of the uterus and repair difficulty. For grade II PAS (shallow placental implantation), prophylactic balloon occlusion may not be necessary before surgery. Uterine artery embolization can be performed in case of postoperative hemorrhage.

Attenuation of NLRP3 Inflammasome by Cigarette Smoke is Correlated with Decreased Defense Response of Oral Epithelial Cells to Candida albicans.

BACKGROUND: It is well recognized that both smoke and Candida infection are crucial risk factors for oral mucosal diseases. The nucleotide-binding domain-like receptor family pyrin domain containing 3 (NLRP3) inflammasome and its downstream effectors, interleukin (IL)-1ß and IL-18, are pivotal to the host defense against Candida and other pathogens. METHODS: The present study was designed to explore the effects of cigarette smoke and C. albicans on the NLRP3 inflammasome and its downstream signal pathway via in vitro cell model. Oral epithelial cells (Leuk-1 cells) were exposed to cigarette smoke extract (CSE) for 3 days and/or challenged with C. albicans. RESULTS: Microscopically, Leuk-1 cells exerted a defense response to C. albicans by markedly limiting the formation of germ tubes and microcolonies. CSE clearly eliminated the defense response of Leuk-1 cells. Functionally, CSE repressed NLRP3 inflammasome, and IL-1ß and IL-18 activation induced by C. albicans in Leuk-1 cells. CONCLUSION: Our results suggested that in oral epithelial cells, the NLRP3 inflammasome might be one of the target pathways by which CSE attenuates innate immunity and leads to oral disorders.

The effects of glucocorticoid plus intravenous immunoglobulin (IVIG) vs IVIG alone on platelet activation in children with Kawasaki disease.

BACKGROUND: Even though intravenous immunoglobulin (IVIG) is a current treatment for Kawasaki disease (KD), 10-20% of patients require additional therapy. This study seeks to investigate the therapeutic effects of glucocorticoids plus IVIG on KD and to ascertain the subsequent effect on platelet activation during the acute phase. METHODS: A total of 32 children with KD were randomly classified into two groups: the experimental group (16 cases) and the control group (16 cases). The control group was exposed to IVIG (2 g/kg), whereas children in the experimental group were treated with IVIG (2 g/kg) + glucocorticoid. Peripheral venous blood samples were obtained from all participants before treatment as well as three days post-treatment to test platelet activation levels with procaspase activating compound-1 (PAC-1) antibody, Toll-like receptor 4 (TLR4), interleukin-6 (IL- 6), tumor necrosis factor-α (TNF-α), procalcitonin (PCT), and C-reactive protein (CRP). Fever duration posttreatment was documented for both groups. Additionally, the coronary arteries in both groups were evaluated during three months of treatment. RESULTS: After treatment, the experimental group had remarkably lower levels of TNF-α, CRP, PCT, IL-6, PAC- 1, and TLR4 relative to the control group. The fever persistence rate was considerably elevated in the control group compared to the experimental group (log-rank, P=0.024). In addition, the z-score of coronary artery size dropped after IVIG + glucocorticoids treatment compared to the control group, although this difference was not significant. CONCLUSIONS: The IVIG + glucocorticoids can quickly mitigate the inflammatory response and platelet activation. Moreover, it can also improve clinical symptoms in children with KD.

LncRNA CASC15 activated by TCF12 promote colorectal cancer progression via EMT.

BACKGROUND: Colorectal cancer (CRC) is one of the most common gastrointestinal malignancies. LncRNA CASC15 has also been found to play a vital role in malignant tumors. OBJECTIVE: Our objective is to explore the role of CASC15 in colorectal cancer and its regulation of EMT and to clarify the reasons for its up-regulated expression in CRC. METHODS: Quantitative real-time PCR was performed to evaluate the expression of CASC15 in CRC. The biology function of CASC15 on CRC was assessed by in vitro experiments, including CCK8, colony formation, transwell assays and flow cytometry. Luciferase reporter assays were used to confirm the regulation between TCF12 and CASC15. Quantitative real-time PCR and western blot analysis were used to evaluate the biomarkers associated with epithelial-mesenchymal transition (EMT). RESULTS: We found that CASC15 was remarkably upregulated in CRC and positively correlated with poorer relapse-free survival. CASC15 knockdown significantly suppressed the proliferation and migration of CRC. Furthermore, CASC15 downregulation mediated apoptosis of CRC. Mechanistically, TCF12 activates CASC15 transcription to mediate its up-regulation, which activates EMT and promotes CRC progression. CONCLUSION: Our study identified TCF12/CASC15/EMT as a new regulatory signal axis of CRC. CASC15 may be a new molecular marker and target for CRC.

