Resistance Risk and Molecular Mechanism of Tomato Wilt Pathogen Fusarium oxysporum f. sp. lycopersici to Pyraclostrobin.

Tomato wilt disease caused by Fusarium oxysporum f. sp. lycopersici (Fol) results in a decrease in tomato yield and quality. Pyraclostrobin, a typical quinone outside inhibitor (QoI), inhibits the cytochrome bc1 complex to block energy transfer. However, there is currently limited research on the effectiveness of pyraclostrobin against Fol. In this study, we determined the activity of pyraclostrobin against Fol and found the EC50 values for pyraclostrobin against 100 Fol strains (which have never been exposed to QoIs before). The average EC50 value is 0.3739 ± 0.2413 µg/mL, indicating a strong antifungal activity of pyraclostrobin against Fol, as shown by unimodal curves of the EC50 values. Furthermore, we generated five resistant mutants through chemical taming and identified four mutants with high-level resistance due to the Cytb-G143S mutation and one mutant with medium-level resistance due to the Cytb-G137R mutation. The molecular docking results indicate that the Cytb-G143S or Cytb-G137R mutations of Fol lead to a change in the binding mode of Cytb to pyraclostrobin, resulting in a decrease in affinity. The resistant mutants exhibit reduced fitness in terms of mycelial growth (25 and 30 °C), virulence, and sporulation. Moreover, the mutants carrying the Cytb-G143S mutation suffer a more severe fitness penalty compared to those carrying the Cytb-G137R mutation. There is a positive correlation observed among azoxystrobin, picoxystrobin, fluoxastrobin, and pyraclostrobin for resistant mutants; however, no cross-resistance was detected between pyraclostrobin and pydiflumetofen, prochloraz, or cyazofamid. Thus, we conclude that the potential risk of resistance development in Fol toward pyraclostrobin can be categorized as ranging from low to moderate.

Effective delivery of miR-511-3p with mannose-decorated exosomes with RNA nanoparticles confers protection against asthma.

Our previous studies have shown that miR-511-3p treatment has a beneficial effect in alleviating allergic airway inflammation. Here, we sought to explore its therapeutic potential in animal models and gain a deeper understanding of its therapeutic value for asthma. miR-511-3p knockout mice (miR-511-3p-/-) were generated by CRISPR/Cas and showed exacerbated airway hyper-responsiveness and Th2-associated allergic airway inflammation compared with wild-type (WT) mice after exposed to cockroach allergen. RNA nanoparticles with mannose decorated EV-miR-511-3p were also created by loading miR-511-3p mimics into the mannose decorated EVs with engineered RNA nanoparticle PRNA-3WJ (Man-EV-miR-511-3p). Intra-tracheal inhalation of Man-EV-miR-511-3p, which could effectively penetrate the airway mucus barrier and deliver functional miR-511-3p to lung macrophages, successfully reversed the increased airway inflammation observed in miR-511-3p-/- mice. Through microarray analysis, complement C3 (C3) was identified as one of the major targets of miR-511-3p. C3 was increased in LPS-treated macrophages but decreased after miR-511-3p treatment. Consistent with these findings, C3 expression was elevated in the lung macrophages of an asthma mouse model but decreased in mice treated with miR-511-3p. Further experiments, including miRNA-mRNA pulldown and luciferase reporter assays, confirmed that miR-511-3p directly binds to C3 and activates the C3 gene. Thus, miR-511-3p represents a promising therapeutic target for asthma, and RNA nanotechnology reprogrammed EVs are efficient carriers for miRNA delivery for disease treatment.

The intrinsic resistance of Fusarium solani to the Fusarium-specific fungicide phenamacril is attributed to the natural variation of both T218S and K376M in myosin5.

