Pediatric oncology drug development remains uniquely challenging due to the rarity and biological heterogeneity of childhood cancers, ethical considerations in trial conduct, and the limited feasibility of large, randomized studies. Despite these barriers, recent years have seen a notable acceleration in the approval of oncology therapies for pediatric populations, driven by advances in molecularly targeted treatments, evolving regulatory requirements, and innovation in trial design. Reducing nonclinical data requirements and increasing the adaptation of model‑informed drug development approaches are also contributing to advances in pediatric oncology treatment by supporting dose selection, optimizing study design, and reducing unnecessary patient burden. In this review, recent regulatory requirements from the United States, the EU, and other key regions on pediatric oncology drug development are discussed. Thirty-three drugs with oncology indications in pediatric populations approved by the US FDA between 2018 and 2025 are reviewed. These approvals provide examples of how nonclinical and clinical data were generated with a focus on strategies for dose-finding and justification. Common challenges and considerations related to clinical operations and formulation development in pediatric populations and the emerging use of real-world data, external controls, and artificial intelligence/machine learning are also discussed.
To evaluate the regulatory approval, epidemiology, clinical benefits and pricing of orphan drugs approved by the National Medical Products Administration (NMPA) in China. Cross-sectional analysis. Orphan drugs approved by the NMPA for rare disease indications between 1 January 2005 and 31 December 2022. The outcomes included regulatory approval lag time, National Reimbursement Drug List (NRDL) coverage, monthly treatment costs, clinical benefit (SMR, Service Médical Rendu) and additional therapeutic value (ASMR, Amélioration du Service Médical Rendu) ratings from the French National Health Authority (HAS, Haute Autorité de santé). Data were analysed at the drug indication level. The approval time lag was defined as the interval between the earliest global marketing authorisation and subsequent approval by China's NMPA. A total of 59 orphan drugs were approved by the NMPA for 32 rare disease indications in 2005-2022. Of the 24 indications with epidemiological data, the incidence ranged from 0.098 to 9.62 cases per 100 000 persons and the prevalence ranged from 0.017 to 25.7 cases per 100 000 population. A total of 51 drug-indication pairs had SMR ratings: 40 (63.5%) were rated as important, 2 (3.2%) as moderate, 6 (9.5%) as weak and 5 (7.9%) as insufficient. For the 61 indications with pricing data, the median annual treatment price was US$18 259.8 (IQR: US$6504.6 to US$184 011.9), while negotiated drugs, those included in the NRDL through price negotiation, had significantly lower prices than non-negotiated drugs (US$13 677.8 vs US$62 870.0, p=0.015). The ASMR ratings indicated that 5 (7.9%) were rated as important (II), 10 (15.9%) as moderate (III), 11 (17.5%) as minor (IV), and 25 (39.7%) as no improvement (V). The orphan drug policy in China has improved access to and affordability of orphan drugs, particularly through priority reviews and NRDL price negotiations. However, substantial barriers remain in accessing orphan drugs, including limited definitions of rare diseases, the unavailability of overseas-approved orphan drugs and the high costs of non-NRDL drugs. Therefore, 'Three Medical Linkage' healthcare reform, which integrates health insurance, medical service delivery and pharmaceutical regulation, should continue to incentivise the development of orphan drugs and improve patient accessibility and affordability.
