Abatacept and non-melanoma skin cancer in patients with rheumatoid arthritis: a comprehensive evaluation of randomised controlled trials and observational studies.

OBJECTIVES: This study aims to evaluate non-melanoma skin cancer (NMSC) risk associated with abatacept treatment for rheumatoid arthritis (RA). METHODS: This evaluation included 16 abatacept RA clinical trials and 6 observational studies. NMSC incidence rates (IRs)/1000 patient-years (p-y) of exposure were compared between patients treated with abatacept versus placebo, conventional synthetic (cs) disease-modifying antirheumatic drugs (DMARDs) and other biological/targeted synthetic (b/ts)DMARDs. For observational studies, a random-effects model was used to pool rate ratios (RRs). RESULTS: ~49 000 patients receiving abatacept were analysed from clinical trials (~7000) and observational studies (~42 000). In randomised trials (n=4138; median abatacept exposure, 12 (range 2-30) months), NMSC IRs (95% CIs) were not significantly different for abatacept (6.0 (3.3 to 10.0)) and placebo (4.0 (1.3 to 9.3)) and remained stable throughout the long-term, open-label period (median cumulative exposure, 28 (range 2-130 months); 21 335 p-y of exposure (7044 patients over 3 years)). For registry databases, NMSC IRs/1000 p-y were 5-12 (abatacept), 1.6-10 (csDMARDs) and 3-8 (other b/tsDMARDs). Claims database IRs were 19-22 (abatacept), 15-18 (csDMARDs) and 14-17 (other b/tsDMARDs). Pooled RRs (95% CIs) from observational studies for NMSC in patients receiving abatacept were 1.84 (1.00 to 3.37) vs csDMARDs and 1.11 (0.98 to 1.26) vs other b/tsDMARDs. CONCLUSIONS: Consistent with the warnings and precautions of the abatacept label, this analysis suggests a potential increase in NMSC risk with abatacept use compared with csDMARDs. No significant increase was observed compared with b/tsDMARDs, but the lower limit of the 95% CI was close to unity.

Comparison of efficacy and safety of PD-1/PD-L1 combination therapy in first-line treatment of advanced NSCLC: an updated systematic review and network meta-analysis.