Relationship between emotional intelligence and job stressors of psychiatric nurses: A multi-centre cross-sectional study.

AIM: To investigate the impact of socio-demographic factors and job stressors on the emotional intelligence of psychiatric nurses. BACKGROUND: Emotional intelligence plays a crucial role in enabling nurses to effectively manage their own emotions, comprehend the emotions of others and assist individuals in dealing with diverse stressors. Nevertheless, a comprehensive conceptualization of the relationship between job stressors and emotional intelligence remains lacking. DESIGN: This study employs a multi-centre cross-sectional design. METHODS: A multi-centre cross-sectional survey involving 1083 registered nurses from 11 psychiatric hospitals across four provinces in China was conducted. Non-probability sampling was utilised. The survey encompassed assessments of nurse job stressors, emotional intelligence using a scale and socio-demographic characteristics using a questionnaire. A multiple linear regression model was applied to identify significant variables associated with emotional intelligence based on demographic attributes and various nurse job stressors. The study adhered to the STROBE checklist. RESULTS: The findings revealed a noteworthy negative correlation between nurse job stressors and emotional intelligence. Socio-demographic factors and job stressors of certain nurses were able to predict emotional intelligence and its dimensions among psychiatric nurses, with percentages of 44.50%, 40.10%, 36.40%, 36.60% and 34.60%. CONCLUSION: Providing emotional intelligence training for psychiatric nurses could enhance their capacity to cope effectively with workplace stress, particularly among younger nurses who engage in limited physical activities. RELEVANCE TO CLINICAL PRACTICE: The analysis of the relationship between emotional intelligence and nurse job stressors could facilitate early detection and intervention by managers based on pertinent factors. This, in turn, could elevate the emotional intelligence level of psychiatric nurses. NO PATIENT OR PUBLIC CONTRIBUTION: This study did not recruit participants, so details of participants were not be involved.

Clinical, radiological, and pathological features of minute pulmonary meningothelial-like nodules and diffuse pulmonary meningotheliomatosis.

Background: Minute pulmonary meningothelial-like nodules (MPMNs) and diffuse pulmonary meningotheliomatosis (DPM) are both rare lung diseases that involve the proliferation of cells of meningothelial origin in the lungs. However, few studies have focused on the clinical, pathological, and radiological features of MPMNs and DPMs. Methods: The clinicopathological data of 167 cases diagnosed as MPMNs and 13 cases diagnosed as DPM in the China National Center for Respiratory Medicine were examined. Based on clinical data, CT images, and morphological features, this study analyzed the similarities and differences between MPMNs and DPM. Results: The detection rates of MPMNs and DPM were 1.9 and 0.15%, respectively. Compared to MPMNs, DPM patients were all women (100% vs. 79.4%, P = 0.066), had a younger age (51.4 ± 7.7 vs. 57.9 ± 8.5, P < 0.01), and had higher pulmonary function (P < 0.01 or P < 0.05). The chest CT of DPM patients showed diffuse ground-glass opacity nodules measuring 2.0-8.0 mm in diameter, with the number of nodules ranging from 40 to >600 per lung. There were no significant differences in nodule volume [28.0 (12.1, 65.1) mm3 vs. 28.7 (17.1, 48.9) mm3, P = 0.451] and CT values [-646.8 (-732.5, -514.5) Hu vs. -588 (-674, -480) Hu, P = 0.215] between MPMNs and DPM. MPMNs are characterized by reactive hyperplasia pulmonary nodules, which can be solitary or multiple. Conclusion: This study suggests that there are many different characteristics between patients with MPMNs and DPM. The limited findings challenge the notion that DPM is a rare subtype of MPMNS.

sEMG-Based End-to-End Continues Prediction of Human Knee Joint Angles Using the Tightly Coupled Convolutional Transformer Model.

