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Objective The relative efficacy and tolerability of tofacitinib, baricitinib, upadacitinib, and filgotinib were assessed in patients with rheumatoid arthritis (RA) with inadequate responses to biologic disease-modifying antirheumatic drugs (bDMARDs). Methods We performed a Bayesian network meta-analysis to combine direct and indirect evidence from randomized controlled trials (RCTs) to examine the efficacy and safety of tofacitinib, baricitinib, upadacitinib, and filgotinib in RA patients with inadequate responses to bDMARDs. Results Four RCTs comprising 1399 patients met the inclusion criteria. Tofacitinib, baricitinib, upadacitinib, and filgotinib achieved significant American College of Rheumatology 20% (ACR20) responses versus placebo. The ranking probability based on the surface under the cumulative ranking curve (SUCRA) indicated that upadacitinib 15 mg had the highest probability of being the best treatment for achieving the ACR20 response rate, followed by filgotinib 200 mg, baricitinib 4 mg, filgotinib 100 mg, tofacitinib 5 mg, and placebo. The ranking in SUCRA based on the ACR50 response rate indicated that baricitinib 4 mg had the highest probability of achieving the ACR50 response rate, followed by filgotinib 200 mg, tofacitinib 5 mg, upadacitinib 15 mg, filgotinib 100 mg, and placebo. Tofacitinib 5 mg showed a significantly higher ACR70 response rate than filgotinib 100 mg and upadacitinib 15 mg. Tofacitinib 5 mg, filgotinib 200 mg, and placebo showed a significantly lower serious adverse event rate than upadacitinib 15 mg. Conclusion Tofacitinib, baricitinib, upadacitinib, and filgotinib were effective treatment options for RA patients with an inadequate response to bDMARDs but with different efficacy and safety profiles.

Objective This study aimed to evaluate whether urinary monocyte chemoattractant protein-1 (MCP-1) could serve as a biomarker for lupus nephritis (LN). Methods We performed a meta-analysis to examine the relationship between urinary MCP-1 level and LN in three comparisons: active LN versus inactive LN, active LN versus control, and inactive LN versus control. Results Eight studies of a total of 399 patients with LN (204 with active LN, and 195 with inactive LN) and 130 controls were available for this meta-analysis. The meta-analysis revealed that the urinary MCP-1 level was significantly higher in the active-LN group than in the inactive-LN group (standard mean difference [SMD] = 1.883, 95 % confidence interval [CI] = 0.811–2.954, p  = 0.001). The meta-analysis showed that the urinary MCP-1 level was significantly higher in the active-LN group than in the control group (SMD = 3.085, 95 % CI = 1.684–4.485, p  = 1.6 × 10 −5 ). Furthermore, stratification by ethnicity showed significantly elevated urinary MCP-1 levels in the active-LN group in Caucasian, Asian, and Egyptian populations (SMD = 2.408, 95 % CI = 1.711–3.105, p  < 1.0 × 10 −8 ; SMD = 1.020, 95 % CI = 0.623–2.153, p  = 4.6 × 10 −7 ; and SMD = 7.370, 95 % CI = 1.467–2.157, p  = 5.9 × 10 −5 , respectively). The meta-analysis indicated that the urinary MCP-1 level was also significantly higher in the inactive-LN group than in the control group (SMD = 1.812, 95 % CI = 0.628–2.996, p  = 0.003). Conclusions The meta-analysis demonstrated that urinary MCP-1 was significantly higher in patients with active LN than in those with inactive LN and control subjects, and the patients with inactive LN showed significantly higher urinary MCP-1 levels than the controls.

Regulatory T cells (Treg) play a crucial role in maintaining immune homeostasis since Treg dysfunction in both animals and humans is associated with multi-organ autoimmune and inflammatory disease. While IL-2 is generally considered to promote T-cell proliferation and enhance effector T-cell function, recent studies have demonstrated that treatments that utilize low-dose IL-2 unexpectedly induce immune tolerance and promote Treg development resulting in the suppression of unwanted immune responses and eventually leading to treatment of some autoimmune disorders. In the present review, we discuss the biology of IL-2 and its signaling to help define the key role played by IL-2 in the development and function of Treg cells. We also summarize proof-of-concept clinical trials which have shown that low-dose IL-2 can control autoimmune diseases safely and effectively by specifically expanding and activating Treg. However, future studies will be needed to validate a better and safer dosing strategy for low-dose IL-2 treatments utilizing well-controlled clinical trials. More studies will also be needed to validate the appropriate dose of IL-2/anti-cytokine or IL-2/anti-IL-2 complex in the experimental animal models before moving to the clinic.