BACKGROUND: The use of immune checkpoint inhibitors has led to an increase in randomized controlled trials exploring various first-line combination treatment regimens. With the introduction of new PD-1/PD-L1 inhibitors, there are now more clinical options available. For the first time, the AK105 monoclonal antibody Penpulimab, developed in China, was included. The AK105-302 Phase III trial studied the efficacy and safety of Penpulimab combined with chemotherapy in patients with advanced or metastatic squamous NSCLC. To determine the optimal treatment options, we conducted an updated network meta-analysis to compare the effectiveness and safety of these regimens. METHODS: The system retrieves data from Chinese and English electronic databases, Clinical Trials, and the gov Clinical Trial Registration website up to September 6, 2023. The study indirectly compared the efficacy and safety of PD-1/PD-L1 combination regimens, including overall survival (OS), progression-free survival (PFS), objective response rate (ORR), all-grade adverse events, and above-grade III adverse events. Subgroup analyses were conducted based on programmed death ligand 1 (PD-L1) level, histological type, ECOG score, sex, and smoking history. RESULTS: Nineteen RCTS were included, with a total of ten thousand eight hundred patients. Penpulimab plus chemotherapy (Pen + CT) provided the best OS (HR = 0.55, 95% CI 0.38-0.81) for PD-L1 patients with non-selective advanced NSCLC. Except Nivolumab plus Ipilimumab (Niv + Ipi), other PD-1/PD-L1 combination therapies significantly extended PFS compared with CT, and Nivolumab plus Bevacizumab combined with chemotherapy (Niv + Bev + CT) (HR = 0.43, 95% CI 0.26-0.74) provided the best PFS benefit and was comparable to Pen + CT (HR = 1.0) for PFS prolongation. For ORR, except Niv + Ipi, all the other regimens significantly improved ORR compared with CT. In terms of safety, except Tor + CT, the incidence of any-grade AEs or grade ≥ 3 adverse events may be higher than those of chemotherapy. The subgroup analysis revealed that for patients with PD-L1 levels below 1%, treatment with Tor + CT resulted in the best progression-free survival (HR = 0.47, 95% CI 0.25-0.86). For patients with PD-L1 levels of 1% or higher, Sintilimab plus chemotherapy (Sin + CT) (HR = 0.56, 95% CI 0.31-0.99) and Camrelizumab plus chemotherapy (Cam + CT) (HR = 0.43, 95% CI 0.28-0.64) were associated with the best overall survival and progression-free survival, respectively. For patients with SqNSCLC, combined immunotherapy may provide greater survival benefits. For patients with Non-sqNSCLC, Niv + Bev + CT and Tor + CT were associated with optimal PFS and OS, respectively. Cam + CT provided the best PFS in male patients with a history of smoking and an ECOG score of 0. In both female and non-smoking patient subgroups, Pem + CT was associated with the best PFS and OS benefits. CONCLUSION: For patients with advanced non-selective PD-L1 NSCLC, two effective regimens are Pen + CT and Niv + Bev + CT, which rank first in OS and PFS among all patients. Cam + CT and Tor + CT have advantages for OS in patients with SqNSCLC and Non-sqNSCLC, respectively. Niv + Ipi + CT provided the best OS benefit for patients with an ECOG score of 0, while Pem + CT may be the most effective treatment for patients with an ECOG score of 1. Pem + CT has a better effect on female patients and non-smokers. Sin + CT was found to be the most effective treatment for male patients and the smoking subgroup, while Cam + CT was found to be the most effective for PFS. In addition, Tor + CT was associated with the best PFS for patients with negative PD-L1 expression. Pem + CT was found to significantly improve both PFS and OS compared to CT alone. For patients with positive PD-L1 expression, Sin + CT and Cam + CT were found to be optimal for OS and PFS, respectively. It is important to note that, with the exception of Tor + CT, the toxicity of the other combinations was higher than that of CT alone.

The prognostic value of absolute lymphocyte count and neutrophil-to-lymphocyte ratio for patients with metastatic breast cancer: a systematic review and meta-analysis.

Background: Neutrophil-to-lymphocyte ratio (NLR) is considered a potential prognostic marker in early breast cancer. However, the prognosis of absolute lymphocyte count (ALC) and NLR in metastatic breast cancer (MBC) has been reported in a few studies, and conclusions are still conflicting. This present manuscript aims to provide further solid evidence regarding the prognostic values of ALC and NLR in MBC patients. Method: Eligible studies that reported the associations between ALC or NLR and MBC were included by searching relative electronic databases. Overall survival (OS) and progression-free survival (PFS) were used as outcome measures. The hazard ratio (HR) values and 95% confidence interval (CI) of the outcome measures were collected as effect sizes, and further analysis and discussion were conducted according to the pooled HR, subgroup analysis, publication bias, and interstudy heterogeneity. Results: Twenty-nine studies comprising 3,973 patients with MBC were included. According to our findings, lower ALC was significantly associated with poorer prognosis of OS (HR = 0.57, 95% CI 0.48 to 0.68) and PFS (HR = 0.68, 95% CI 0.58 to 0.79), and greater NLR was associated with poorer OS (HR = 1.50, 95% CI 1.35 to 1.67) and PFS (HR = 1.82, 95% CI 1.42 to 2.35). Furthermore, the prognostic values of ALC and NLR in MBC were also observed in the subgroup analyses regarding cutoff values and ethnicities. Conclusion: Low ALC and elevated NLR were observed to be significantly associated with adverse OS and PFS in MBC, indicating that ALC and NLR may act as potential prognostic biomarkers of MBC patients. Meanwhile, our results will also provide some novel evidence and research clues for the selection and development of clinical treatment strategies for MBC patients. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42021224114.

