Type III interferon inhibits bladder cancer progression by reprogramming macrophage-mediated phagocytosis and orchestrating effective immune responses.

BACKGROUND: Interferons (IFNs) are essential for activating an effective immune response and play a central role in immunotherapy-mediated immune cell reactivation for tumor regression. Type III IFN (λ), related to type I IFN (α), plays a crucial role in infections, autoimmunity, and cancer. However, the direct effects of IFN-λ on the tumor immune microenvironment have not been thoroughly investigated. METHODS: We used mouse MB49 bladder tumor models, constructed a retroviral vector expressing mouse IFN-λ3, and transduced tumor cells to evaluate the antitumor action of IFN-λ3 in immune-proficient tumors and T cell-deficient tumors. Furthermore, human bladder cancer samples (cohort 1, n=15) were used for immunohistochemistry and multiplex immunoflurescence analysis to assess the expression pattern of IFN-λ3 in human bladder cancer and correlate it with immune cells' infiltration. Immunohistochemistry analysis was performed in neoadjuvant immunotherapy cohort (cohort 2, n=20) to assess the correlation between IFN-λ3 expression and the pathological complete response rate. RESULTS: In immune-proficient tumors, ectopic Ifnl3 expression in tumor cells significantly increased the infiltration of cytotoxic CD8+ T cells, Th1 cells, natural killer cells, proinflammatory macrophages, and dendritic cells, but reduced neutrophil infiltration. Transcriptomic analyses revealed significant upregulation of many genes associated with effective immune response, including lymphocyte recruitment, activation, and phagocytosis, consistent with increased antitumor immune infiltrates and tumor inhibition. Furthermore, IFN-λ3 activity sensitized immune-proficient tumors to anti-PD-1/PD-L1 blockade. In T cell-deficient tumors, increased Ly6G-Ly6C+I-A/I-E+ macrophages still enhanced tumor cell phagocytosis in Ifnl3 overexpressing tumors. IFN-λ3 is expressed by tumor and stromal cells in human bladder cancer, and high IFN-λ3 expression was positively associated with effector immune infiltrates and the efficacy of immune checkpoint blockade therapy. CONCLUSIONS: Our study indicated that IFN-λ3 enables macrophage-mediated phagocytosis and antitumor immune responses and suggests a rationale for using Type III IFN as a predictive biomarker and potential immunotherapeutic candidate for bladder cancer.

OTUB1/NDUFS2 axis promotes pancreatic tumorigenesis through protecting against mitochondrial cell death.

Pancreatic cancer is one of the most fatal cancers in the world. A growing number of studies have begun to demonstrate that mitochondria play a key role in tumorigenesis. Our previous study reveals that NDUFS2 (NADH: ubiquinone oxidoreductase core subunit S2), a core subunit of the mitochondrial respiratory chain complex I, is upregulated in Pancreatic adenocarcinoma (PAAD). However, its role in the development of PAAD remains unknown. Here, we showed that NDUFS2 played a critical role in the survival, proliferation and migration of pancreatic cancer cells by inhibiting mitochondrial cell death. Additionally, protein mass spectrometry indicated that the NDUFS2 was interacted with a deubiquitinase, OTUB1. Overexpression of OTUB1 increased NDUFS2 expression at the protein level, while knockdown of OTUB1 restored the effects in vitro. Accordingly, overexpression and knockdown of OTUB1 phenocopied those of NDUFS2 in pancreatic cancer cells, respectively. Mechanically, NDUFS2 was deubiquitinated by OTUB1 via K48-linked polyubiquitin chains, resulted in an elevated protein stability of NDUFS2. Moreover, the growth of OTUB1-overexpressed pancreatic cancer xenograft tumor was promoted in vivo, while the OTUB1-silenced pancreatic cancer xenograft tumor was inhibited in vivo. In conclusion, we revealed that OTUB1 increased the stability of NDUFS2 in PAAD by deubiquitylation and this axis plays a pivotal role in pancreatic cancer tumorigenesis and development.

Preclinical evaluation of the SARS-CoV-2 Mpro inhibitor RAY1216 shows improved pharmacokinetics compared with nirmatrelvir.