Accelerating the transition to value-based health care (VBHC) is essential to ensure sustainable care delivery. VBHC maximizes patient value by optimizing outcomes, controlling costs, and leveraging data to improve quality and patient-doctor communication. Integrating real-world data in health care is important to achieve informed decisions, especially in palliative care, where choices are complex. This study described the development and pilot-testing of an information tool that incorporates real-world outcome data for women with metastatic breast cancer who are initiating CDK4/6 inhibitor treatment. Real-world insights are needed to better inform these patients, in particular because real-world outcomes are known to differ from trial results because of larger heterogeneity in patient characteristics, and differences in frequency of check-ups and handling side effects. We developed an information tool together with patient representatives and clinicians using a participatory development approach that consisted of five key steps: (1) establishment of a multidisciplinary steering group (n=10 steering group members), (2) mapping of the patient journey and patients' needs through focus groups (n=9) and semistructured interviews (n=8), (3) extraction of real-world outcome data from electronic health records systems of 229 patients, (4) prototyping of the tool (n=10), and (5) pilot evaluation with the targeted patient population using semistructured interviews (n=38). We used qualitative analysis methods to analyze the focus group and interview data. We developed a tool consisting of (1) a communication aid for use during doctor-patient consultations (ie, KIJKgesprek [Stichting Kijksluiter]) and (2) a 2-component companion app with informational videos for use at home, both incorporating real-world outcome data (ie, KIJKbericht and KIJKsluiter [Stichting Kijksluiter]). Participants valued the tool for its clarity and structured design, reporting that the outcome data reinforced their experiences and facilitated the setting of realistic expectations. However, some participants described the outcome data as overwhelming, underscoring the importance of careful framing and delivery. Preferences regarding the type, level of detail, and timing of information presentation varied among participants, highlighting the necessity of individualizing information tools to meet diverse informational needs. Most patients valued the inclusion of real-world outcome data in the information tool, although many found it challenging to process. Preferences for the type and presentation of information varied widely among individuals. Information tools incorporating outcome data have the potential to enhance patient understanding and support informed decision-making about care that they value most. However, these tools must be designed to allow for customization, ensuring they address individual informational needs and preferences effectively.
Apurinic/apyrimidinic endonuclease 1/redox factor-1 (APE1/Ref-1) is a multifunctional stress-response regulator that coordinates genome maintenance, redox signaling, RNA biology, and cellular metabolism. Its expression and subcellular localization further determine disease states and severity. The growing appreciation of its biological complexity and clinical relevance makes APE1/Ref-1 an increasingly attractive therapeutic target for redox-stress-related diseases. In this review, we aim to consolidate information on the structural and mechanistic basis of APE1/Ref-1 redox and repair functions, while recognizing emerging evidence in DNA/RNA-forming G-quadruplex (rG4) biology, RNA metabolism, protein homeostasis, and mitochondrial function. We discuss mechanisms regulating APE1/Ref-1 expression, activity, and trafficking, which dynamically influence function in physiological and disease contexts. We specifically emphasize therapeutic strategies including redox-specific inhibition, endonuclease-targeted approaches, and genetic perturbations that result in distinct effects across disease models. Evolving understanding of APE1/Ref-1 biology has accelerated therapeutic development, particularly through redox-selective targeting strategies. Small-molecule inhibitors such as APX3330 and new-generation analogs like APX2009 and APX2014 have advanced into therapeutic applications spanning cancer, inflammatory disorders, and ocular diseases. Continued investigation into the context-dependent and multifunctional roles of APE1/Ref-1, together with the progression of mechanism-informed therapeutic design, is steadily strengthening the translational potential of APE1/Ref-1-directed therapies. APE1/Ref-1 is a protein central to how cells respond to stress. It assists in repairing damaged DNA and governs key signaling pathways that promote inflammation, survival, and adaptation to low-oxygen environments. These same pathways are often overactive in diseases such as cancer, eye conditions like diabetic retinopathy, inflammatory bowel disease, and other disorders linked to chronic inflammation. Because of this, APE1/Ref-1 has been studied for many years as a potential drug target. However, its high abundance in disease states and its multiple functions make targeting this protein challenging. Moreover, since this protein is vital for normal cell function, completely inhibiting it can damage healthy tissues and hinder the development of safe, effective treatments. Recent research has shifted how APE1/Ref-1 can be targeted: newer strategies aim to selectively interfere with specific functions that are more active in disease states, especially those involved in the cellular response to stress. Several drugs designed with this approach have shown promising results in laboratory studies and early clinical trials, particularly for eye diseases and cancer. In this review, we compile decades of research to explain how APE1/Ref-1 works, why it has been difficult to target, and the emerging strategies. We highlight both progress and ongoing challenges and discuss how more precise targeting of this protein could lead to safer, more effective therapies in the future.