Fusarium solani is responsible for causing root rot in various crops, resulting in wilting and eventual demise. Phenamacril, a specific inhibitor of myosin5 protein, has gained recognition as an effective fungicide against a broad spectrum of Fusarium species. It has been officially registered for controlling Fusarium diseases through spray application, root irrigation, and seed dipping. In this study, phenamacril was observed to exhibit negligible inhibitory effects on F. solani causing crop root rot, despite the absence of prior exposure to phenamacril. Considering the high selectivity of phenamacril, this phenomenon was attributed to intrinsic resistance and further investigated for its underlying mechanism. Sequence alignment analysis of myosin5 proteins across different Fusarium species revealed significant differences at positions 218 and 376. Subsequent homology modeling and molecular docking results indicated that substitutions T218S, K376M, and T218S&K376M impaired the binding affinity between phenamacril and myosin5 in F. solani. Mutants carrying these substitutions were generated via site-directed mutagenesis. A phenamacril-sensitivity test showed that the EC50 values of mutants carrying T218S, K376M, and T218S&K376M were reduced by at least 6.13-fold, 9.66-fold, and 761.90-fold respectively compared to the wild-type strain. Fitness testing indicated that mutants carrying K376M or T218S&K376M had reduced sporulation compared to the wild-type strain. Additionally, mutants carrying T218S exhibited an enhanced virulence compared to the wild-type strain. However, there were no significant differences observed in mycelial growth rates between the mutants and the wild-type strain. Thus, the intrinsic differences observed at positions 218 and 376 in myosin5 between F. solani and other Fusarium species are specifically associated with phenamacril resistance. The identification of these resistance-associated positions in myosin5 of F. solani has significantly contributed to the understanding of phenamacril resistance mechanisms, thereby discouraging the use of phenamacril for controlling F. solani.

Effects of Early Short-Course Corticosteroids on Immune-Related Adverse Events in Non-Small Cell Lung Cancer Patients Receiving Immune Checkpoint Inhibitors.

INTRODUCTION: In real-world practice, most non-small cell lung cancer (NSCLC) patients receiving combined immunochemotherapy are exposed to short-course corticosteroids following immune checkpoint inhibitor (ICI) infusion to prevent chemotherapy-related adverse events. However, whether this early short-course corticosteroid use prevents immune-related adverse events (irAEs) remains unknown. METHODS: Between January 1st 2015 and December 31st 2020, NSCLC patients who received at least one cycle of ICI with or without chemotherapy were enrolled. Early short-course corticosteroids were defined as corticosteroids administered following ICI injection and before chemotherapy on the same day and no longer than 3 days afterwards. The patients were categorized as either "corticosteroid group" or "non-corticosteroid group" depending on their exposure to corticosteroid premedication. The frequencies of irAEs requiring systemic corticosteroid use and irAEs leading to ICI discontinuation were compared between the two groups, and exploratory survival analyses were performed. RESULTS: Among 252 eligible patients, 137 patients were categorized as "corticosteroid group," and 115 patients as "non-corticosteroid group". The corticosteroid group enriched patients in the first-line setting (n = 75, 54.7%), compared to the non-corticosteroid group (n = 28, 24.3%). Thirty patients (21.9%) in the corticosteroid group and 35 patients (30.4%) in the non-corticosteroid group developed irAEs requiring systemic corticosteroid use (Odds ratio [OR], 0.64; 95% confidence interval [CI], 0.35 to 1.18; p = 0.15). Eight patients (5.8%) in the corticosteroid group, as compared with 18 patients (15.7%) in the non-corticosteroid group, permanently discontinued ICI due to irAEs (OR, 0.34; 95% CI, 0.12 to 0.85; p = 0.013). CONCLUSION: Early short-course corticosteroids following each ICI injection may reduce the rate of irAEs that leads to ICIs discontinuation, warranting further investigation of its prophylactic use to mitigate clinically significant irAEs.

Disparity in survival benefits of pembrolizumab between Asian and non-Asian patients with advanced cancers: A systematic review and meta-regression analysis.

BACKGROUND: Immune checkpoint inhibitors have revolutionized the treatment of malignancies. However, disproportionate enrollment among races and ethnicities places the generalizability of global trial results in doubt. METHODS: In this systematic review, phase 3 randomized controlled trials investigating pembrolizumab in advanced cancers and providing subgroup analyses of Asian and non-Asian participants were included. The primary and secondary effect measures were the mean differences (MDs) in the natural logarithms of the hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS) between these two subgroups, respectively. We used random-effects meta-analysis to calculate the pooled ratios of HRs (i.e., exp(MD)) and implemented a meta-regression analysis to identify significant covariates. RESULTS: A total of 17 and 11 trials were included in the meta-analyses of OS and PFS, respectively. These trials included 2732 (25.49%) Asian and 7000 (65.32%) non-Asian participants in the OS analysis and 1438 (22.5%) Asian and 4129 (64.61%) non-Asian participants in the PFS analysis. The pooled ratio of HRs for OS was 0.87 (95% CI: 0.76-0.99; p = 0.0391), favoring Asian participants, but no significant difference was found in PFS (pooled ratio of HRs: 0.93; 95% CI: 0.82-1.07; p = 0.2391). Both linear meta-regression analyses revealed an open-label design as a crucial covariate, which indicated more benefits for non-Asian participants. CONCLUSIONS: Compared with non-Asian patients, Asian patients with advanced cancers may derive superior OS benefits from pembrolizumab. Although the results warrant further exploration, this meta-analysis provides insight into clinical research design.

