Endometrial cancer (EC) stem cells (ECSCs) are pivotal in the oncogenesis, metastasis, immune escape, chemoresistance, and recurrence of EC. However, the specific mechanism of stem cell maintenance in EC cells (ECCs) has not been clarified. We found that WTAP and m6A levels decreased in both EC and ECSCs, and that knocking down WTAP promoted ECCs and ECSCs properties, including proliferation, invasion, migration, cisplatin resistance, and self-renewal. The downregulation of WTAP leads to a decrease in the m6A modification of EGR1 mRNA, and it is difficult for IGF2BP3, as an m6A reader, to recognize and bind to EGR1 mRNA that has lost m6A modification, resulting in a decrease in the stability of EGR1 mRNA. A decrease in the EGR1 level led to a decrease of in the expression tumor suppressor gene PTEN, resulting in deregulation and loss of cellular homeostasis and thereby fostering EC stem cell traits. Notably, the enforced overexpression of WTAP, EGR1, and PTEN inhibited the oncogenic effects of ECCs and ECSCs in vivo, and the combined overexpression of WTAP + EGR1 and EGR1 + PTEN further diminished the tumorigenic potential of these cells. Our findings revealed that the WTAP/EGR1/PTEN pathway is important regulator of EC stem cell maintenance, chemotherapeutic resistance, and tumorigenesis, suggesting a novel and promising therapeutic avenue for treating EC.

This study aimed to quantitatively evaluate factors influencing the efficacy and safety of the docetaxel–platinum regimen to provide reliable information for optimizing chemotherapy regimens. A parametric survival function model was used to describe the time course of overall survival (OS) of patients with advanced non-small cell lung cancer (NSCLC) receiving a docetaxel–platinum regimen. A random-effects model in a single-arm meta-analysis was used to analyze the objective response rate and grade 3–4 adverse event rates based on various docetaxel–platinum regimens. The model revealed that the risk of death in East Asians was approximately 1.5-fold higher than that in non-East Asians, with a median OS of 13.7 (95% confidence interval [CI]: 12.8–14.7) months and 9.3 (95% CI: 7.7–11.1) months, respectively. No significant impact of different administration regimens on OS was found. However, when drug exposure increased, the incidence of grade 3-4 anemia or neutropenia significantly increased. The docetaxel–platinum regimen has different efficacies in the treatment of advanced NSCLC between East Asian and non-East Asian populations. A better benefit–risk ratio can be obtained with a lower exposure regimen of docetaxel combined with platinum.

Previous studies have consistently revealed that both local and systemic inflammations are the key to the onset and progression of osteoarthritis (OA). Thus, anti-inflammatory biologic agents could potentially attenuate the progression of OA. We conducted this meta-analysis to examine the efficacy and safety of ant-inflammatory biologic agents among OA patients. Methods: Five databases were searched for randomized controlled trials (RCTs) comparing biologics with placebo or each other in OA patients. Data of pain, physical function, stiffness, and adverse events (AEs) were extracted for a conventional and a Bayesian network meta-analysis. Results: 15 studies with data for 1566 patients were analyzed. In the conventional meta-analysis, etanercept (SMD −0.47; 95% CI −0.89, −0.05) and infliximab (SMD −2.04; CI −2.56, −1.52) were superior to placebo for knee pain. In the network meta-analysis, infliximab was superior to all the other biologic agents in improving pain (vs. hyaluronic acid (SMD −22.95; CI −34.21, −10.43), vs. adalimumab (SMD −21.71; CI −32.65, −11.00), vs. anakinra (SMD −24.63; CI −38.79, −10.05), vs. canakinumab (SMD −32.83; CI −44.45, −20.68), vs. etanercept (SMD −18.40; CI −29.93, −5.73), vs. lutikizumab (SMD −25.11; CI −36.47, −14.78), vs. naproxen (SMD −30.16; CI −41.78, −17.38), vs. tocilizumab (SMD −24.02; CI −35.63, −11.86) and vs. placebo (SMD −25.88; CI −34.87, −16.60)). No significant differences were observed between biologics and placebo regarding physical function, stiffness, and risk of AEs. Conclusions: The findings suggest that infliximab may relieve pain more than other biological agents in OA patients. No significant differences were observed between biologics and placebo regarding physical function, stiffness, and risk of AEs. The results must be interpreted cautiously; therefore, further randomized controlled trials are warranted.

