To investigate the effect of ARL67156, a small-molecule inhibitor of CD39, on cytotoxicity of natural killer (NK) cells against gastric cancer cells.
Human peripheral blood-derived primary NK cells ...isolated and purified using a magnetic bead antibody method were treated with 100 μmol/L ARL67156 for 24 h, and the signaling pathway of NK cell activation was detected by Western blotting. The level of interferon-γ (IFN-γ) in the supernatant of NK cells co-cultured with gastric cancer cells was detected using ELISA, and NK cell CD107a degranulation was measured with flow cytometry. The cytotoxicity of NK cells against co-cultured gastric cancer cells was evaluated using flow cytometry. In a nude mouse model bearing subcutaneous gastric cancer xenografts, the therapeutic effect of intravenous transfusion of NK cells and intraperitoneal injection of ARL67156 was assessed by measuring the changes in tumor volume.
(25.97 ± 5.69) % of peripheral blood NK cells from healthy individuals positive for CD39 expression. Trea
A novel regularized interface integral equation for three-dimensional steady state heat conduction problems with non-homogeneous inclusions is developed. The proposed formulation only contains the ...fundamental solution of isotropic matrix. As a result, the fundamental solution of non-homogeneous inclusion, usually very difficult to obtain, is avoided. Domain integrals caused by the contrast of heat conductivities between the inclusions and the matrix are converted into equivalent interface integrals using the radial integration method by expressing the temperature gradient as a series of radial basis functions. Therefore, a pure interface integral equation is obtained and there is no need to discretize the inclusion into finite elements to evaluate the domain integral. For the determination of the flux and temperature, collocation points are distributed inside the inclusion to form a system of linear equations. To eliminate the geometrical errors and study the inclusions with arbitrary geometry, bivariate Non-Uniform Rational B-Splines basis functions are used to depict the boundaries of the inclusions. Numerical results are compared with available analytical solutions or finite element solutions.
The effect of transport stress on blood metabolism, glycolytic potential, and meat quality in broilers was investigated. Arbor Acres chicks (n = 360, 1 d old, males) were randomly allotted to 1 of 5 ...treatments: unstressed control, 45-min (short-term) transport with 45-min (short-term) recovery, 45-min transport with 3-h (long-term) recovery; 3 h (long-term) transport with 45-min recovery, and 3-h transport with 3-h recovery. Each treatment consisted of 6 replicates with 12 birds each. On d 46, all birds (except the control group) were transported according to a designed protocol. Transport time affected plasma glucose level (P < 0.05) and glycogen level (P = 0.06) in breast muscle as well as the area (P < 0.01) and density (P < 0.01) of IIa fibers. Glucose concentration increased slightly during the first 45 min of transport and then decreased dramatically in the long-term transported broilers (P < 0.05). Long-term transport decreased the concentration of breast glycogen (P = 0.06) and affected the size of IIa fibers in tibialis anterior by decreasing the area (P < 0.01) with an increase in density (P < 0.01). However, a long-term recovery after transport contributed to the homeostasis of blood corticosterone (CORT, P = 0.05) and low levels of glycogen (P < 0.05), lactate (P < 0.01), and glycolytic potential (P < 0.01) in thigh muscles. Interactions existed between transport and recovery time on area (P < 0.05) and density (P < 0.01) of IIa fibers. Furthermore, plasma nonesterified fatty acids increased significantly in the 3-h transport with 3-h recovery group (P < 0.05) in comparison with the control. These results suggested that transport induced the release of plasma CORT and glycopenia, which affected the contractive status of muscle fibers by changing their area and density, and enhanced glycolysis and even lipolysis. A long-term recovery after transport was beneficial in lowering plasma CORT levels and reducing muscle glycolysis, which might improve broiler meat quality.
There has been remarkable progress during the past decade in understanding of how genetic variations in drug metabolizing enzymes and transporters contribute to observed variation in drug ...responsiveness. Among drug transporters, the organic anion transporting polypeptide (OATP) class of transporters have proven to be remarkably important to the cellular uptake disposition of a variety of clinically important drugs, particularly in organs such as the intestine and liver; we now know that altered OATP activity may confer reduced efficacy and potentially increased risk of drug-related toxicity. OATP1B1 and OATP1B3 are widely recognized liver-specific members of the family known to modulate the hepatocellular uptake of drugs from the portal vein and thereby modulate systemic exposure and hepatic substrate drug extraction. On the other hand, OATP2B1 and OATP1A2 are expressed on the apical membrane of intestinal enterocytes and though to affect absorption of its drug substrates. Accordingly, genetic variations in these OATP transporters have clinically relevant functional consequences for drug absorption, distribution and excretion, as well as pharmacodynamics response in terms of drug efficacy and toxicity. This article addresses the present evidence of relevance to genetic variations in OATP1B1, OATP1B3, OATP2B1, and OATP1A2 in terms of drug response, efficacy and optimal therapeutics.