Phase/Interfacial-Engineered Two-Dimensional-Layered WSe2 Films by a Plasma-Assisted Selenization Process: Modulation of Oxygen Vacancies in Resistive Random-Access Memory.

Here, we propose phase and interfacial engineering by inserting a functional WO3 layer and selenized it to achieve a 2D-layered WSe2/WO3 heterolayer structure by a plasma-assisted selenization process. The 2D-layered WSe2/WO3 heterolayer was coupled with an Al2O3 film as a resistive switching (RS) layer to form a hybrid structure, with which Pt and W films were used as the top and bottom electrodes, respectively. The device with good uniformity in SET/RESET voltage and high low-/high-resistance window can be obtained by controlling a conversion ratio from a WO3 film to a 2D-layered WSe2 thin film. The Pt/Al2O3/(2D-layered WSe2/WO3)/W structure shows remarkable improvement to the pristine Pt/Al2O3/W and Pt/Al2O3/2D-layered WO3/W in terms of low SET/RESET voltage variability (-20/20)%, multilevel characteristics (uniform LRS/HRS distribution), high on/off ratio (104-105), and retention (∼105 s). The thickness of the obtained WSe2 was tuned at different gas ratios to optimize different 2D-layered WSe2/WO3 (%) ratios, showing a distinctive trend of reduced and uniform SET/RESET voltage variability as 2D-layered WSe2/WO3 (%) changes from 90/10 (%) to 45/55 (%), respectively. The electrical measurements confirm the superior ability of the metallic 1T phase of the 2D-layered WSe2 over the semiconducting 2H phase. Through systemic studies of RS behaviors on the effect of 1T/2H phases and 2D-layered WSe2/WO3 ratios, the low-temperature plasma-assisted selenization offers compatibility with the temperature-limited 3D integration process and also provides much better thickness control over a large area.

Embedded Integration of Sb2Se3 Film by Low-Temperature Plasma-Assisted Chemical Vapor Reaction with Polycrystalline Si Transistor for High-Performance Flexible Visible-to-Near-Infrared Photodetector.

Flexible optoelectronics have garnered considerable interest for applications such as optical communication, motion capture, biosignal detection, and night vision. Transition-metal dichalcogenides are widely used as flexible photodetectors owing to their outstanding electrical and optical properties and high flexibility. Herein, a two-dimensional (2D) Sb2Se3 film-based one transistor-one resistor (1T1R) flexible photodetector with high photosensing current and detection ranges from visible to near-infrared was developed. The flexible 1T1R was fabricated using an efficient field-effect transistor platform with the 2D Sb2Se3 film directly deposited on the sensing region using a low-temperature plasma-assisted chemical vapor reaction. The photodetector could achieve a maximum Iphoto/Idark of 15,000 under white light with a power density of 26 mW/cm2, in which the photodetector showed quick rising and falling response times of 0.16 and 0.28 s, respectively. The 2D Sb2Se3 film exhibits broadband absorption in the visible and IR regions, yielding an excellent photoresponse under laser illumination with different wavelengths. To investigate the flexibility and stability of the 1T1R photodetector, the photoresponses were measured under different bending cycles and curvatures, which maintained its functions and exhibited high stability under convex and concave bending at a curvature radius of 20 mm.

Sarcopenia and myosteatosis are associated with survival in patients receiving immunotherapy for advanced hepatocellular carcinoma.