The dysregulation of both reduced (IL-33red) and oxidised (IL-33ox) interleukin (IL)-33 has been implicated in chronic obstructive pulmonary disease (COPD) inflammation and remodelling processes. Tozorakimab, an anti-IL-33 monoclonal antibody, inhibits both IL-33red and IL-33ox activity. The tozorakimab LUNA programme comprises four ongoing, multicentre, randomised, double-blind, parallel-group, placebo-controlled, phase III studies evaluating the efficacy and safety of tozorakimab in participants with symptomatic COPD and a history of exacerbations receiving optimised inhaled therapy. In OBERON (NCT05166889) and TITANIA (NCT05158387), 1132 and 1172 participants, respectively, were randomised to receive tozorakimab 300 mg every 4 or 8 weeks or placebo for 52 weeks. In MIRANDA (NCT06040086), 1454 participants were randomised 3:2 to tozorakimab 300 mg every 2 weeks or placebo for ≥52 weeks. In PROSPERO (NCT05742802), participants who completed treatment with tozorakimab in OBERON or TITANIA will continue treatment for an additional 28 weeks or 52 weeks; participants recruited from the placebo arm will be re-randomised 1:1 to tozorakimab or placebo. The primary endpoint in OBERON, TITANIA and MIRANDA is the annualised rate of moderate-to-severe COPD exacerbations; the primary endpoint in PROSPERO is the annualised rate of severe COPD exacerbations. For all studies, the primary endpoint will be first assessed in former smokers, then in current and former smokers. Secondary key endpoints include measures of lung function, respiratory symptoms, health status and safety. The tozorakimab LUNA programme is assessing the efficacy and safety of tozorakimab in participants with COPD. It is the largest pivotal programme of any biologic therapy in COPD to date. The protocols were approved by independent ethics committees and institutional review boards. Results of the studies will be submitted to the EU Clinical Trials Information System within a year from the global end of trial data in all participating countries and will be published or presented at scientific meetings. OBERON: NCT05166889; TITANIA: NCT05158387; MIRANDA: NCT06040086; PROSPERO: NCT05742802.
Quadruple antiemetic prophylaxis with olanzapine (OLZ) is internationally recommended for cisplatin-based chemotherapy. However, OLZ is contraindicated by country-specific regulatory labeling in patients with diabetes mellitus (DM) in Japan due to concerns regarding hyperglycemia. This study aimed to evaluate the safety of short-term low-dose OLZ (≤10 mg) in patients with cancer and DM. We conducted a retrospective cohort study using the TriNetX multi-institutional electronic medical records network. Patients aged ≥18 years who received cisplatin were included in the study. The primary outcome was the incidence of DM-related adverse events (hyperosmolar hyperglycemic state or diabetic ketoacidosis) within 30 days. Secondary outcomes included glucose elevation, neuropsychiatric events, and acute inpatient visits. Propensity score matching was used to balance the baseline covariates. In the matched cohorts (n = 84 per group), no DM-related adverse events occurred within 30 days in either group; however, the occurrence of zero events limited definitive comparative inferences. Although patients with DM had higher glucose levels than those without DM at multiple time points, these increases remained modest (mean, approximately 150 mg/dL). No acute inpatient visits or neuropsychiatric events were reported. Sensitivity analyses stratified by the timing and frequency of OLZ exposure confirmed these findings across various exposure patterns. Based on the absence of detected events rather than demonstrated equivalence, short-term low-dose OLZ administration was not associated with detectable severe glycemic complications in this real-world cohort, supporting prospective evaluation and individualized monitored use in selected patients. Chemotherapy often causes severe nausea and vomiting, which can be effectively prevented by a drug called olanzapine (OLZ). However, OLZ is strictly banned for patients with diabetes in Japan. This is because of concerns that OLZ might dangerously raise blood sugar levels, a side effect typically observed when the drug is used long-term for psychiatric conditions. Researchers wanted to determine whether short-term, low-dose OLZ is actually safe for cancer patients who also have diabetes. The research team examined a large medical database to identify adult patients receiving a chemotherapy drug called cisplatin. They tracked blood sugar levels and severe diabetes-related complications over 30 days and compared diabetic patients who received OLZ with those who did not. The results showed no severe diabetes-related emergencies, such as diabetic ketoacidosis or coma, in any of the patient groups. Although blood sugar levels were slightly higher in the diabetic patients taking OLZ, these increases were modest and manageable. These findings indicate that using low-dose OLZ for a few days does not pose a severe risk to patients with diabetes undergoing chemotherapy. The current strict ban might unnecessarily deprive these patients of highly effective treatment for nausea. The researchers suggest that doctors should be allowed to offer OLZ to diabetic patients alongside regular blood sugar monitoring.