Abstract Objective We examined the surface characteristics and corrosion properties of selective laser melted (SLM) cobalt–chromium (Co–Cr) dental alloys before and after porcelain-fused-to-metal ...(PFM) firing. Methods Samples were manufactured utilizing SLM techniques and control specimens were fabricated using traditional casting methods. The microstructure and surface composition were examined using metallographic microscopy, X-ray diffraction (XRD), and X-ray photoelectron spectroscopy (XPS). Corrosion properties were evaluated using electrochemical impedance spectroscopy. Student's t -test was used to evaluate differences in numerical results of electrochemical corrosion tests between SLM and cast specimens before or after PFM firing. The results of electrochemical corrosion tests of the SLM and cast samples before and after firing were analyzed using one-way ANOVA. Results Although PFM firing altered the microstructure of the SLM specimens, they still exhibited a compact and homogeneous structure, and XPS analysis indicated that there were no significant differences in the surface composition of the specimens after firing. In artificial saliva at pH 5, the Rp value of the SLM specimens was 6.21 MΩ cm−2 before firing and 2.84 MΩ cm−2 after firing, suggesting there was no significant difference in electrochemical corrosion properties ( P > 0.05). In artificial saliva at pH 2.5, the Rp value of the SLM group was 4.80 MΩ cm−2 before firing and 2.88 MΩ cm−2 after firing, again indicating no significant difference in electrochemical corrosion properties ( P > 0.05). At pH 2.5, there was a significant difference in corrosion behavior between the cast and SLM groups, with the Rp value of the cast group being 0.78 MΩ cm−2 vs. 2.88 MΩ cm−2 for the SLM group. Significance The improved post-firing corrosion resistance of SLM specimens provides further support for their use in prosthodontic applications, as the oral environment may become temporarily acidic following meals.
The aim of this network meta-analysis was to elucidate the efficacy and safety of various immune checkpoint inhibitors (ICIs) used in combination with chemotherapy for the treatment of non-small cell ...lung cancer (NSCLC).
Data from randomised controlled trials comparing perioperative ICI-chemotherapy and chemotherapy alone were acquired from the EMBASE, Web of Science, Cochrane Library databases, PubMed, and meeting abstracts from inception until August 2023. The endpoints for this analysis were pathological complete response, event-free survival and treatment-related adverse events of any grade or adverse events of grade 3 or higher.
In total, six randomised controlled trials with 2538 NSCLC patients were selected for this network meta-analysis. Compared with other ICIs, toripalimab + chemotherapy demonstrated increased pathological complete response rates and prolonged event-free survival in NSCLC. In patients with negative/low PD-L1 expression or squamous cell pathology, toripalimab + chemotherapy was the most effective regimen. In contrast, nivolumab + chemotherapy was preferable for patients with high PD-L1 expression or non-squamous cell pathology. Among the analysed regimens, toripalimab + chemotherapy presented the highest risk of adverse events of any grade, whereas nivolumab + chemotherapy showed the highest risk of grade 3-4 adverse events. Conversely, durvalumab + chemotherapy exhibited the lowest risk of grade 3-4 adverse events.
Among the evaluated perioperative immunochemotherapy regimens, toripalimab + chemotherapy indicated a significantly increased survival benefit for most resectable NSCLC patients. However, for high PD-L1 expression and non-squamous NSCLC patients, nivolumab + chemotherapy provided the most potent outcomes. Perioperative durvalumab + chemotherapy is a relatively safe treatment. The findings of this investigation are expected to assist clinicians in making informed decisions among promising treatment options.
Pragmatic end points, such as time-to-treatment discontinuation (TTD), defined as the date of starting a medication to the date of treatment discontinuation or death has been proposed as a potential ...efficacy end point for real-world evidence (RWE) trials, where imaging evaluation is less structured and standardized.