OBJECTIVES: To investigate the association of sarcopenia, myosteatosis, and sarcopenic obesity with survival outcomes among patients who underwent immunotherapy for advanced hepatocellular carcinoma (HCC). METHODS: In this retrospective analysis, patients who initiated immunotherapy for advanced HCC were enrolled. Sarcopenia and myosteatosis were evaluated on pretreatment CT at L3 level by skeletal muscle index and mean muscle attenuation using predefined cutoff values. Sarcopenic obesity was defined as concurrent sarcopenia and body mass index > 25 kg/m2. The log-rank test and the Cox proportional hazards model were used to compare overall survival (OS) and progression-free survival (PFS). RESULTS: A total of 138 patients was included (discovery cohort n = 111, validation cohort n = 27). In the discovery cohort, patients with sarcopenia exhibited significantly poorer PFS (p = 0.048) and OS (p = 0.002) than patients without sarcopenia. Patients with myosteatosis exhibited significantly poorer PFS (p < 0.001) and OS (p < 0.001) than patients without myosteatosis. Patients with sarcopenic obesity compared to patients without sarcopenic obesity exhibited significantly poorer OS (p = 0.006) but not PFS (p = 0.31). In multivariate analysis adjusting for patient demographics, tumor extent, and liver function reserve, myosteatosis remained an independent predictor of poor PFS (p = 0.014) and OS (p = 0.007); sarcopenia remained an independent predictor for poor OS (p = 0.007). The prediction models for survival outcomes built by the discovery cohort showed similar performance in the validation cohort. CONCLUSIONS: Sarcopenia and myosteatosis are independent prognostic factors in patients who received immunotherapy for advanced HCC. KEY POINTS: • Sarcopenia and myosteatosis can be evaluated by CT at L3 level. • Sarcopenia, myosteatosis, and sarcopenic obesity were associated with poor survival outcomes in patients who underwent immunotherapy for advanced HCC. • Myosteatosis was an independent predictor of PFS and OS, and sarcopenia was independent for OS in these patients.

Rational Design on Polymorphous Phase Switching in Molybdenum Diselenide-Based Memristor Assisted by All-Solid-State Reversible Intercalation toward Neuromorphic Application.

In this work, a low-power memristor based on vertically stacked two-dimensional (2D) layered materials, achieved by plasma-assisted vapor reaction, as the switching material, with which the copper and gold metals as electrodes featured by reversible polymorphous phase changes from a conducting 1T-phase to a semiconducting 2H-one once copper cations interacted between vertical lamellar layers and vice versa, was demonstrated. Here, molybdenum diselenide was chosen as the switching material, and the reversible polymorphous phase changes activated by the intercalation of Cu cations were confirmed by pseudo-operando Raman scattering, transmission electron microscopy, and scanning photoelectron microscopy under high and low resistance states, respectively. The switching can be activated at about ±1 V with critical currents less than 10 µA with an on/off ratio approaching 100 after 100 cycles and low power consumption of ∼0.1 microwatt as well as linear weight updates controlled by the amount of intercalation. The work provides alternative feasibility of reversible and all-solid-state metal interactions, which benefits monolithic integrations of 2D materials into operative electronic circuits.

Bevacizumab and atezolizumab as first-line therapy for advanced hepatocellular carcinoma: A Taiwanese subgroup analysis on efficacy and safety.

BACKGROUND: The combination of bevacizumab and atezolizumab has been established as a standard first-line systemic treatment for unresectable hepatocellular carcinoma (HCC). We examined the treatment outcomes of patients in Taiwan who received the combination in 2 pivotal clinical trials. METHODS: All patients who resided in Taiwan, were enrolled in the IMbrave150 and GO30140 studies, and received bevacizumab and atezolizumab as the first-line systemic therapy for unresectable HCC were included. We extracted and pooled anonymous raw data from the study records. RESULTS: We enrolled 40 patients, with the median age of 62.5 years; 36 (90%) had Barcelona Clinic Liver Cancer stage C disease. The response rate was 37.5%, including 3 (7.5%) complete responses. The disease control rate was 85%. The median duration of response was 21.4 months (95% confidence interval [CI], 16.6-not estimable). The median progression-free survival (PFS) and overall survival (OS) were 8.6 (95% CI, 5.6-18.6) and 24.9 months (95% CI, 14.2-not estimable), respectively. The most common adverse events of all grades were proteinuria (50%) and hypertension (37.5%), the median onset of which were 157 and 127 days, respectively. Bevacizumab and atezolizumab treatment had to be interrupted in 20 (50%) and 13 (32.5%) patients, respectively. Among patients whose treatment duration was ≥6 months, 50% of them had to skip bevacizumab, but no signal of poorer PFS or OS was observed. CONCLUSION: In Taiwanese patients with advanced HCC, the efficacy and safety outcomes of bevacizumab and atezolizumab treatment were generally consistent with the global intent-to-treat populations.