In psychiatry, therapeutic drug monitoring (TDM) is routinely used to improve treatment safety and efficacy, yet its association with hospitalization duration and cost-effectiveness remains unclear. We hypothesized that the frequency of routinely requested TDM is associated with hospitalization duration. In this retrospective study, patients with major depressive disorder receiving TDM of antidepressants between 2015 and 2021 (N = 383) were analyzed. Inclusion criteria were a hospital stay ≥7 days and a first TDM request at admission. Regression analyses assessed associations between TDM frequency and hospitalization duration. Receiver operating characteristic analysis identified a minimum effective TDM frequency of 0.66/week, which was associated with a mean reduction in hospitalization duration of 21 days (p < 2.2*10-¹⁶). The upper effective threshold was approximated at 1.3/week. Higher TDM frequency was associated with more therapy adjustments within 7 days after TDM, including dose adaptations (p = 3.07*10-¹⁶) and drug initiation/discontinuation (p = 6.70*10-6). Drug-specific analyses for amitriptyline, venlafaxine, and mirtazapine confirmed these associations. Cost-effectiveness analysis demonstrated a 37% cost reduction for patients with TDM frequencies ≥0.66/week. In conclusion, frequent, clinically integrated TDM of antidepressants and timely treatment adaptations were associated with shorter hospitalization and reduced hospitalization costs. These findings suggest that at least biweekly TDM combined with subsequent treatment adaptations may represent a previously underappreciated strategy to improve clinical and economic outcomes in a tertiary referral center for severe major depression. Whether these findings are transferable to other inpatient and outpatient settings of depression care requires further studies.
To explore the safety and efficacy of the novel G protein-biased μ-opioid receptor agonist oliceridine for painless gastroscopy. This study is a single-center randomized controlled clinical trial. One hundred and eighty-eight patients scheduled for painless gastroscopy were randomly assigned to four groups: Group L (oliceridine 10 μg/kg + propofol 2mg/kg), Group M (oliceridine 20 μg/kg + propofol 2mg/kg), Group H (oliceridine 30 μg/kg + propofol 2mg/kg) and Group C (sufentanil 0.1 μg/kg + propofol 2mg/kg). The primary outcome was the incidence of respiratory depression. Secondary outcomes included the incidence of respiratory arrest, bradypnea (respiratory rate<8 bpm) and hypoxemia (pulse oxygen saturation (SpO2) < 90%). Other outcomes included procedure and sedation-related outcomes, perioperative vital signs and adverse effects were recorded. Among the 184 patients, 46, 46, 45 and 47 patients were randomly assigned to the L, M, H and C groups, respectively, and completed the trial. The incidence of respiratory depression in Group C (55.32%) and Group H (46.67%) was significantly higher than that in Group L (15.22%) and Group M (17.39%) (P<0.05). The incidence of respiratory arrest was higher in group H (42.22%) and group C (51.06%) compared to group L (13.04%) and group M (15.22%) (P < 0.05). The incidence of bradypnea and hypoxemia in group C (31.90% and 14.89%) was higher than that in group M (6.5% and 0) (P < 0.05). The sedation success rate was significantly lower in Group L than in Group M (71.74% vs 93.48%; P < 0.05). No significant differences were observed in the incidence of postoperative adverse effects. 10 μg/kg and 20 μg/kg oliceridine is associated with a reduced risk of respiratory depression when co-administered with propofol for painless gastroscopy in adults, and the 20 μg/kg oliceridine exhibits superior sedative efficacy.