Calycosin inhibits hepatocyte apoptosis in acute liver failure by suppressing the TLR4/NF-κB pathway: An in vitro study.

BACKGROUND: Acute liver failure (ALF) is a serious liver disease that is difficult to treat owing to its unclear pathogenesis. This study aimed to investigate the roles and molecular mechanisms of calycosin (CA) in ALF. METHODS: In this study, the roles and mechanism of CA in ALF were explored using an in vitro lipopolysaccharide (LPS)-induced ALF cell model. Additionally, 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyltetrazolium bromide assay was used to assess the effect of CA on the activity of LPS-induced L02 human liver epithelial cells, and flow cytometry was used to detect apoptosis in L02 cells. Expression levels of apoptosis-related genes, Bax and Bcl-2, were measured using reverse transcription-quantitative polymerase chain reaction and Western blot analysis. Expression levels of inflammatory factors in LPS-induced L02 cells were measured using an enzyme-linked immunosorbent assay. Additionally, the effect of CA on ALF was inhibited via transfection of a toll-like receptor 4 (TLR4)-plasmid to elucidate the relationship between CA and TLR4/nuclear factor (NF)-κB signaling pathway in ALF. RESULTS: CA had no toxic effects on L02 cells, but enhanced the activity of LPS-induced L02 cells in a dose-dependent manner. Apoptosis and inflammatory factor release was increased in ALF, activating the TLR4/NF-κB signaling pathway. However, CA treatment inhibited the apoptosis and release of inflammatory factors. Further mechanistic studies revealed that the upregulation of TLR4 expression reversed the alleviating effects of CA on inflammation and apoptosis in LPS-induced L02 cells. CONCLUSION: CA alleviates inflammatory damage in LPS-induced L02 cells by inhibiting the TLR4/NF-κB pathway and may be a promising therapeutic agent for ALF treatment.

Induction of GM1a/GD1b synthase triggers complex ganglioside expression and alters neuroblastoma cell behavior; a new tumor cell model of ganglioside function.

Neuroblastoma is the most common extracranial solid tumor in children and tumor ganglioside composition has been linked to its biological and clinical behavior. We recently found that high expression of complex gangliosides that are products of the enzyme GM1a/GD1b synthase predicts a more favorable outcome in human neuroblastoma, and others have shown that complex gangliosides such as GD1a inhibit metastasis of murine tumors. To determine how a switch from structurally simple to structurally complex ganglioside expression affects neuroblastoma cell behavior, we engineered IMR32 human neuroblastoma cells, which contain almost exclusively (89%) the simple gangliosides (SG) GM2, GD2, GM3, and GD3, to overexpress the complex gangliosides (CG) GM1, GD1a, GD1b and GT1b, by stable retroviral-mediated transduction of the cDNA encoding GM1a/GD1b synthase. This strikingly altered cellular ganglioside composition without affecting total ganglioside content: There was a 23-fold increase in the ratio of complex to simple gangliosides in GM1a/GD1b synthase-transduced cells (IMR32-CG) vs. wild type (IMR32) or vector-transfected (IMR32-V) cells with essentially no expression of the clinical neuroblastoma marker, GD2, confirming effectiveness of this molecular switch from simple to complex ganglioside synthesis. Probing for consequences of the switch, we found that among functional properties of IMR32-CG cells, cell migration was inhibited and Rho/Rac1 activities were altered, while proliferation kinetics and cell differentiation were unaffected. These findings further implicate cellular ganglioside composition in determining cell migration characteristics of tumor cells. This IMR32 model system should be useful in delineating the impact of ganglioside composition on tumor cell function.

Risk of opportunistic infections in patients with rheumatoid arthritis initiating abatacept: cumulative clinical trial data.