Type II alveolar epithelial cell aryl hydrocarbon receptor protects against allergic airway inflammation through controlling cell autophagy.

Rationale: Aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor, has been considered as an important regulator for immune diseases. We have previously shown that AhR protects against allergic airway inflammation. The underlying mechanism, however, remains undetermined. Objectives: We sought to determine whether AhR specifically in type II alveolar epithelial cells (AT2) modulates allergic airway inflammation and its underlying mechanisms. Methods: The role of AhR in AT2 cells in airway inflammation was investigated in a mouse model of asthma with AhR conditional knockout mice in AT2 cells (Sftpc-Cre;AhRf/f ). The effect of AhR on allergen-induced autophagy was examined by both in vivo and in vitro analyses. The involvement of autophagy in airway inflammation was analyzed by using autophagy inhibitor chloroquine. The AhR-regulated gene profiling in AT2 cells was also investigated by RNA sequencing (RNA-seq) analysis. Results: Sftpc-Cre;AhRf/f mice showed exacerbation of allergen-induced airway hyperresponsiveness and airway inflammation with elevated Th2 cytokines in bronchoalveolar lavage fluid (BALF). Notably, an increased allergen-induced autophagy was observed in the lung tissues of Sftpc-Cre;AhRf/f mice when compared with wild-type mice. Further analyses suggested a functional axis of AhR-TGF-ß1 that is critical in driving allergic airway inflammation through regulating allergen-induced cellular autophagy. Furthermore, inhibition of autophagy with autophagy inhibitor chloroquine significantly suppressed cockroach allergen-induced airway inflammation, Th2 cytokines in BALFs, and expression of autophagy-related genes LC3 and Atg5 in the lung tissues. In addition, RNA-seq analysis suggests that autophagy is one of the major pathways and that CALCOCO2/NDP52 and S1009 are major autophagy-associated genes in AT2 cells that may contribute to the AhR-mediated cockroach allergen-induced airway inflammation and, subsequently, allergic asthma. Conclusion: These results suggest that AhR in AT2 cells functions as a protective mechanism against allergic airway inflammation through controlling cell autophagy.

Immune checkpoint inhibitors for hepatocellular carcinoma - A game changer in treatment landscape.

Rapidly expanding armamentarium of systemic therapy for advanced hepatocellular carcinoma (HCC) occurred in the recent few years. Multikinase inhibitors (MKI) or targeted therapy with antiangiogenic properties have been the focus of clinical studies in advanced HCC in the past decade. The remarkable efficacy of single agent immune checkpoint inhibitors (ICI), including nivolumab and pembrolizumab, in early phase studies led to accelerated approvals as second-line treatment for advanced HCC. The excellent toxicity profile of single agent ICI also lends support to be developed as combination therapy with other targeted therapies. The success of combining atezolizumab and bevacizumab over sorafenib as the first-line treatment in advanced HCC marked the newest paradigm shift in advanced HCC. The combination exhibited unprecedented objective response rate of 30% and a median survival of 19.2 months. Many other similar ICI-based combinations are expected to be approved in the foreseeable future. In this narrative review, the development of ICI alone and in combination in advanced HCC were described and the potential impact in all stages of HCC, safety issues of ICI-based combinations, and future perspectives were discussed.

Dendritic cell immunoreceptor drives atopic dermatitis by modulating oxidized CaMKII-involved mast cell activation.

Allergens have been identified as potential triggers in patients with atopic dermatitis (AD). Patients with AD are highly sensitive to cockroach allergen. The underlying mechanism, however, remains undetermined. Here, we established a cockroach allergen-induced AD-like mouse model, and we demonstrate that repeated exposure to cockroach allergen led to aggravated mouse skin inflammation, characterized by increased type 2 immunity, type 2 innate lymphoid cells (ILC2s), and mast cells. Increased mast cells were also observed in patients with AD. Mast cell-deficient mice (KitW-sh/W-sh) showed diminished skin inflammation, suggesting that mast cells are required in allergen-induced skin inflammation. Furthermore, DC immunoreceptor (DCIR) is upregulated in skin mast cells of patients with AD and mediates allergen binding and uptake. DCIR-/- mice or reconstituted KitW-sh/W-sh mice with DCIR-/- mast cells showed a significant reduction in AD-like inflammation. Both in vitro and in vivo analyses demonstrate that DCIR-/- mast cells had reduced IgE-mediated mast cell activation and passive cutaneous anaphylaxis. Mechanistically, DCIR regulates allergen-induced IgE-mediated mast cell ROS generation and oxidation of calmodulin kinase II (ox-CaMKII). ROS-resistant CaMKII (MM-VVδ) prevents allergen-induced mast cell activation and inflammatory mediator release. Our study reveals a DCIR/ROS/CaMKII axis that controls allergen-induced mast cell activation and AD-like inflammation.