A major limitation of conventional two and three-dimensional preclinical in vitro cancer models is their inability to reproduce the drug-delivery barriers. Tumor assembloids, which integrate patient-derived cancer cells with stromal, endothelial, and immune components in three-dimensional architectures, provide a manipulable framework for simulating these multicellular impediments. This review specifically examines the application of tumor assembloids to investigate drug delivery constraints, including stromal exclusion, vascular transport, immune-mediated resistance, penetration gradients, and spatially heterogeneous drug exposure. We compared three major construction strategies, including self-assembly, 3D bioprinting, and microfluidic compartmentalization, and evaluated their respective strengths for drug assessment. We also discussed assembloids' current limitations, including reproducibility, incomplete physiological dynamics, insufficient spatial analytics, and the need for standardized benchmarking. Overall, tumor assembloids represent promising mechanistic platforms for studying tumor drug delivery barriers. However, broader clinical application will necessitate rigorous validation and harmonized assay standards.
Tenosynovial giant cell tumors (TGCT) are rare, locally aggressive neoplasms causing pain, stiffness, swelling, limited range of motion, and joint degeneration, which can be debilitating. Therapeutic options include surgery or systemic therapy with colony-stimulating factor 1 receptor (CSF-1R) pathway inhibitors. However, many are not amenable to surgery or have high postsurgical recurrence rates. Available systemic therapies require long-term administration and can have burdensome side effects. Emactuzumab is a novel, potent, CSF-1R inhibiting monoclonal antibody with a unique mechanism of action targeting the receptor dimerization interface of the CSF-1R to reduce tumor-associated macrophages and inflammation within the TGCT microenvironment. It is the only short-course, intravenous therapy in development for TGCT. In a phase I study, emactuzumab resulted in robust and durable responses, and a manageable safety profile in patients with TGCT, supporting further research as a treatment option to address unmet need and improve quality of life in patients with TGCT. TANGENT is a randomized, double-blind, global, phase III study (NCT05417789) to investigate the safety and efficacy of intravenous emactuzumab versus placebo in patients with TGCT not amenable to surgery.Clinical trial registration: www.clinicaltrials.gov identifier is NCT05417789 initially registered on 1 June 2022. What is this article about?The TANGENT trial examines a new treatment for tenosynovial giant cell tumors (TGCTs). TGCTs are rare tumors in the joints or tendon. TGCTs have two types, nodular (N-TGCT), which is typically a single tumor, and diffuse (D-TGCT), which spreads out more. TGCTs grow quickly and can cause joint damage, pain, stiffness, and decrease joint movement. Surgery is usually done to remove the tumor. However, surgery is not an option for all tumors and some tumors may return after surgery. Oral medications that target a pathway involved in TGCT development (CSF-1 inhibitors) are another treatment option. These are taken long term and can have side effects.Emactuzumab is a new treatment for TGCT given intravenously for 8-weeks. In an earlier study, patients treated with emactuzumab responded to treatment and side effects were manageable.What will the study look at?This article describes a trial looking at the safety and effectiveness of emactuzumab in patients with TGCT that cannot have surgery. The trial evaluates a short 8-week Intravenous treatment. If emactuzumab reduces tumor burden and improves function, it could become a new treatment for TGCT.