Although vaccines are available for SARS-CoV-2, antiviral drugs such as nirmatrelvir are still needed, particularly for individuals in whom vaccines are less effective, such as the immunocompromised, to prevent severe COVID-19. Here we report an α-ketoamide-based peptidomimetic inhibitor of the SARS-CoV-2 main protease (Mpro), designated RAY1216. Enzyme inhibition kinetic analysis shows that RAY1216 has an inhibition constant of 8.4 nM and suggests that it dissociates about 12 times slower from Mpro compared with nirmatrelvir. The crystal structure of the SARS-CoV-2 Mpro:RAY1216 complex shows that RAY1216 covalently binds to the catalytic Cys145 through the α-ketoamide group. In vitro and using human ACE2 transgenic mouse models, RAY1216 shows antiviral activities against SARS-CoV-2 variants comparable to those of nirmatrelvir. It also shows improved pharmacokinetics in mice and rats, suggesting that RAY1216 could be used without ritonavir, which is co-administered with nirmatrelvir. RAY1216 has been approved as a single-component drug named 'leritrelvir' for COVID-19 treatment in China.

A prospective randomized double-blind study comparing the dose-response curves of epidural ropivacaine for labor analgesia initiation between parturients with and without obesity.

Background: Previous studies have explored the median effective concentration (EC50) of ropivacaine for labor epidural analgesia in parturients with obesity. However, the clinical relevance of the 90% effective concentration (EC90) remains unclear. This study aimed to determine and compare the dose-response curve of epidural ropivacaine for labor analgesia between parturients with and without obesity. Methods: Parturients were divided into two groups based on body mass index (BMI): group N, consisting of parturients with BMI <30 kg/m2, and group O, consisting of parturients with BMI >30 kg/m2. Within each group, the patients were randomized to receive one of five concentrations (0.0375%, 0.075%, 0.1125%, 0.15%, or 0.1875%) of epidural ropivacaine for labor analgesia. Analgesia was induced with a loading dose of 15 mL of the assigned concentration. Visual analogue scale (VAS) scores were recorded at baseline and 30 min post-dose to calculate the response (%) using the formula [(baseline VAS pain score-VAS pain score at 30 min)/baseline VAS pain score] ×100%. The EC50 and EC90 values were determined via nonlinear regression analysis. Results: The EC50 and EC90 values of ropivacaine were 0.061% (95% confidence interval [CI], 0.056%-0.066%) and 0.177% (95% CI, 0.152%-0.206%) in group N and 0.056% (95% CI, 0.051%-0.061%) and 0.161% (95% CI, 0.138%-0.187%) in group O, respectively. No significant differences were observed in the EC50 and EC90 values between the two groups (p-values = 0.121 and 0.351, respectively. Conclusion: In conclusion, within the parameters of this study, our findings suggest that obesity, characterized by a mean BMI value of 30.9, does not significantly influence the EC50 and EC90 values of epidural ropivacaine for labor analgesia. Further investigations are warranted to elucidate the dose-response relationship between ropivacaine and obesity with higher BMI values. Clinical trial registration: https://www.chictr.org.cn/showproj.html?proj=190747, Identifier ChiCTR2300073273.

Dissecting the roles of calcium cycling and its coupling with voltage in the genesis of early afterdepolarizations in cardiac myocyte models.

Early afterdepolarizations (EADs) are abnormal depolarizations during the plateau phase of the action potential, which are known to be associated with lethal arrhythmias in the heart. There are two major hypotheses for EAD genesis based on experimental observations, i.e., the voltage (Vm)-driven and intracellular calcium (Ca)-driven mechanisms. In ventricular myocytes, Ca and Vm are bidirectionally coupled, which can affect each other's dynamics and result in new dynamics, however, the roles of Ca cycling and its coupling with Vm in the genesis of EADs have not been well understood. In this study, we use an action potential model that is capable of independent Vm and Ca oscillations to investigate the roles of Vm and Ca coupling in EAD genesis. Four different mechanisms of EADs are identified, which are either driven by Vm oscillations or Ca oscillations alone, or oscillations caused by their interactions. We also use 5 other ventricular action potential models to assess these EAD mechanisms and show that EADs in these models are mainly Vm-driven. These mechanistic insights from our simulations provide a theoretical base for understanding experimentally observed EADs and EAD-related arrhythmogenesis.