Magnetic compression stricturoplasty in patients with severe stricture after simultaneous esophageal atresia and duodenal obstruction repair: A case report.

Combined esophageal atresia (EA), tracheoesophageal fistula (TEF) and duodenal obstruction result in various challenges in management, and a well-defined management protocol is still lacking. Esophageal stricture is the most common complication after EA repair. The use of magnetic compression alimentary tract anastomosis has been reported in children. By searching the literature, the present study reports the first case of simultaneous repair (EA repair followed by duodenal obstruction repair) and magnetic compression stricturoplasty for refractory esophageal stricture after EA repair in two male neonates. One of the neonates received delayed treatment of duodenal obstruction, and the other successfully underwent a simultaneous emergency operation of these combined anomalies. These two infants developed refractory strictures despite multiple endoscopic dilatation procedures during the postoperative follow-up period. Magnetic compression stricturoplasty procedures were successfully performed under fluoroscopic and endoscopic guidance without any leakage or complication. At the follow-up 10-months after stricturoplasty, the two patients achieved durable esophageal patency in the absence of dysphagia. Combination of early chest and abdominal X-ray detection is recommended to avoid a delayed diagnosis and treatment, as well as the synchronous operation for EA/TEF repair and duodenoduodenostomy in a single surgery for combined EA/TEF and duodenal obstructions. Therefore, magnetic compression stricturoplasty is a feasible and efficient method for establishing early patency of the esophagus in patients with refractory EA stricture.

Targeting CD38 and PD-1 with isatuximab plus cemiplimab in patients with advanced solid malignancies: results from a phase I/II open-label, multicenter study.

BACKGROUND: Preclinical data suggest that concurrent treatment of anti-CD38 and antiprogrammed death 1 (PD-1)/programmed death ligand 1 (PD-L1) antibodies substantially reduce primary tumor growth by reversing T-cell exhaustion and thus enhancing anti-PD-1/PD-L1 efficacy. METHODS: This phase I/II study enrolled patients with metastatic castration-resistant prostate cancer (mCRPC) or advanced non-small cell lung cancer (NSCLC). The primary objectives of phase I were to investigate the safety and tolerability of isatuximab (anti-CD38 monoclonal antibody)+cemiplimab (anti-PD-1 monoclonal antibody, Isa+Cemi) in patients with mCRPC (naïve to anti-PD-1/PD-L1 therapy) or NSCLC (progressed on anti-PD-1/PD-L1-containing therapy). Phase II used Simon's two-stage design with response rate as the primary endpoint. An interim analysis was planned after the first 24 (mCRPC) and 20 (NSCLC) patients receiving Isa+Cemi were enrolled in phase II. Safety, immunogenicity, pharmacokinetics, pharmacodynamics, and antitumor activity were assessed, including CD38, PD-L1, and tumor-infiltrating lymphocytes in the tumor microenvironment (TME), and peripheral immune cell phenotyping. RESULTS: Isa+Cemi demonstrated a manageable safety profile with no new safety signals. All patients experienced ≥1 treatment-emergent adverse event. Grade≥3 events occurred in 13 (54.2%) patients with mCRPC and 12 (60.0%) patients with NSCLC. Based on PCWG3 criteria, assessment of best overall response with Isa+Cemi in mCRPC revealed no complete responses (CRs), one (4.2%) unconfirmed partial response (PR), and five (20.8%) patients with stable disease (SD). Per RECIST V.1.1, patients with NSCLC receiving Isa+Cemi achieved no CR or PR, and 13 (65%) achieved SD. In post-therapy biopsies obtained from patients with mCRPC or NSCLC, Isa+Cemi treatment resulted in a reduction in median CD38+ tumor-infiltrating immune cells from 40% to 3%, with no consistent modulation of PD-L1 on tumor cells or T regulatory cells in the TME. The combination triggered a significant increase in peripheral activated and cytolytic T cells but, interestingly, decreased natural killer cells. CONCLUSIONS: The present study suggests that CD38 and PD-1 modulation by Isa+Cemi has a manageable safety profile, reduces CD38+ immune cells in the TME, and activates peripheral T cells; however, such CD38 inhibition was not associated with significant antitumor activity. A lack of efficacy was observed in these small cohorts of patients with mCRPC or NSCLC. TRIAL REGISTRATION NUMBERS: NCT03367819.