Wearable exoskeleton robots can promote the rehabilitation of patients with physical dysfunction. And improving human-computer interaction performance is a significant challenge for exoskeleton robots. The traditional feature extraction process based on surface Electromyography(sEMG) is complex and requires manual intervention, making real-time performance difficult to guarantee. In this study, we propose an end-to-end method to predict human knee joint angles based on sEMG signals using a tightly coupled convolutional transformer (TCCT) model. We first collected sEMG signals from 5 healthy subjects. Then, the envelope was extracted from the noise-removed sEMG signal and used as the input to the model. Finally, we developed the TCCT model to predict the knee joint angle after 100 ms. For the prediction performance, we used the Root Mean Square Error(RMSE), Pearson Correlation Coefficient(CC), and Adjustment R2 as metrics to evaluate the error between the actual knee angle and the predicted knee angle. The results show that the model can predict the human knee angle quickly and accurately. The mean RMSE, Adjustment R2, and (CC) values of the model are 3.79°, 0.96, and 0.98, respectively, which are better than traditional deep learning models such as Informer (4.14, 0.95, 0.98), CNN (5.56, 0.89, 0.96) and CNN-BiLSTM (3.97, 0.95, 0.98). In addition, the prediction time of our proposed model is only 11.67±0.67 ms, which is less than 100 ms. Therefore, the real-time and accuracy of the model can meet the continuous prediction of human knee joint angle in practice.

The Effects of a Low Linoleic Acid/α-Linolenic Acid Ratio on Lipid Metabolism and Endogenous Fatty Acid Distribution in Obese Mice.

A reduced risk of obesity and metabolic syndrome has been observed in individuals with a low intake ratio of linoleic acid/α-linolenic acid (LA/ALA). However, the influence of a low ratio of LA/ALA intake on lipid metabolism and endogenous fatty acid distribution in obese patients remains elusive. In this investigation, 8-week-old C57BL/6J mice were randomly assigned to four groups: low-fat diet (LFD) as a control, high-fat diet (HFD), high-fat diet with a low LA/ALA ratio (HFD+H3L6), and high-fat diet with a high LA/ALA ratio (HFD+L3H6) for 16 weeks. Our results show that the HFD+H3L6 diet significantly decreased the liver index of HFD mice by 3.51%, as well as the levels of triacylglycerols (TGs) and low-density lipoprotein cholesterol (LDL-C) by 15.67% and 10.02%, respectively. Moreover, the HFD+H3L6 diet reduced the pro-inflammatory cytokines interleukin-6 (IL-6) level and aspartate aminotransferase/alanine aminotransferase (AST/ALT) ratio and elevated the level of superoxide dismutase (SOD) in the liver. The HFD+H3L6 diet also resulted in the downregulation of fatty acid synthetase (FAS) and sterol regulatory element binding proteins-1c (SREBP-1c) expression and the upregulation of peroxisome proliferator-activated receptor-α (PPAR-α) and acyl-CoA oxidase 1 (ACOX1) gene expression in the liver. The low LA/ALA ratio diet led to a notable increase in the levels of ALA and its downstream derivative docosahexaenoic acid (DHA) in the erythrocyte, liver, perienteric fat, epididymal fat, perirenal fat, spleen, brain, heart, and gastrocnemius, with a strong positive correlation. Conversely, the accumulation of LA in abdominal fat was more prominent, and a high LA/ALA ratio diet exacerbated the deposition effect of LA. In conclusion, the low LA/ALA ratio not only regulated endogenous fatty acid levels but also upregulated PPAR-α and ACOX1 and downregulated SREBP-1c and FAS gene expression levels, thus maintaining lipid homeostasis. Optimizing dietary fat intake is important in studying lipid nutrition. These research findings emphasize the significance of understanding and optimizing dietary fat intake.