Inhibition of HMGB1 improves experimental mice colitis by mediating NETs and macrophage polarization.

OBJECTIVE: Inflammatory bowel disease (IBD) is listed by the World Health Organization as one of the modern intractable diseases. High mobility histone box 1 (HMGB1), originally described as a non-histone nucleoprotein involved in transcriptional regulation, was later identified as a pro-inflammatory cytokine that may contribute to the pathogenesis of inflammatory diseases such as IBD. Neutrophil extracellular traps (NETs) play an important role in the pathophysiology of IBD The aim of this study was to investigate the role of HMGB1 in experimental colitis mice and its potential mechanisms of action. METHODS: We first constructed the experimental colitis mouse model. Intervention of mice by rhHMGB1 supplementation or HMGB1 inhibition. The pathological morphology of the colon was observed using HE staining. Apoptosis of colonic tissue intestinal epithelial cells was evaluated using Tunel assay. The expression of HMGB1, ZO-1 and occludin in colon tissue was detected by immunohistochemistry, ELISA and western-blot. We also assessed the effects of HMGB1 on colonic injury, NETs content, macrophage polarization and inflammatory cells in mice. The regulatory effect of HMGB1 inhibition on NETs was assessed by combining DNase I. RESULTS: Inhibition of HMGB1 significantly reduced the inflammatory model in experimental colitis mice, as evidenced by reduced body weight, increased colonic length, reduced DAI scores and apoptosis, reduced inflammatory response, and improved colonic histopathological morphology and intestinal mucosal barrier function. Meanwhile, inhibition of HMGB1 was able to reduce the expression of CD86, citH3 and MPO and increase the expression of CD206 in the colonic tissue of mice. In addition, DNase I intervention was also able to improve colonic inflammation in mice. And the best effect was observed when DNase I and inhibition of HMGB1 were intervened together. CONCLUSION: Inhibition of HMGB1 ameliorates IBD by mediating NETs and macrophage polarization.

Optimizing cervical target volume in patients with nasopharyngeal cancer based on nodal drainage distance.

OBJECTIVES: To determine the potential nodal drainage distances of nasopharyngeal carcinoma (NPC) by investigating spatial distribution of metastatic lymph nodes (LNs). METHODS: NPC patients with at least two ipsilateral metastatic LNs were enrolled. LN spreading distances were analyzed in non-restricted direction, cranial-to-caudal direction, and between the two most caudal LNs. Euclidean distance (ED) and vertical distance (VD) between any two LNs were computed. The nearest-neighbor ED and VD covering 95% of LNs or patients (p95-ED and p95-VD) were considered drainage distances, and were further validated by independent internal and external cohorts with recurrent LNs. RESULTS: In all, 5836 metastatic LNs in 948 patients were contoured. Corresponding to the three scenarios, Per-LN level, the p95-EDs were 2.83, 3.28, and 3.55 cm; and p95-VDs were 2.17, 2.32, and 2.63 cm, respectively. Per-patient level, the p95-EDs were 3.25, 3.95, and 3.81 cm; and p95-VDs were 2.67, 2.81, and 2.73 cm, respectively. In internal validation, over 95% of recurred-LNs occurred within ED of 2.91 cm and VD of 0.82 cm to the neighbor LN, and the corresponding distances in external validation were 2.77 and 0.67 cm, respectively. CONCLUSIONS: In NPC, the maximum LN drainage distance was 3.95 cm without considering the direction. Specifically, in cranial-to-caudal direction, the sufficient vertical drainage distance was 2.81 cm, indicating that a 3-cm extension from the most inferior node may be rational as caudal border of the prophylactic clinical target volume (CTV). These findings promote in-depth understanding of nodal spreading patterns, uncovering paramount evidence for individualized CTV.

NUDT21 interacts with NDUFS2 to activate the PI3K/AKT pathway and promotes pancreatic cancer pathogenesis.