This preliminary study aimed to describe the effectiveness and safety of obinutuzumab as a rescue and maintenance anti-CD20 strategy in children with difficult-to-treat nephrotic syndrome after failure or intolerance of rituximab-based multi-target immunosuppression. This exploratory single-center retrospective real-world study included consecutive children who received obinutuzumab between April 2024 and January 2025. Nine patients were included in the safety set, and eight who completed treatment and had follow-up data comprised the efficacy set. The primary outcome was 12-month relapse-free survival. Secondary outcomes included annualized relapse rate, peripheral B-cell depletion, glucocorticoid-free status, reduction or discontinuation of background immunosuppression, and safety. Median follow-up in the efficacy set was 1.24 years (IQR 1.01-1.67). No relapses occurred after obinutuzumab in this small efficacy set, corresponding to an observed 12-month relapse-free proportion of 8/8 (100%; exact 95% CI 63.1-100) and reducing the annualized relapse rate from 2.50 to 0 episodes/person-year. All eight efficacy-set patients achieved complete peripheral B-cell depletion and remained depleted at 6 months. At last follow-up, seven had discontinued both glucocorticoids and all non-obinutuzumab immunosuppressants, while one had discontinued glucocorticoids with a reduced dose of mycophenolate mofetil. In the safety set, one child developed severe anaphylactic shock during the first infusion; infectious events were limited to CTCAE grade 1-2 events. In this exploratory, hypothesis-generating study, obinutuzumab was associated with a favorable relapse profile, sustained peripheral B-cell depletion, and reduction of background immunosuppression in a highly selected pediatric population. Larger prospective studies are required to confirm these preliminary observations and define long-term safety. Why was the study done? Some children with nephrotic syndrome keep relapsing or remain difficult to control despite steroids, other immunosuppressive drugs, and rituximab. Treatment options for these children are limited. What did the researchers do? We reviewed the preliminary real-world outcomes of nine children who received obinutuzumab at a single pediatric nephrology center after failure or intolerance of rituximab-based multi-target therapy. Eight children completed treatment and had follow-up data for effectiveness analyses. What did the researchers find out? No relapses were observed during follow-up in the eight children included in the effective analysis. B-cell depletion was achieved in all eight children and persisted at 6 months. Most children were able to stop steroids and other immunosuppressive drugs. One child had severe anaphylactic shock during the first infusion and treatment was stopped; infections during follow-up were limited to mild-to-moderate events. What do these results mean? These early findings suggest that obinutuzumab may be worth further study as a rescue or maintenance treatment strategy for carefully selected children with difficult-to-treat nephrotic syndrome after rituximab failure or intolerance. Larger studies are needed to confirm these findings and better define long-term safety.
Diabetes mellitus, particularly type 2 diabetes mellitus (T2DM), represents a major global health challenge, driven by the increasing prevalence of obesity and sedentary lifestyles. T2DM is characterized by insulin resistance and progressive β-cell dysfunction, leading to chronic hyperglycemia and multiple complications. Among the molecular targets investigated for therapeutic intervention, protein tyrosine phosphatase 1B (PTP1B) has emerged as a key negative regulator of insulin signaling. By dephosphorylating the insulin receptor and its downstream substrates, PTP1B attenuates insulin action and contributes to metabolic dysfunction. In addition to its role in glucose homeostasis, PTP1B is implicated in obesity, diabetic complications, neurodegenerative disorders, and cancer, highlighting its relevance as a multifunctional therapeutic target. However, the development of PTP1B inhibitors remains challenging due to the highly conserved and polar nature of its catalytic site, which limits selectivity and cell permeability. Recent research has focused on alternative strategies, including allosteric modulation and multi-site inhibition, to overcome these limitations. This review provides a comprehensive overview of PTP1B inhibitors from both synthetic (2019-2025) and natural sources, with particular emphasis on natural products reported from 2022 onwards, while including selected earlier studies to provide historical context and illustrate representative structural classes and inhibition mechanisms. Although PTP1B remains an attractive therapeutic target, its clinical validation for diabetes treatment has yet to be achieved. Continued advances in medicinal chemistry and allosteric modulation may help overcome the current translational barriers.