FASN deficiency induces a cytosol-to-mitochondria citrate flux to mitigate detachment-induced oxidative stress.

Fatty acid synthase (FASN) maintains de novo lipogenesis (DNL) to support rapid growth in most proliferating cancer cells. Lipogenic acetyl-coenzyme A (CoA) is primarily produced from carbohydrates but can arise from glutamine-dependent reductive carboxylation. Here, we show that reductive carboxylation also occurs in the absence of DNL. In FASN-deficient cells, reductive carboxylation is mainly catalyzed by isocitrate dehydrogenase-1 (IDH1), but IDH1-generated cytosolic citrate is not utilized for supplying DNL. Metabolic flux analysis (MFA) shows that FASN deficiency induces a net cytosol-to-mitochondria citrate flux through mitochondrial citrate transport protein (CTP). Previously, a similar pathway has been shown to mitigate detachment-induced oxidative stress in anchorage-independent tumor spheroids. We further report that tumor spheroids show reduced FASN activity and that FASN-deficient cells acquire resistance to oxidative stress in a CTP- and IDH1-dependent manner. Collectively, these data indicate that by inducing a cytosol-to-mitochondria citrate flux, anchorage-independent malignant cells can gain redox capacity by trading off FASN-supported rapid growth.

Clinical characteristics of severe influenza virus-associated pneumonia complicated with bacterial infection in children: a retrospective analysis.

BACKGROUND: We aimed to investigate the clinical characteristics of severe influenza virus-associated pneumonia complicated with bacterial infection in children. METHODS: We retrospectively analysed data concerning 64 paediatric patients with severe influenza virus-associated pneumonia who had been treated at our hospital. The patients were divided into observation (44 patients) and control (20 patients) groups, based on the presence or absence of concomitant bacterial infection, and clinical data were compared between the groups. RESULTS: The mean age in the observation group was 2.71 ± 1.44 years, 42 (95.45%) were aged ≤ 5 years, and 18 (40.9%) had underlying diseases. The mean age in the control group was 4.05 ± 2.21 years, 13 (65%) were aged ≤ 5 years, and 3 (15%) had underlying diseases. There was a statistically significant difference in patient age and the proportion of patients with underlying diseases (P < 0.05). The observation group had higher duration of fever values, a higher number of patients with duration of fever ≥ 7 days, a higher incidence of gasping, and a higher incidence of seizures/consciousness disturbance, and the differences were statistically significant (P < 0.05). Secondary bacterial infections in the observation group were mainly due to gram-negative bacteria, with Haemophilus influenzae and Moraxella catarrhalis being the most common pathogens. The observation group had a higher proportion of patients treated in the paediatric intensive care unit and a longer hospital stay, and the differences were statistically significant (P < 0.05). CONCLUSION: Severe influenza virus-associated pneumonia complicated with bacterial infection was more common in children aged ≤ 5 years. Younger patients with underlying diseases were more susceptible to bacterial infection (mainly due to gram-negative bacteria). The timely administration of neuraminidase inhibitors and antibiotics against susceptible bacteria is likely to help improve cure rates.

Efficacy and safety of Tripterygium wilfordii multiglucoside for idiopathic membranous nephropathy: a systematic review with bayesian meta-analysis.