BACKGROUND: To evaluate incidence of opportunistic infections (OIs) in patients with rheumatoid arthritis (RA) treated with abatacept in clinical trials. METHODS: This pooled analysis of 16 randomized, double-blind/open-label trials, with ≥ 1 abatacept (intravenous or subcutaneous) arm, and with/without placebo control covered cumulative (controlled short-term and open-label long-term) abatacept exposure periods. OIs were analyzed separately in controlled (abatacept and placebo individually) and cumulative periods. OIs were identified using a prespecified list; events were independently adjudicated. Unadjusted incidence rates (IRs; per 100 patient-years) with 95% confidence intervals (CIs) were calculated. RESULTS: In cumulative periods, 7044 patients received abatacept, with a mean (standard deviation) duration of exposure of 36.9 (26.2) months (21,274 patient-years of exposure). IRs (95% CIs) of OIs were 0.17 (0.05-0.43) for abatacept and 0.56 (0.22-1.15) for placebo during the controlled periods and 0.21 (0.15-0.28) for abatacept during the cumulative periods. There was 1 case of tuberculosis in both the abatacept (IR [95% CI] 0.04 [0.00-0.24]) and placebo (IR [95% CI] 0.08 [0.00-0.44]) groups during the controlled periods; 13 verified tuberculosis cases (IR [95% CI] 0.06 [0.03-0.10]) were reported in the cumulative period. Herpes zoster was reported numerically more often with abatacept (IR 1.9 [1.4-2.5]), versus placebo (1.7 [1.1-2.6]) in the controlled periods; within the cumulative period, herpes zoster IR (95% CI) was 1.53 (1.36-1.71) for abatacept-treated patients. CONCLUSION: In controlled periods of the clinical trials, abatacept-treated patients had similarly low rates of OIs compared with placebo-treated patients. Overall, OI rates were similar among abatacept-treated patients in the controlled and cumulative periods and consistent with the ranges reported in the literature.

[Arsenic speciation and bioavailability in the Yangtze estuary in spring, 2006].

Field work was conducted in the Yangtze (Changjiang River) estuary in April, 2006. Water and surface sediment samples were collected to analyze total arsenic and different arsenic species, and to assess the bioavailability. Water samples were filtered through 0.45 microm filter membrane to determine the concentrations of dissolved arsenic, while the unfiltered water samples were digested by acid to determine the concentrations of total arsenic, and the difference between them was the concentrations of particulate arsenic. It is showed that the concentrations of total arsenic varied from 0.88 microg x L(-1) to 1.35 microg x L(-) at the slack of flood tide, and from 2.37 microg x L(-1) to 3.35 microg x L(-1) at the slack of ebb tide in water column of the Qingcaosha waters in the Yangtze estuary. The concentrations of both dissolved and particulate arsenic varied with the tide time. The concentrations of arsenic species at the slack of ebb tide were higher than those at the slack of flood tide, so did the percentage of particulate arsenic accounting for total arsenic. Phosphoric acid of 0.3 mol x L(-1) can effectively extract arsenate, arsenite, monomethylarsenate (MMA) and dimethylarsenite (DMA) from the sediments with the aid of microwave. The arsenic species in the extracts were detected by the hyphenated method of High Performance Liquid Chromatography-Hydrogenation-Atom Absorption Spectrometry (HPLC-HGAAS). The concentrations of total arsenic in surface sediments varied between 6.3 mg x kg(-1) and 30.7 mg x kg(-1), which were mainly contributed by inorganic arsenic species. Arsenate was dominated in the sediments in the offshore waters while arsenite was dominated in the sediments in longshore waters. The concentrations of available arsenic in the sediments, which were estimated by the method of acetate cellulose composite membrane embedded with iron oxides (FeO/CAM), accounted for 0.6% to 3.9% (averaged as 2.1%) of the total arsenic concentrations. The available arsenic concentrations had no significant correlation with the total arsenic concentrations, but had significant positive correlation with the arsenate concentrations and had significant negative correlation with the arsenite concentrations. The results also showed that the distribution of arsenic species in the sediments and their bioavailability in the South Branch of the Yangtze estuary were significantly influenced by the tributary river flows and effluents from the urban area.