Myopia is increasingly recognized as an inflammatory ocular disease. Vitamin D3 is a potential modulator of the gut-eye axis, but its role in inflammation-induced myopia remains unclear. This study investigated whether vitamin D3 supplementation attenuates myopia progression by regulating retinal inflammation, gut microbiota composition, and microbiota-derived metabolites in a TGF-β2-induced myopia model. Three-week-old Brown Norway rats received weekly periocular TGF-β2 injections with or without daily oral vitamin D3, and myopia development was evaluated on days 1 and 21 by axial length and refractive error. Cecal contents were analyzed for α- and β-diversity and taxonomic differences, and day-21 serum underwent untargeted metabolomic profiling of microbiota-derived metabolites, including bile acids and imidazole derivatives; Spearman correlation linked microbial or metabolic alterations with myopia progression. TGF-β2 induced axial elongation, myopic refractive shifts, and upregulated retinal pro-inflammatory cytokines (p-NFκB, IL-1β, TNF-α), while vitamin D3 supplementation markedly attenuated myopia progression and retinal inflammation. Cecal α-diversity did not differ among control, vitamin D3, TGF-β2, and TGF-β2+vitamin D3 groups, but vitamin D3 significantly reshaped β-diversity and reduced the Firmicutes/Bacteroidota ratio. Distinct metabolite profiles were observed, with the vitamin D3 group showing reduced hyodeoxycholic acid and elevated imidazole derivatives (imidazolepropionic and methylimidazoleacetic acids). Vitamin D3 supplementation attenuated myopia progression by reducing retinal inflammation and concurrently reshaping the gut microbiome and its metabolites compared to the control and myopic groups. These results underscore the potential of vitamin D3 to modulate the gut-retina axis as a nutritional approach for mitigating myopia development.
Critical-size bone defects remain a clinical challenge due to limited intrinsic bone regeneration. This study developed a composite scaffold composed of osteoinductive biphasic calcium phosphate (BCP) ceramic particles and gelatin methacryloyl (GelMA) hydrogel, loaded with calvarial osteoblasts (OBs) pretreated with the glycogen synthase kinase-3β (GSK-3β) inhibitor Tideglusib on surface of BCP particles, and evaluated its bone regenerative efficacy. BCP particles were characterized by X-ray diffraction and scanning electron microscopy. GelMA was synthesized and characterized by FTIR and 1H-NMR spectroscopy. Mechanical properties were assessed by compression testing. OBs were treated with Tideglusib to determine optimal concentration via CCK-8, scratch assays, qPCR, ALP and Alizarin Red S staining. Tideglusib-pretreated OBs seeded on BCP particles were evaluated for viability, proliferation, and osteogenic gene expression (COL-I, ALP). In vivo, 3.5 mm rat femoral defects were used to assess the bone regeneration potential of T-OB/BCP particle/GelMA (GPCT) composites in comparison with other groups by micro-CT and histology at 4 and 8 weeks. BCP (200-300 μm, HA/β-TCP ~30:70) incorporation enhanced GelMA compressive modulus ~4-fold. In vitro, 1 μM Tideglusib optimally activated Wnt/β-catenin signaling and promoted OB proliferation, migration, and osteogenic differentiation, with sustained effects after drug removal. OBs on BCP particles showed time-dependent upregulation of osteogenic genes, and Tideglusib pretreatment further elevated this expression. In vivo, micro-CT revealed significantly higher BV/TV, Tb.N, Tb.Th, and BMD in the GPCT group versus others. Histology showed more mature bone with numerous osteocytes, partial degradation of BCP particles, and new bone area fraction >70% in GPCT. The composite BCP particle/GelMA scaffold with Tideglusib-pretreated OBs provides mechanical reinforcement and sustained osteogenic stimulation, effectively accelerating critical-size bone defect regeneration. This ex vivo pharmacological priming strategy represents a promising translational approach for bone tissue engineering. Why was the study done? Repairing large bone defects remains a major clinic challenge. Current treatments, such as taking bone from another body part, cause additional injury and are limited in supply. A leading direction involves designing combined three elements: a supportive scaffold, bone-forming cells, and molecular signals that instruct cells to build new tissue. This study explored whether a scaffold that physically supports new bone growth—while delivering bone-forming cells temporarily “primed” with a bone-stimulating drug—could effectively repair large bone defects. What did the researchers do and find? We created a composite made of a gel reinforced with ceramic particles that naturally encourage bone growth. Bone-forming cells were briefly treated outside the body with a drug called Tideglusib, which activates a key bone-building pathway. The drug was then removed, leaving cells in a primed state without long-term drug exposure. This composite was implanted into a critical-sized leg bone defect in rats—a wound too large to heal on its own. After eight weeks, over 70% of the defect was filled with mature bone in treated animals, while untreated defects remained largely hollow. What do these results mean? This approach—combining a reinforced scaffold, bone-friendly particles, and temporarily boosted cells—can robustly regenerate bone in severe injuries. By briefly priming cells before implantation, we capture the benefits of a powerful bone-building drug while avoiding risks of long-term exposure. This strategy provides a foundation for developing next-generation bone graft for patients with severe bone loss.