BACKGROUND: NUDT21 (Nudix Hydrolase 21) has been shown to play an essential role in multiple biological processes. Pancreatic adenocarcinoma (PAAD) is one of the most fatal cancers in the world. However, the biological function of NUDT21 in PAAD remains rarely understood. The aim of this research was to identify the prediction value of NUDT21 in diagnosis, prognosis, immune infiltration, and signal pathway in PAAD. METHODS: Combined with the data in online databases, we analyzed the expression, immune infiltration, function enrichment, signal pathway, diagnosis, and prognosis of NUDT21 in PAAD. Then, the biological function of NUDT21 and its interacted protein in PAAD was identified through plasmid transduction system and protein mass spectrometry. Expression of NUDT21 was further verified in clinical specimens by immunofluorescence. RESULTS: We found that NUDT21 was upregulated in PAAD tissues and was significantly associated with the diagnosis and prognosis of pancreatic cancer through bioinformatic data analysis. We also found that overexpression of NUDT21 enhanced PAAD cells proliferation and migration, whereas knockdown NUDT21 restored the effects through in vitro experiment. Moreover, NDUFS2 was recognized as a potential target of NUDT21.We further verified that the expression of NDUFS2 was positively correlated with NUDT21 in PAAD clinical specimens. Mechanically, we found that NUDT21 stabilizes NDUFS2 and activates the PI3K-AKT signaling pathway. CONCLUSION: Our investigation reveals that NUDT21 is a previously unrecognized oncogenic factor in the diagnosis, prognosis, and treatment target of PAAD, and we suggest that NUDT21 might be a novel therapeutic target in PAAD.

High-Performance 3D Stacked Micro All-Solid-State Thin-Film Lithium-Ion Batteries Based on the Stress-Compensation Effect.

A novel all-solid-state thin-film lithium-ion battery (LIB) is presented to address the trade-off issue between the specific capacity and stabilities in a conventional LIB. Different from the conventional one, this LIB device consists of two same LIB components located at the front and back surfaces of the substrate, respectively. These two LIB components form parallel connection by using the conductive through vias distributed in the substrate. Compared with the conventional one, this LIB device doubles the areal specific capacity. More importantly, due to the stress-compensation effect, this device effectively suppresses the stress induced by its volume changes resulting from the lithiation/delithiation processes and thermal expansion. Consequently, this device shows good cycling and thermal stabilities even when working at an industrial-grade high temperature of 125 °C. To further improve the specific capacity without sacrificing the stabilities, a 3D stacked LIB is successfully realized by using this LIB device as the cell, in which each cell is parallelly connected by using the above-mentioned conductive through vias. This 3D stacked LIB is experimentally demonstrated to obtain high specific capacity (79.9 µAh cm-2 ) and good stabilities (69.3% of retained capacity after 100 cycles at 125 °C) simultaneously.

Implementation of Highly Reliable Contacts for RF MEMS Switches.

A contact is the key structure of RF MEMS (Radio Frequency Microelectromechanical System) switches, which has a direct impact on the switch's electrical and mechanical properties. In this paper, the implementation of highly reliable contacts for direct-contact RF MEMS switches is provided. As a soft metal material, gold has the advantages of low contact resistance, high chemical stability, and mature process preparation, so it is chosen as the metal material for the beam structure as well as the contacts of the switch. However, a Pt film is used in the bottom contact area to enhance the reliability of the contact. Three kinds of contacts with various shapes are fabricated using different processes. Particularly, a circular-shaped contact is obtained by dry/wet combined processes. The detailed fabrication process of the contacts as well as the Pt film on the bottom contact area are given. The experimental test shows that the contact shape has little effect on the RF performance of the switches. However, the circular contact shows better reliability than other contacts and can work well even after 1.2 × 109 cycles.

Genetic variants of ABCC8 and clinical manifestations in eight Chinese children with hyperinsulinemic hypoglycemia.