Vanadium exposure exacerbates allergic airway inflammation and remodeling through triggering reactive oxidative stress.

Background: Metal components of environmental PM2.5 are associated with the exacerbation of allergic diseases like asthma. In our recent hospital-based population study, exposure to vanadium is shown to pose a significant risk for current asthma, but the causal relationship and its underlying molecular mechanisms remain unclear. Objective: We sought to determine whether vanadium co-exposure can aggravate house dust mite (HDM)-induced allergic airway inflammation and remodeling, as well as investigate its related mechanisms. Methods: Asthma mouse model was generated by using either vanadium pentoxide (V2O5) or HDM alone or in combination, in which the airway inflammation and remodeling was investigated. The effect of V2O5 co-exposure on HDM-induced epithelial-derived cytokine release and oxidative stress (ROS) generation was also examined by in vitro analyses. The role of ROS in V2O5 co-exposure-induced cytokine release and airway inflammation and remodeling was examined by using inhibitors or antioxidant. Results: Compared to HDM alone, V2O5 co-exposure exacerbated HDM-induced airway inflammation with increased infiltration of inflammatory cells and elevated levels of Th1/Th2/Th17 and epithelial-derived (IL-25, TSLP) cytokines in the bronchoalveolar lavage fluids (BALFs). Intriguingly, V2O5 co-exposure also potentiated HDM-induced airway remodeling. Increased cytokine release was further supported by in vitro analysis in human bronchial epithelial cells (HBECs). Mechanistically, ROS, particularly mitochondrial-derived ROS, was significantly enhanced in HBECs after V2O5 co-exposure as compared to HDM challenge alone. Inhibition of ROS with its inhibitor N-acetyl-L-cysteine (NAC) and mitochondrial-targeted antioxidant MitoTEMPO blocked the increased epithelial release caused by V2O5 co-exposure. Furthermore, vitamin D3 as an antioxidant was found to inhibit V2O5 co-exposure-induced increased airway epithelial cytokine release and airway remodeling. Conclusions: Our findings suggest that vanadium co-exposure exacerbates epithelial ROS generation that contribute to increased allergic airway inflammation and remodeling.

Multifunctional Ion-Sensitive Floating Gate Fin Field-Effect Transistor with Three-Dimensional Nanoseaweed Structure by Glancing Angle Deposition Technology.

A multifunctional ion-sensitive floating gate Fin field-effect transistor (ISFGFinFET) for hydrogen and sodium detection is demonstrated. The ISFGFinFET comprises a FGFET and a sensing film, both of which are used to detect and improve sensitivity. The sensitivity of the ISFGFinFET can be adjusted by modulating the coupling effect of the FG. A nanoseaweed structure is fabricated via glancing angle deposition (GLAD) technology to obtain a large sensing area to enhance the sensitivity for hydrogen ion detection. A sensitivity of 266 mV per pH can be obtained using a surface area of 3.28 mm2 . In terms of sodium ion detection, a calix[4]arene sensing film to monitor sodium ions, obtaining a Na+ sensitivity of 432.7 mV per pNa, is used. In addition, the ISFGFinFET demonstrates the functionality of multiple ions detection simultaneously. The sensor arrays composed of 3 × 3 pixels are demonstrated, each of which comprise of an FGFET sensor and a transistor. Furthermore, 16 × 16 arrays with a decoder and other peripheral circuits are constructed and simulated. The performance of the proposed ISFGFinFET is competitive with that of other state-of-the-art ion sensors.

Epithelial Aryl Hydrocarbon Receptor Protects From Mucus Production by Inhibiting ROS-Triggered NLRP3 Inflammasome in Asthma.