Background: Currently, the optimal therapy plan for idiopathic membranous nephropathy (IMN) remains controversial as there has been no comprehensive and systematic comparison of therapy plans for IMN. Therefore, in this study, a Bayesian meta-analysis was used to systematically evaluate the clinical efficacy and safety of various intervention plans involving traditional Chinese medicine TWM in the treatment of IMN. Methods: An electronic search in 7 databases was conducted from their inception to August 2022 for all published randomized controlled trials (RCTs) of various intervention plans for IMN. Network meta-analysis (NMA) was performed by using software R, and the surface under the cumulative ranking area (SUCRA) probability curve was plotted for each outcome indicator to rank the efficacy and safety of different intervention plans. Results: A total of 30 RCTs were included, involving 13 interventions. The results showed that (1) in terms of total remission (TR), ① GC + CNI + TWM was the best effective among all plans, and the addition and subtraction plan of CNI + TWM was the best effective for IMN; ② All plans involving TWM were more effective than GG; ③ Among monotherapy plans for IMN, TWM was more effective distinctly than GC, while TWM and CNI were similarly effective; ④ Among multidrug therapy plans for IMN, the addition of TWM to previously established therapy plans made the original plans more effective; ⑤The efficacy of combining TWM with other plans was superior to that of TWM alone. (2) In terms of lowering 24 h-UTP, GC + TWM was the best effective and more effective than TWM. (3) In terms of safety, there was no statistically significant difference between all groups. However, CNI + TWM was the safest. No serious adverse events (AEs) occurred in all the included studies. Conclusion: The addition of TWM may be beneficial to patients with IMN. It may enhance the efficacy of previously established treatment protocols without leading to additional safety risks. In particular, GC + CNI + TWM, GC + TWM, and CNI + TWM with better efficacy and higher safety can be preferred in clinical decision-making as the therapy plans for IMN.

Nimotuzumab Plus Gemcitabine for K-Ras Wild-Type Locally Advanced or Metastatic Pancreatic Cancer.

PURPOSE: In a phase IIb trial of nimotuzumab plus gemcitabine, substantial clinical benefits were observed in patients with locally advanced or metastatic pancreatic cancer (PC). Therefore, we conducted a phase III clinical study to verify the efficacy and safety of this combination regimen in patients with K-Ras wild-type tumors (ClinicalTrials.gov identifier: NCT02395016). PATIENTS AND METHODS: Eligible patients were randomly assigned to receive nimotuzumab (400 mg once per week) or placebo followed by gemcitabine (1,000 mg/m2 on days 1, 8, and 15, once every 4 weeks) until disease progression or unacceptable toxicity. The primary end point was overall survival (OS) and the secondary end points were progression-free survival (PFS), response rates, and safety. RESULTS: A total of 480 patients were screened; 92 patients were enrolled and 82 patients with K-Ras wild-type tumors were eligible. In the full analysis set, the median OS was 10.9 versus 8.5 months, while the restricted mean survival time (RMST) was 18.05 versus 11.14 months for the investigational versus control arm (ratio of control v investigation = 0.62 [0.40-0.97]; P = .036). Median PFS was 4.2 versus 3.6 months in the investigational versus control arm (log-rank P = .04; hazard ratio, 0.60 [0.37-0.99]) and the restricted mean PFS time was 8.08 versus 4.76 months (RMST ratio, 0.58 [0.38-0.90]; P = .036). Both OS and PFS were longer in the nimotuzumab group than in the placebo group. The objective response rates and disease control rates were 7% versus 10% and 68% versus 63% for the investigational and control groups, respectively. The incidence of adverse events were comparable between the two groups. CONCLUSION: In patients with locally advanced or metastatic K-Ras wild-type PC, nimotuzumab plus gemcitabine significantly improved OS and PFS with a good safety profile.

Spatial nanopores promote laccase degradation of bisphenol A and its analogs.

Bisphenol A (BPA) and its analogs are endocrine-disrupting chemicals that are frequently detected in environmental and human samples. However, the effective removal of BPA and its analogs has not yet been extensively studied. Herein, we introduce a novel enzyme reactor for the degradation of BPA and its analogs in water. The influence of pore size on the degradation efficiency of immobilized laccase in the spatial nanopores of hydrogel was investigated using BPA as a representative compound. This showed that nanopores enhance the activity of immobilized laccases in a pore size-dependent manner and increase their stability. Compared with the same amount of free laccase, the 50 mg/L BPA degradation performance of laccase immobilized in 76 nm nanopores increased to 300 %. Taking advantage of magnetic separation, this immobilized laccase can be reused, and its degradation capacity was maintained at over 73.7 % after ten reactions. Moreover, the degradation of seven BPA analogs was 1.03-5.88 times higher using laccase immobilized in nanopores compared with free laccase. Also, the biocatalyst could efficiently degrade BPA analogs in real water matrix. This study opens up a new avenue for the removal of BPA and its analogs by immobilizing laccase in nanopores, overcoming the key limitations introduced by the short enzyme life span and non-reusability.