BACKGROUND: ABCC8 variants can cause hyperinsulinemia by activating or deactivating gene expression. This study used targeted exon sequencing to investigate genetic variants of ABCC8 and the associated phenotypic features in Chinese patients with hyperinsulinemic hypoglycemia (HH). METHODS: We enrolled eight Chinese children with HH and analyzed their clinical characteristics, laboratory results, and genetic variations. RESULTS: The age at presentation among the patients ranged from neonates to 0.6 years old, and the age at diagnosis ranged from 1 month to 5 years, with an average of 1.3 ± 0.7 years. Among these patients, three presented with seizures, and five with hypoglycemia. One patient (Patient 7) also had microcephaly. All eight patients exhibited ABCC8 abnormalities, including six missense mutations (c. 2521 C > G, c. 3784G > A, c. 4478G > A, c. 4532T > C, c. 2669T > C, and c. 331G > A), two deletion-insertion mutations (c. 3126_3129delinsTC and c. 3124_3126delins13), and one splicing mutation (c. 1332 + 2T > C). Two of these mutations (c. 3126_3129delinsTC and c. 4532T > C) are novel. Six variations were paternal, two were maternal, and one was de novo. Three patients responded to diazoxide and one patient responded to octreotide treatment. All there patients had diazoxide withdrawal with age. Two patients (patients 3 and 7) were unresponsive to both diazoxide and octreotide and had mental retardation. CONCLUSIONS: Gene analysis can aid in the classification, treatment, and prognosis of children with HH. In this study, the identification of seven known and two novel variants in the ABCC8 gene further enriched the variation spectrum of the gene.

Long-Term Outcomes of Endoscopic Resection versus Open Surgery for Locally Advanced Sinonasal Malignancies in Combination with Radiotherapy.

Objective Our objective was to compare the long-term outcomes of endoscopic resection versus open surgery in combination with radiotherapy for locally advanced sinonasal malignancies (SNMs). Methods Data for continuous patients with sinonasal squamous cell carcinoma and adenocarcinoma who received surgery (endoscopic or open surgery) combined with radiotherapy in our center between January 1999 and December 2016 were retrospectively reviewed. A 1:1 matching with propensity scores was performed. Overall survival (OS), progression-free survival (PFS), and local recurrence rate (LRR) were evaluated. Results We identified 267 eligible patients, 90 of whom were included after matching: 45 patients in the endoscopy group and 45 in the open group. The median follow-up time was 87 months. In the endoscopic group, 84.4% of patients received intensity-modulated radiotherapy (IMRT), with a mean gross tumor volume (GTV) dose of 68.28 Gy; in the open surgery group, 64.4% of patients received IMRT, with a mean GTV dose of 64 Gy. The 5-year OS, PFS, and LRR were 69.9, 58.6, and 24.5% in the endoscopic group and 64.6, 54.4, and 31.8% in the open surgery group, respectively. Multivariable regression analysis revealed that the surgical approach was not associated with lower OS, PFS, or LRR. The overall postoperative complications were 13% in the endoscopic group, while 21.7% in the open group. Conclusion For patients with locally advanced SNMs, minimally invasive endoscopic resection, in combination with a higher radiation dose and new radiation techniques such as IMRT, yields survival outcomes similar to those of open surgery in combination with radiotherapy.

CXCL6 promotes the progression of NAFLD through regulation of PPARα.

An increasing number of studies have shown that Nonalcoholic fatty liver disease (NAFLD) is strongly associated with obesity, insulin resistance, dyslipidemia, hypertension and metabolic syndrome, but its specific pathogenesis remains unclear. By analyzing GEO database, we found CXCL6 was upregulated in liver tissues of patients with NAFLD. We also confirmed with qPCR that CXCL6 is highly expressed in serum of patients with NAFLD. To identify the underlying impact of CXCL6 on NAFLD, we established animal and cell models of NAFLD. Similarly, we confirmed by qPCR and Western blot that CXCL6 was upregulated in the NAFLD model in vitro and vivo. After transfecting NAFLD cells with siRNA targeting CXCL6 (si-CXCL6), a series of functional experiments were carried out, and these data indicated that the inhibition of CXCL6 reduced intracellular lipid deposition, decreased AST, ALT and TG level, facilitate cell proliferation and suppress their apoptosis. Furthermore, western blot and qPCR analyses displayed that the suppression of CXCL6 could raise the PPARα expression, but PPAR α inhibitor, GW6471 could partially counteract this effect. What's more, Oil Red O staining, biochemical analyzer and TG detection kit revealed that GW6471 could reverse the inhibitory effect of si-CXCL6 on NAFLD. In summary, we provide convincing evidence that CXCL6 is markedly elevated in NAFLD, and the CXCL6/PPARα regulatory network mediates disease progression of NAFLD.