[Determination of triazines in surface water using solid phase extraction-high performance liquid chromatography].

A method was developed to monitor triazines in surface water using the combination of solid phase extraction (SPE) and high performance liquid chromatography. Four different SPE cartridges were tested for extracting six triazines, including atrazine (A), simazine (S), prometryn (P), desethylatrazine (DEA), 2-hydroxyatrazine (OHA) and desisopropylatrazine (DIA), and finally ENVI-18 was selected as optimal. The method for solid phase extraction was further systematically studied for details. Optimal results of orthogonal design were determined as follows: pH 6, 5 mL methanol as eluting solvent, and no methanol added into water sample before extraction. The detection limits of six triazines were 0.14 microg/L for P, 0.12 microg/L for A, 0.08 microg/L for S, 0.08 microg/L for DEA, 0.10 microg/L for OHA and 0.18 microg/L for DIA. This method was applied for environmental aquatic samples, and the results showed that the concentration of prometryn in a lake was detected as (9.33 +/- 0.27) microg/L, as well as the concentrations of atrazine and prometryn in a river were detected as (5.28 +/- 0.43) microg/L and (7.12 +/- 0.54) microg/L respectively.

Role of the N-terminus in permeability of chicken connexin45.6 gap junctional channels.

Previous studies have shown that gap junctional channels formed from the lens connexins Cx50 (or its chicken orthologue, Cx45.6) and Cx43 exhibit marked differences in transjunctional voltage gating and unitary conductance. In the present study, we used the negatively charged dye, Lucifer Yellow (LY), to examine and compare quantitative differences in dye transfer between pairs of HeLa cells stably transfected with Cx45.6 or Cx43. Our results show that Cx45.6 gap junctional channels are three times less permeable to LY than Cx43 channels. Replacement of the N-terminus of Cx45.6 with the corresponding domain of Cx43 increased LY permeability, reduced the transjunctional voltage (V(j)) gating sensitivity, and reduced the unitary conductance of Cx45.6-43N gap junctional channels. Further experiments, using a series of Alexa probes that had similar net charge but varied in size showed that the Cx45.6-43N had a significantly higher permeability for the two largest Alexa dyes than Cx45.6. These data suggest that the N-terminus plays a critical role in determining many of biophysical properties of Cx45.6 gap junctional channels, including molecular permeability and voltage gating.

Exchange of gating properties between rat cx46 and chicken cx45.6.

Cx46 and Cx50 are coexpressed in lens fiber cells where they form fiber-fiber gap junctions. Recent studies have shown that both proteins play a critical role in maintaining lens transparency. Although both Cx46 and Cx50 (or its chicken ortholog, Cx45.6) show a high degree of sequence homology, they exhibit marked differences in gap junctional channel gating, unitary gap junctional channel conductance, and hemichannel gating. To better understand which regions of the protein are responsible for these functional differences, we have constructed a series of chimeric Cx46-Cx45.6 gap junctional proteins in which a single transmembrane or intracellular domain of Cx45.6 was replaced with the corresponding domain of Cx46, expressed them in Xenopus oocyte pairs or N2A cells, and examined the resulting gap junctional conductances. Our results showed that four out of six of the chimeras induced high levels of gap junctional coupling. Of these chimeras, only Cx45.6-46NT showed significant changes in voltage-dependent gating properties. Exchanging the N-terminus had multiple effects. It slowed the inactivation kinetics of the macroscopic junctional currents so that they resembled those of Cx46, reduced the voltage sensitivity of the steady-state junctional conductance, and decreased the conductance of single gap junctional channels. Additional point mutations identified a uniquely occurring arginine in the N-terminus of Cx46 as the main determinant for the change in voltage-dependent gating.