Objective: While platelet rich plasma (PRP) has been extensively studied in treating osteoarthritis (OA), there has been an ongoing debate regarding the efficacy of PRP and the optimal subpopulation for PRP treatment remains unknown. The authors hereby aim to establish a pharmacodynamic model-based meta-analysis to quantitatively evaluate PRP efficacy, comparing with hyaluronic acid (HA) and identify relevant factors that significantly affect the efficacy of PRP treatment for OA. Methods: The authors searched for PubMed and the Cochrane Library Central Register of Controlled Trials of PRP randomized controlled trials (RCTs) for the treatment of symptomatic or radiographic OA from the inception dates to 15 July 2022. Participants’ clinical and demographic characteristics and efficacy data, defined as Western Ontario and McMaster Universities Osteoarthritis Index and visual analog scale pain scores at each time point were extracted. Results: A total of 45 RCTs (3829 participants) involving 1805 participants injected with PRP were included in the analysis. PRP reached a peak efficacy at ~ 2–3 months after injection in patients with OA. Both conventional meta-analysis and pharmacodynamic maximal effect models showed that PRP was significantly more effective than HA for joint pain and function impairment (additional decrease of 1.1, 0.5, 4.3, and 1.1 scores compared to HA treatment at 12 months for Western Ontario and McMaster Universities Osteoarthritis Index pain, stiffness, function, and visual analog scale pain scores, respectively). Higher baseline symptom scores, older age (≥60 years), higher BMI (≥30), lower Kellgren–Lawrence grade (≤2) and shorter OA duration (<6 months) were significantly associated with greater efficacy of PRP treatment. Conclusion: These findings suggest that PRP is a more effective treatment for OA than the more well-known HA treatment. The authors also determined the time when the PRP injection reaches peak efficacy and optimized the targeting subpopulation of OA. Further high-quality RCTs are required to confirm the optimal population of PRP in the treatment of OA.

A sensitive, convenient, rapid and economic liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed to determine cinacalcet concentration in human plasma. A stable isotope cinacalcet (cinacalcet-D₃) was selected as internal standard and the analytes were extracted from plasma samples by a one-step precipitation procedure. Chromatography separation was conducted on an Eclipse Plus C18 column by gradient elution with mobile phase of methanol-water-ammonium formate system at a constant flow rate of 0.6 mL/min. Mass spectrometric detection was conducted by multiple reaction monitoring using positive electrospray ionization. Cinacalcet concentrations in human plasma were determined over the concentration range of 0.1–50 ng/mL. The accuracies of lower limit of quantification (LLOQ) and quality control samples were all within the range of 85–115%, and the inter- and intra-batch precisions (CV%) were all within 15%. The average extraction recovery rates were 95.67–102.88%, and the quantification was not interfered by the matrix components. The validated method was successfully applied to determined cinacalcet concentrations in human plasma from secondary hyperparathyroidism patients.

Context: Cinacalcet, the first FDA-approved calcimimetic agent for treating secondary hyperparathyroidism (SHPT), has unclear factors influencing its therapeutic efficacy in clinical practice. Objective: To establish a pharmacodynamic model for cinacalcet use in SHPT, analyze drug effect distribution and influencing factors, and determine optimal treatment strategy. Methods: We searched public databases for randomized trials on cinacalcet for SHPT, modeling changes in serum parathyroid hormone (PTH), calcium, and phosphorus postintervention. Key pharmacodynamic parameters and influencing factors were identified, with subgroup analysis for factors not in the covariate model. We also compared cinacalcet efficacy between United States/European Union (30-180 mg) and Asia (25-100 mg) dosage ranges. Results: Twenty-six studies (4242 subjects) were analyzed. Covariate analysis showed increasing PTH baseline and vitamin D use proportionally affected PTH and calcium decrease. Postintervention, maximum effects were observed with onset times of 0.46, 0.15, and 0.29 months. Subgroup analysis showed factors such as dialysis time, baseline calcium and phosphorus, phosphate binder use, gender proportion, patient ethnicity, blinding, and age influenced PTH, calcium, and phosphorus decrease. The efficacy of cinacalcet at a dosage of 25 to 100 mg in Asian populations was comparable to that observed at a dose range of 30 to 180 mg in Western populations, suggesting that reducing the therapeutic dose of cinacalcet may potentially yield a better benefit–risk ratio. Conclusion: We established a pharmacokinetic model for cinacalcet in SHPT treatment, providing crucial data for identifying effective patient populations and optimizing treatment strategies.