Inactivation of Carotenogenic-Biosynthesizing Genes Altered Lipids Composition and Intensity in Cronobacter sakazakii.

Cronobacter sakazakii, an opportunistic milk-borne pathogen responsible for severe neonatal meningitis and bacteremia, can synthesize yellow pigment (various carotenoids) benefiting for bacterial survival, while little literature was available about the influence of various carotenoids on bacterial resistance to a series of stresses and the characteristics of cell membrane, obstructing the development of novel bactericidal strategies overcoming the strong tolerance of C. sakazakii. Thus in this study, for the first time, five carotenogenic genes of C. sakazakii BAA-894 were inactivated, respectively, to construct a series of mutants producing various carotenoids and their effects on the cell membrane properties, and resistances to food- and host-related stresses, were investigated systematically. Furthermore, to explore its possible mode of action, comparative lipidomics analysis was performed to reveal the change of lipids that were mainly located at cell membranes. The results showed that five mutants (ΔcrtB, ΔcrtI, ΔcrtY, ΔcrtZ, and ΔcrtX) displayed negligible change in growth rate but higher permeability of the outer membrane and lower fluidity of cell membrane compared to the wild type. Besides, these mutants exhibited poorer ability of biofilm formation and lower resistances to acid, oxidative, osmotic, and desiccation stresses, indicating that different carotenoid composition significantly affected environmental tolerance of C. sakazakii. To discover the possible causes, lipidomics analysis of C. sakazakii was conducted and more than 500 lipid species belonging to 27 classes had been identified at first. Compared to that of BAA-894, the composition and relative intensity of lipid species in five mutants varied significantly, especially the monounsaturated and biunsaturated phosphatidylethanolamine. The evidence presented in this study demonstrated that the varied composition of carotenoids in C. sakazakii significantly altered the lipid profile and intensity, which maybe a crucial means to influencing the characteristics of cell membranes and resistance to environmental stresses.

Oxytocin infusion for maintenance of uterine tone under prophylactic phenylephrine infusion for prevention of post-spinal hypotension in cesarean delivery: a prospective randomised double-blinded dose-finding study.

BACKGROUND: Prior studies have shown that, when administered as an intravenous bolus to prevent uterine atony, prophylactic phenylephrine infusion increased the dose requirement of oxytocin and second-line uterotonics. For the prevention of uterine atony, oxytocin should be delivered by continuous infusion. Here, we aimed to determine the ED50 and ED90 parameters (the effective doses for 50 and 90% patients without uterine atony) of oxytocin for co-infusion with prophylactic phenylephrine during cesarean delivery. METHODS: In this prospective randomized double-blinded dose-finding study, one hundred patients were divided into four groups to receive 2.5, 5.0, 7.5, or 10 IU/h oxytocin infusion, after the umbilical cord was clamped during the study period. The uterine tone was evaluated and defined as either adequate or inadequate. Probit regression analysis was applied to calculate the ED50 and ED90 of oxytocin infusion. Uterine tone, the percentage of patients who needed additional oxytocin bolus, second-line uterotonics, side effects, estimated blood loss, and neonatal outcomes were monitored. RESULTS: The estimated ED50 and ED90 values of the oxytocin infusion doses for the prevention of uterine atony were 1.9 IU/h (95% CI -4.6-3.8) IU/h and 9.3 IU/h (95% CI 7.3-16.2) IU/h, respectively. Across groups, there was a significant linear trend between the infusion dose and the percentage of patients who required additional oxytocin (p-value = 0.002). No differences were observed in the incidence of side effects and neonatal outcomes. CONCLUSION: Under the conditions of this study, the ED90 of oxytocin infusion for the prevention of uterine atony was 9.3 IU/h, which is higher than the current recommendation. This finding is helpful for clinical practice, because of the routine use of phenylephrine in cesarean delivery. Further studies are needed to determine the appropriate initial bolus of oxytocin after neonatal delivery. TRIAL REGISTRATION: The study was registered on the Chinese Clinical Trial Register (register no. ChiCTR2200059556 ).