Highly Efficient Production of UDP-Glucose from Sucrose via the Semirational Engineering of Sucrose Synthase and a Cascade Route Design.

Nucleotide sugars are essential precursors for carbohydrate synthesis but are in scarce supply. Uridine diphosphate (UDP)-glucose is a core building block in nucleotide sugar preparation, making its efficient synthesis critical. Here, a process for producing valuable UDP-glucose and functional mannose from sucrose was established and improved via a semirational sucrose synthase (SuSy) design and the accurate D-mannose isomerase (MIase) cascade. Engineered SuSy exhibited enzyme activity 2.2-fold greater than that of the WT. The structural analysis identified a latch-hinge combination as the hotspot for enhancing enzyme activity. Coupling MIase, process optimization, and reaction kinetic analysis revealed that MIase addition during the high-speed UDP-glucose synthesis phase distinctly accelerated the entire process. The simultaneous triggering of enzyme modules halved the reaction time and significantly increased the UDP-glucose yield. A maximum UDP-glucose yield of 83%, space-time yield of 70 g/L/h, and mannose yield of 32% were achieved. This novel and efficient strategy for sucrose value-added exploitation has industrial promise.

Toll-like Receptor Agonist CBLB502 Protects Against Cisplatin-induced Liver and Kidney Damage in Mice.

BACKGROUND/AIM: CBLB502, a Toll-like receptor-5 agonist derived from Salmonella flagellin, exerts protective roles against irradiation and chemical drugs in mammalian tissues and stimulates tissue regeneration. This study aimed to investigate whether CBLB502 can protect against liver and kidney damage induced by the chemotherapeutic drug cisplatin (CDDP) and the underlying mechanism of the protective effect. MATERIALS AND METHODS: Mice were pretreated with CBLB502 [0.2 mg/kg, intraperitoneal (i.p.) injection] 0.5 h prior to administration of CDDP (20 mg/kg, i.p. injection), and analyses of the liver and kidney indices, blood biochemistry, and histopathology were performed. RESULTS: Pretreatment with CBLB502 alleviated CDDP-induced liver and kidney damage. RNA sequencing and bioinformatic analysis indicated that CDDP induced a similar damage-promoting gene regulation pattern in the liver and kidney. CBLB502 protected against liver and kidney damage only after CDDP treatment primarily via different pathways. However, some CBLB502-regulated genes were common between the liver and kidney, including those involved in blood coagulation, fibrinolysis, hemostasis, apoptotic regulation, NF-kappaB signaling, and response to lipopolysaccharide, suggesting a general protective effect by CBLB502. CONCLUSION: Our data provide insights into the protective mechanism of CBLB502 against CDDP-induced tissue damage in the liver and kidney and might provide a basis for future studies on functional genes and regulatory mechanisms that mediate protection against chemoradiotherapy-induced damage.

R-loop-dependent promoter-proximal termination ensures genome stability.

The proper regulation of transcription is essential for maintaining genome integrity and executing other downstream cellular functions1,2. Here we identify a stable association between the genome-stability regulator sensor of single-stranded DNA (SOSS)3 and the transcription regulator Integrator-PP2A (INTAC)4-6. Through SSB1-mediated recognition of single-stranded DNA, SOSS-INTAC stimulates promoter-proximal termination of transcription and attenuates R-loops associated with paused RNA polymerase II to prevent R-loop-induced genome instability. SOSS-INTAC-dependent attenuation of R-loops is enhanced by the ability of SSB1 to form liquid-like condensates. Deletion of NABP2 (encoding SSB1) or introduction of cancer-associated mutations into its intrinsically disordered region leads to a pervasive accumulation of R-loops, highlighting a genome surveillance function of SOSS-INTAC that enables timely termination of transcription at promoters to constrain R-loop accumulation and ensure genome stability.