Background: Despite long-standing recognition in the significance of mucus overproduction in asthma, its etiology remains poorly understood. Muc5ac is a secretory mucin that has been associated with reduced pulmonary function and asthma exacerbations. Objectives: We sought to investigate the immunological pathway that controls Muc5ac expression and allergic airway inflammation in asthma. Methods: Cockroach allergen-induced Muc5ac expression and aryl hydrocarbon receptor (AhR) signaling activation was examined in the human bronchial epithelial cells (HBECs) and mouse model of asthma. AhR regulation of Muc5ac expression, mitochondrial ROS (Mito-ROS) generation, and NLRP3 inflammasome was determined by AhR knockdown, the antagonist CH223191, and AhR-/- mice. The role of NLRP3 inflammasome in Muc5ac expression and airway inflammation was also investigated. Results: Cockroach allergen induced Muc5ac overexpression in HBECs and airways of asthma mouse model. Increased expression of AhR and its downstream genes CYP1A1 and CYP1B1 was also observed. Mice with AhR deletion showed increased allergic airway inflammation and MUC5AC expression. Moreover, cockroach allergen induced epithelial NLRP3 inflammasome activation (e.g., NLRP3, Caspase-1, and IL-1ß), which was enhanced by AhR knockdown or the antagonist CH223191. Furthermore, AhR deletion in HBECs led to enhanced ROS generation, particularly Mito-ROS, and inhibition of ROS or Mito-ROS subsequently suppressed the inflammasome activation. Importantly, inhibition of the inflammasome with MCC950, a NLRP3-specifc inhibitor, attenuated allergic airway inflammation and Muc5ac expression. IL-1ß generated by the activated inflammasomes mediated cockroach allergen-induced Muc5ac expression in HBECs. Conclusions: These results reveal a previously unidentified functional axis of AhR-ROS-NLRP3 inflammasome in regulating Muc5ac expression and airway inflammation.

MCC950 Ameliorates Acute Liver Injury Through Modulating Macrophage Polarization and Myeloid-Derived Suppressor Cells Function.

Acute liver injury (ALI) raises high mortality rates due to a rapid pathological process. MCC950, a highly selective nod-like receptor family pyrin domain containing 3 (NLRP3) inhibitor, has already been reported to show strong hepatoprotective effects in many different liver diseases. In this study, we unveiled the role of MCC950 in carbon tetrachloride (CCl4)-induced ALI and its underlying molecular mechanisms on days 1, 2, and 3. MCC950 could significantly inhibit liver injury, evidenced by decreased serum alamine aminotransferase (ALT) and aspartate aminotransferase (AST) levels on days 1 and 2, increased Albumin (ALB) level on day 3, and decreased histological score during the whole period. Moreover, lower M1 macrophage related to pro-inflammatory genes expression was observed in MCC950-treated ALI mice on day 1, while MCC950 pretreatment also polarized macrophage to M2 phenotype indicating anti-inflammatory response on days 2 and 3. Additionally, MDSC was significantly increased in blood, liver, and spleen in ALI mice at different time courses. Specifically, upregulated myeloid-derived suppressor cell (MDSC) proportions were found in blood and spleen on days 1 and 2, but showed decreased trend on day 3. However, liver MDSC numbers were increased on days 2 and 3, but no significance on day 1. In conclusion, MCC950 pretreatment alleviates CCl4-induced ALI through enhanced M2 macrophage and MDSC function at different time points of ALI. Further understanding of MCC950 in ALI may be a new potential therapeutic strategy.

Rational Design on Controllable Cation Injection with Improved Conductive-Bridge Random Access Memory by Glancing Angle Deposition Technology toward Neuromorphic Application.

A conductive-bridge random access memory (CBRAM) has been considered a promising candidate for the next-generation nonvolatile memory technology because of its excellent performance, for which the resistive switching behavior depends on the formation/dissolution of conducting filaments in an electrolyte layer originated by the cation injection from the active electrode with electrochemical reactions. Typically, the controllability of cations into the electrolyte layer is a main issue, leading to stable switching reliability. In this work, an architecture combining spike-shaped Ag electrodes created by Al2O3 nanopillar arrays as a physical diffusion barrier by glancing angle deposition technology was proposed to localize Ag cation injection for the formation of controllable filaments inside TiOx as the switching layer. Interestingly, the dimension of the Ag plugs defined by the topography of Al2O3 nanopillar arrays can control Ag cation injection to influence the dimensionality of conductive filaments. Compared to the typical planar-Ag/TiOx/Pt device, the spiked-Ag/Al2O3 nanopillar arrays/TiOx/Pt device shows improvement of endurance and voltage disturbance. With enhanced multilevel characteristics, the spiked active-metal-based CBRAM device can be expected to serve as an analogue synapse for neuromorphic applications.