PD-1/L1 inhibitors can improve but not replace chemotherapy for advanced urothelial carcinoma: A systematic review and network meta-analysis.

Background: Programmed cell death-1/ligand 1 inhibitors are a new treatment strategy for advanced urothelial carcinoma. Therefore, a comparative evaluation of their efficacy and toxicity compared with chemotherapy is necessary. Methods: We comprehensively searched PubMed, Web of Science, Embase, and Cochrane Library databases and performed a meta-analysis of randomized controlled trials up to July 2021. We considered overall survival as the primary outcome, and progression-free survival, objective response rate, and treatment-related adverse events as secondary outcomes. Results: Overall, 3584 patients from five studies were evaluated. Compared with first-line chemotherapy, programmed cell death-1/ligand 1 inhibitors were significantly associated with worse progression-free survival (p < 0.001) and adverse objective response rates (p < 0.001). However, the treatments were not significantly different in terms of overall survival (p = 0.33). Compared with second-line chemotherapy, programmed cell death-1/ligand 1 inhibitors significantly improved overall survival (p < 0.001), and there was no statistically significant difference in progression-free survival (p = 0.89) or objective response rate (p = 0.34). Compared with chemotherapy, programmed cell death-1/ligand 1 inhibitors were well tolerated (first-line chemotherapy: p < 0.001; second-line chemotherapy: p < 0.001). Conclusions: The efficacy of programmed cell death-1/ligand 1 inhibitors in patients with advanced urothelial carcinoma is not superior to that of first-line platinum-based chemotherapy but is better than second-line chemotherapy; however, programmed cell death-1/ligand 1 inhibitors are safer than first- and second-line chemotherapy and have a broader prospect for use in combination therapy.

Unveiling the Mystery of LiF within Solid Electrolyte Interphase in Lithium Batteries.

Over the past decades, significant advances have been made in lithium-ion batteries. However, further requirement on the electrochemical performance is still a powerful motivator to improve battery technology. The solid electrolyte interphase (SEI) is considered as a key component on negative electrode, having been proven to be crucial for the performance, even in safety of batteries. Although numerous studies have focused on SEI in recent years, its specific properties, including structure and composition, remain largely unclear. Particularly, LiF, a common and important component in SEI, has sparked debates among researchers, resulting in divergent viewpoints. In this review, the recent research findings on SEI and delve into the characteristics of the LiF component is aim to consolidated. The cause of SEI formation and the evolution of SEI models is summarized. The distinctive properties of SEI generated on various negative electrodes is further discussed, the ongoing scholarly controversy surrounding the function of LiF within SEI, and the specific physicochemical properties about LiF and its synergistic effect in heterogeneous components. The objective is to facilitate better understanding of SEI and the role of the LiF component, ultimately contributing to the development of Li batteries with enhanced electrochemical performance and safety for battery communities.

Bone marrow mesenchymal stem cell-derived exosomal microRNA regulates microglial polarization.

Objective: This study aimed to explore the effects of bone marrow mesenchymal stem cell (BMSC)-derived exosomal miR-146a-5p on microglial polarization and the potential underlying mechanisms in oxygen-glucose deprivation (OGD)-exposed microglial cells. Methods: Exosomes were isolated from BMSCs, and their characteristics were examined. The effects of BMSC-derived exosomes on microglial polarization were investigated in OGD-exposed BV-2 cells. Differentially expressed miRNAs were identified and their biological function was explored using enrichment analyses. The regulatory role of miR-146a-5p in microglial polarization was studied via flow cytometry. Finally, the downstream target gene Traf6 was validated, and the role of the miR-146a-5p/Traf6 axis in modulating microglial polarization was investigated in OGD-exposed BV-2 cells. Results: BMSC-derived exosomes were successfully isolated and characterized. A total of 10 upregulated and 33 downregulated miRNAs were identified. Exosomal treatment resulted in significant changes in microglial polarization markers. miR-146a-5p was found to be significantly downregulated in OGD-exposed microglial cells treated with exosomes. Manipulation of miR-146a-5p expression modulated microglial polarization. Moreover, the miR-146a-5p/Traf6 axis regulated microglial polarization. Conclusion: Our findings demonstrate that BMSC-derived exosomal via miR-146a-5p modulates microglial polarization by targeting Traf6, providing a potential thermal target for the treatment of neurological diseases involving microglial activation.