Benthic nitrogen transformation pathways were investigated in the sediment of the East China Sea (ECS) in June of 2010 using the 15N isotope pairing technique. Slurry incubations indicated that denitrification, anammox and dissimilatory nitrate reduction to ammonium (DNRA) as well as intracellular nitrate release occurred in the ECS sediments. These four processes did not exist independently, nitrate release therefore diluted the 15N labeling fraction of NO3−, and a part of the 15NH4+ derived from DNRA also formed 30N2 via anammox. Therefore, current methods of rate calculations led to over and underestimations of anammox and denitrification respectively. Following the procedure outlined in Thamdrup and Dalsgaard (2002), denitrification rates were slightly underestimated by an average 6% without regard to the effect of nitrate release, while this underestimation could be counteracted by the presence of DNRA. On the contrary, anammox rates calculated from 15NO3− experiment were significantly overestimated by 42% without considering nitrate release. In our study, this overestimation could only be compensated 14% by taking DNRA into consideration. In a parallel experiment amended with 15NH4++14NO3−, anammox rates were not significantly influenced by DNRA due to the high background of 15NH4+ addition. The significant correlation between potential denitrification rate and sediment organic matter content (r = 0.68, p < 0.001, Pearson) indicated that denitrification was regulated by organic matter, while, no such correlations were found for anammox and DNRA. The relative contribution of anammox to the total N-loss increased from 13% at the shallowest site near the Changjiang estuary to 50% at the deepest site on the outer shelf, implying the significant role of anammox in benthic nitrogen cycling in the ECS sediments, especially on the outer shelf. N-loss as N2 was the main pathway, while DNRA was also an important pathway accounting for 20–31% of benthic nitrate reduction in the ECS. Our study demonstrates the complicated interactions among different benthic nitrogen transformations and the importance of considering denitrification, DNRA, anammox and nitrate release together when designing and interpreting future studies.

Objective In this study, we aimed to assess the safety and efficacy of Janus kinase (JAK) inhibitors in patients with ankylosing spondylitis (AS). Methods We conducted a Bayesian network meta-analysis using direct and indirect data from randomized controlled trials (RCTs), and examined the safety and efficacy of JAK inhibitors in active AS patients exhibiting inadequate response or intolerance to two or more non-steroidal anti-inflammatory drugs (NSAIDs). Results RCTs included a total of 406 patients (203 experimental subjects and 203 controls) from three studies on upadacitinib, filgotinib, and tofacitinib. Assessment of SpondyloArthritis International Society 20% improvement (ASAS20), ASAS40, and ASAS5/6 responses were significantly higher in the JAK inhibitor group than in the placebo group. Other efficacy outcomes, such as ASAS partial remission, Bath Ankylosing Spondylitis Disease Activity Index (BASDAI50), Ankylosing Spondylitis Disease Activity Score (ASDAS), Spondyloarthritis Research Consortium of Canada (SPARCC) Magnetic Resonance Imaging (MRI) scores, and Bath Ankylosing Spondylitis Functional Index (BASFI) were also significantly higher in the JAK inhibitor group compared to the placebo group. The JAK inhibitors significantly improved disease activity (ASAS partial remission, BASDAI50, ASDAS), function (BASFI), and MRI outcomes (SPARCC MRI spine). However, the incidence of adverse events (AEs) and serious adverse events (SAEs), and the rate of withdrawal attributed to AEs did not differ between the JAK inhibitor and placebo groups. Conclusion JAK inhibitors were effective in active AS patients exhibiting an inadequate response or intolerance to two or more NSAIDs, without the risk of SAEs; this suggests that based on our data, studies are warranted to further investigate the use of JAK inhibitors for treating AS.