We studied 18 randomized clinical trials of patients with metastatic non-small-cell lung cancer (mNSCLC), initiated after 2007 and submitted to U.S. Food and Drug Administration. TTD was calculated as date of randomization to date of discontinuation or death and compared to progression-free survival (PFS) and overall survival (OS) across all patients, as well as in treatment-defined subgroups EGFR mutation-positive treated with tyrosine kinase inhibitor (TKI), EGFR wild-type treated with TKI, ALK-positive treated with TKI, immune checkpoint inhibitor (ICI), chemotherapy doublet with maintenance, chemotherapy monotherapy.
Overall across 8947 patients, TTD was more closely associated with PFS (r=0.87, 95% CI 0.86–0.87) than with OS (0.68, 95% CI 0.67–0.69). Early TTD (PFS—TTD ≥ 3months) occurred in 7.7% of patients overall, and was more common with chemo monotherapy (15.0%) while late TTD (TTD—PFS ≥ 3months) occurred in 6.0% of patients overall, and was more common in EGFR-positive and ALK-positive patients (12.4% and 22.9%). In oncogene-targeted subgroups (EGFR positive and ALK positive), median TTDs (13.4 and 14.1months) exceeded median PFS (11.4 and 11.3months).
At the patient level, TTD is associated with PFS across therapeutic classes. Median TTD exceeds median PFS for biomarker-selected patients receiving oncogene-targeted therapies. TTD should be prospectively studied further as an end point for pragmatic randomized RWE trials only for continuously administered therapies.
We fabricate transistors from chemical vapor deposition-grown monolayer MoS2 crystals and demonstrate excellent current saturation at large drain voltages (V d). The low-field characteristics of ...these devices indicate that the electron mobility is likely limited by scattering from charged impurities. The current–voltage characteristics exhibit variable range hopping at low V d and evidence of velocity saturation at higher V d. This work confirms the excellent potential of MoS2 as a possible channel-replacement material and highlights the role of multiple transport phenomena in governing its transistor action.
is an important respiratory pathogen of domestic chickens.
has been subtyped into three serogroups and nine serovars according to the Page and revised Kume schemes. The major hemagglutinin antigen of
...is HMTp210, which is a large protein of about 2000 amino acids (aa), including a 70-aa signal peptide at its N-terminal end. However, the regions important for the hemagglutination (HA) activity and serotypes of HMTp210 remain unclear. In this study we constructed a series of
strains expressing HMTp210 in-frame deletion mutants and determined their HA titers to identify the regions important for the HA activity and serotypes of HMTp210. Two distinct types of HA activities were found in HMTp210. The type 1 HA activity resided in the region spanning the full-length HA (aa 71-2084), whereas the type 2 resided in the region spanning aa 1003-2084. The putative ligand binding of the type 1 HA activity was located at aa 176-360, which had a structure similar to YadA of
. The putative ligand binding site of the type 2 HA activity was located at aa 1003-1125, which had a structure similar to UspA1 from
. The type 1 HA activity appeared to be Page serogroup specific, whereas type 2 appeared to be Kume serovar specific. Finally, sequence analyses of the regions spanning aa 1-400 and aa 1100-1600 of HMTp210 could be useful for the molecular serotyping (the Page and revised Kume schemes) of
isolates.
Purpose
The association between metabolic syndrome (MetS) and cardiovascular outcomes in patients with hypertension is still controversial. This meta-analysis sought to evaluate the association of ...MetS with cardiovascular outcomes in hypertensive patients.
Methods
Two authors comprehensively searched PubMed and Embase databases from their inception to April 18, 2020 for the longitudinal studies that evaluated the association of MetS with cardiovascular outcomes in patients with hypertension. The main outcomes were major adverse cardiovascular events (myocardial infarction, revascularization, stroke, hospitalization due to heart failure, etc.) and stroke.
Results
Eight studies consisting of 36,614 hypertensive patients were identified and analyzed. Meta-analysis indicated that MetS was associated with an increased risk of major adverse cardiovascular events (risk ratio RR 1.55; 95% confidence intervals CI 1.28–1.87), cardiovascular mortality (RR 1.44; 95%CI 1.13–1.82), and stroke (RR 1.46; 95%CI 1.22–1.75), respectively. Sensitivity analysis further confirmed the robustness of the prognostic value of MetS.
Conclusions
MetS is associated with higher risk of major adverse cardiovascular events, cardiovascular mortality, and stroke in patients with hypertension. Determination of MetS may contribute to improving cardiovascular risk stratification in hypertension.
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