Clinical Characteristics and Long-Term Outcomes following Surgery Combined with Adjuvant Radiotherapy for Patients with Frontal Sinus Malignancies.

Objectives Primary frontal sinus malignancies (FSMs) are the rarest sinonasal cancers. This study aimed to determine clinicopathologic characteristics of primary FSMs and provide long-term survival outcomes. Design This study is a retrospective review. Setting The study was conducted at a tertiary medical center. Participants Patients who participated in this study were diagnosed with primary FSMs. Main Outcome Measures Median survival time is the primary outcome measure of this study. Results In this series, the median age was 48 years (30-53 years) and all patients were male. There were five cases with squamous cell carcinoma and one with osteosarcoma. All cases presented with locally advanced disease without regional lymphatic metastasis, including five cases of stage III and one case of stage II. The two most common pathways of tumor invasion were as follows: local tumor broke posteriorly through bone wall and invaded dura mater, followed by frontal lobe; local tumor infiltrated downward through the floor of frontal sinus into ethmoid sinus, thereafter invaded laterally orbit and orbital contents. All patients received surgery followed by postoperative radiotherapy at the total doses of 50 to 75.95 Gy. Among them, only one patient underwent R0 resection, the rest of patients underwent R1/R2 resection. With a median survival time of 56 months (32-76 months), two patients receiving R1/R2 resection developed treatment failure and died within 5 years, including one case with local recurrence and one with local recurrence, thereafter distant metastasis. Conclusion The majority of FSMs presented with peripherally invasive progression lesions which led to a high ratio of R1/R2 resection. Surgery combined with postoperative radiotherapy might result in satisfactory efficacy.

Chinese stroke patients with atrial fibrillation used Robert's age-adjusted warfarin loading protocol obtained good INR results within therapeutic range.

To assess whether Roberts' age-adjusted warfarin loading protocol is effective in Chinese patients and whether the SAMeTT2R2 score can predict international normalized ratio (INR) control. Roberts' protocol for warfarin titration was applied to patients with non-valvular atrial fibrillation (NVAF) complicated with ischemic stroke at the Department of Neurology between 2014 and 2019. Clinical and sociodemographic variables were recorded. A minimum of 1-year follow-up was used to calculate the time in therapeutic range (TTR) of the INR. A total of 94 acute ischemic stroke patients with NVAF were included in the study. Seventy-seven (81.9%) of the patients had attained stable INR (2.0-3.0) at the fifth dose, and 90.0% of the patients had achieved stable INR on the ninth day. Seventeen (18.1%) of the patients had an INR > 4 during dose-adjustment period. Patients with INR > 4 had significantly lower body weight (53.8 vs. 63.1 kg, P = 0.014), lower rate of achievement of stable INR (35.3% vs. 92.2%, P = 0.000), and lower rate of TTR ≥ 65% (23.5% vs. 70.1%, P = 0.001), but with no significant increase in bleeding risk. A total of 89 patients underwent long-term INR follow-up, of which 58 (65.2%) patients achieved TTR ≥ 65%. Patients with poor TTR had significantly lower body weight (56.3 vs. 63.7 kg, P = 0.020) and lower rate of stable INR achievement (64.5% vs. 89.7%, P = 0.002). All 94 patients had SAMeTT2R2 score ≥ 2. There was no linear association between SAMeTT2R2 score and the rate of TTR ≥ 65% (Ptrend = 0.095). Chinese ischemic stroke patients with NVAF on warfarin can safely and quickly achieve therapeutic INR using Roberts' age-adjusted protocol and can obtain a good TTR. Lower body weight may be a predictor of poor TTR and INR > 4. Patients who have not attained stable INR after adjusting the dose five times are at high risk for poor TTR. SAMeTT2R2 score may not predict TTR in Chinese ischemic stroke patients with NVAF.