In atopic dermatitis (AD), recent research advances have portrayed a complex disease profile based on different subtypes/ phenotypes and underlying molecular mechanisms/endotypes. Extrinsic and intrinsic subdivision is one of the most common types, defined in terms of total serum immune globulin E (IgE) and/or specific IgE to food and environmental allergens. Extrinsic AD is the most common type (80%), with high IgE, impaired skin barrier, as well as high incidence of comorbid atopic diseases, whereas intrinsic AD accounted for 20% of AD, with normal IgE and intact barrier function. Clinical studies have shown that extrinsic AD was a classic Th2-based inflammatory dermatitis, while the intrinsic subtype presented increased Th1/Th17/Th22 but normal Th2 cytokines. Protein sensitization, a classic Th2 response, has been clearly characterized in extrinsic AD, while metal hapten induces intrinsic AD's sensitization, which may be associated with suprabasin deficiency. In this review, we aimed to further expand our knowledge about similarities and differences between these two subtypes, which will expand our capability to further dissect pathophysiology of AD and enable us to develop personalized medicine approaches. Keywords: intrinsic atopic dermatitis, extrinsic atopic dermatitis, epidermal barrier, immune dysfunction, immune globulin E

Aims This study aimed to assess the relative efficacy and safety of tacrolimus, mycophenolate mofetil (MMF) and cyclophosphamide (CYC) as induction therapy for lupus nephritis. Methods Randomized controlled trials (RCTs) examining the efficacy and safety of tacrolimus, MMF and CYC for induction therapy in patients with lupus nephritis were included. We performed a Bayesian random-effects network meta-analysis to combine direct and indirect evidence from the RCTs. Results Nine RCTs including 972 patients met the inclusion criteria and pair-wise comparisons were performed, including 11 direct comparisons. Tacrolimus showed a significantly higher overall response rate (complete remission plus partial remission) than CYC (OR 2.35, 95% confidence interval (CI) 1.03–5.45), and was more efficacious than MMF (OR 1.60, 95% CI 0.70–3.57). MMF was superior to CYC in terms of overall response (OR 1.45, 95% CI 0.96–2.42). Ranking probability based on the surface under the cumulative ranking curve (SUCRA) indicated that tacrolimus had the highest probability of being the best treatment for achieving the overall response (SUCRA = 0.9321), followed by MMF (SUCRA = 0.5385) and CYC (SUCRA = 0.0294). In terms of safety, tacrolimus showed the highest probability of decreasing the risk of serious infections (SUCRA = 0.9253), followed by MMF (SUCRA = 0.4027) and CYC (SUCRA = 0.1720). Conclusions Tacrolimus was the most efficacious induction treatment for patients with lupus nephritis, and had the highest probability of decreasing the risk of serious infections. Higher remission rates combined with a more favorable safety profile suggest that MMF is superior to CYC as induction treatment in these patients.

Abstract Background Esomeprazole is an S-enantiomer of omeprazole that has favorable pharmacokinetics and efficacious acid suppressant properties in humans. However, the pharmacokinetics and effects on intragastric pH of esomeprazole in dogs have not been reported. Objective To determine the pharmacokinetics of esomeprazole administered via various routes (PK study) and to investigate the effect of esomeprazole on intragastric pH with a Bravo pH monitoring system (PD study). Animals Seven adult male Beagle dogs and 5 adult male Beagle dogs were used for PK and PD study, respectively. Methods Both studies used an open, randomized, and crossover design. In the PK study, 7 dogs received intravenous (IV), subcutaneous (SC), and oral doses (PO) of esomeprazole (1 mg/kg). Each treatment period was separated by a washout period of at least 10 days. Esomeprazole plasma concentrations were measured by HPLC/MS/MS. In the efficacy study, intragastric pH was recorded without medication (baseline pH) and following IV, SC, and PO esomeprazole dosing regimens (1 mg/kg) in 5 dogs. Results The bioavailability of esomeprazole administered as PO enteric-coated granules and as SC injections was 71.4 and 106%, respectively. The half-life was approximately 1 hour. Mean ± SD percent time intragastric pH was ≥3 and ≥4 was 58.9 ± 21.1% and 40.9 ± 17.3% for IV group, 75.8 ± 16.4% and 62.7 ± 17.7% for SC group, 88.2 ± 8.9% and 82.5 ± 7.7% for PO group, and 12.5 ± 3.6% and 3.7 ± 1.8% for baseline. The mean percent time with intragastric pH was ≥3 or ≥4 was significantly increased regardless of the dosing route (P < .05). Conclusion The PK parameters for PO and SC esomeprazole administration were favorable, and esomeprazole significantly increased intragastric pH after IV, PO, and SC administration. IV and SC administration of esomeprazole might be useful when PO administration is not possible. No significant adverse effects were observed.

Oral squamous cell carcinoma is the most common type of malignant tumor in the head and neck region. Despite advancements, metastasis and recurrence rates remain high, and patient survival has not significantly improved. Although miRNA therapies are promising for cancer gene therapy, their applications in treating oral cancer are limited. Targeted medication delivery systems based on nanotechnology offer an efficient way to enhance oral cancer treatment efficacy. We synthesized nanosilver (AgNPs) and loaded them with the tumor suppressor miR-181a-5p. In vitro experiments were conducted to investigate the inhibitory effects of AgNPs and their composites on the malignant behavior of oral cancer cell lines. The xenograft experiment was utilized to examine their effects on tumorigenesis and the potential molecular mechanisms involved. The nanosilver exhibited a spherical morphology with a size distribution ranging from 50 to 100 nm. They exhibited a distinct absorption peak at 330 nm and could be excited to emit green fluorescence. The biocompatible AgNPs effectively shielded miRNA from degradation by RNase and serum. The nanocomposites significantly inhibited the proliferation, invasion, migration, and colony formation of oral cancer cell lines. Notably, treatment with the nanocomposites resulted in substantial tumor growth suppression in the xenograft model. Mechanistically, these composites directly targeted BCL2 and exerted their antitumor effects by suppressing the β-catenin signaling pathway and other downstream genes without inducing acute toxicity. Collectively, the findings demonstrate that the miR-181a-5p/AgNPs combination significantly impedes the growth and progression of oral cancer both in vitro and in vivo, highlighting a pivotal role for the β-catenin signaling pathway. This multifaceted approach holds promise as a prospective therapeutic strategy for oral cancer management in the future.

We surveyed randomized controlled trials (RCTs) examining the efficacy and safety of anifrolumab 300 mg in patients with active systemic lupus erythematosus (SLE) despite receiving standard therapy, using MEDLINE, EMBASE, the Cochrane Controlled Trials Register, and manual searches. Meta-analysis performed to determine treatment efficacy and safety outcomes of three RCTs (459 patients and 468 controls) revealed that the BICLA responses were significantly higher in the anifrolumab group than in the placebo group (OR = 2.071, 95%CI 1.575–2.725, p  < 0.001). Steroid reduction and CLASI reduction were also significantly higher in the anifrolumab group than in the placebo group (OR = 1.811, 95%CI = 1.308–2.506, p  < 0.001; OR = 2.245, 95%CI = 1.437–3.506, p  < 0.001). Compared with placebo, anifrolumab significantly increased the SRI7 and SRI8 responses in SLE patients (OR = 1.866, 95%CI = 1.372–2.536, p  < 0.001; OR = 1.925, 95%CI = 1.387–2.672, p  < 0.001). The SRI4, 5, and 6 responses also tended to be higher in the anifrolumab group than in the placebo group. Adverse event incidence was significantly higher in the anifrolumab group than in the placebo group (OR = 1.815, 95%CI = 1.262–2.611, p  = 0.001); serious adverse events were significantly lower in the anifrolumab group than in the placebo group (OR = 0.679, 95%CI = 0.468–0.986, p  = 0.042). Herpes zoster infection was significantly higher in the anifrolumab group than in the placebo group (OR = 4.089, 95%CI = 1.750–9.522, p  = 0.001). Anifrolumab is effective for treating active SLE. However, anifrolumab increased the incidence of herpes zoster infection compared with placebo.