Mycophenolic acid (MPA), administered as mycophenolate mofetil (MMF) or enteric-coated mycophenolate sodium (EC-MPS), is the first-line immunosuppressant for kidney transplant patients. Traditional plasma-based therapeutic drug monitoring (TDM) for MPA fails to accurately reflect intracellular drug exposure at the pharmacological action site. This study aimed to establish and validate a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for simultaneous quantification of MPA and its glucuronide metabolite, MPAG, in peripheral blood mononuclear cells (PBMCs) to support cellular pharmacokinetic (PK) assessment. Chromatographic separation was performed on a BEH C18 column using methanol-water containing 0.1% formic acid and 5 mmol/L ammonium acetate. A total of 139 PBMC samples from 40 kidney transplant recipients (n=19 receiving EC-MPS; n=21 receiving MMF) were analyzed to evaluate the plasma-PBMC PK correlations and gender-related differences. The method exhibited excellent linearity over the concentration range of 0.2-500 ng/mL (R2 > 0.998), along with acceptable precision, accuracy and matrix effect. The analytes remained stable under various experimental conditions. Significant inter-individual variability in intracellular MPA and MPAG concentrations was observed among patients. Spearman correlation analysis demonstrated a weak-to-moderate positive correlation between plasma and intracellular PBMC concentrations of MPA (EC-MPS, Rs=0.396; MMF, Rs=0.480). Additionally, the concentration-time profiles of MPA and MPAG in PBMCs of kidney transplant recipients after administration of EC-MPS or MMF exhibited different characteristics. No significant gender-based differences in plasma and PBMCs were observed. We established and validated an LC-MS/MS method for simultaneous quantification of intracellular MPA and MPAG. The observed weak-to-moderate correlation between plasma and PBMC exposure highlights the inherent limitations of conventional plasma-based TDM for MPA. Collectively, our study provides a feasible approach for monitoring intracellular drug levels and facilitates the optimization of individualized immunosuppressive dosing regimens for renal transplant recipients.
Histone deacetylases (HDAC) overexpression is associated with oncogenesis. Hence, HDAC inhibitors are a promising class of compounds for targeted cancer therapy. Some HDAC inhibitors, such as vorinostat (SAHA), are already approved for the treatment of hematologic cancer. A number of 4-substituted anilides (para-aminophenol or para-aminobenzoic acid derivatives) were designed and synthesized as potential HDAC inhibitors. Compound 23e behaved as a potent HDAC2 inhibitor (IC50 = 4.2 nM) with greater activity than SAHA. Molecular docking results showed that the ligand 23e well placed to the HDAC2 active site through both hydrogen (Gly32, Asp104, Gly154, and His183) and hydrophobic (His33, Pro34, Phe155, His183, and Phe210) interactions. Molecular dynamics simulations confirmed stable complex formation over 500 ns with only small adaptive conformational fluctuations upon ligand binding. MM/PBSA analysis indicated a favorable binding free energy (ΔGbind = -27.98 kcal/mol), confirming a thermodynamically stable and dynamically compatible protein-ligand interaction. Compound 23e exhibited a pronounced antiproliferative effect comparable to SAHA against HeLa and Raji cells, with IC50 values of 5.07 ± 0.09 µM and 1.87 ± 0.22 µM, respectively, with low toxicity on normal cells. The synthesized derivatives can be considered as potential compounds for further development.
To evaluate the efficacy and safety of antithrombotic treatment for migraine prevention in participants with patent foramen ovale (PFO). Investigator initiated, multicentre, prospective, randomised, active controlled, open label clinical trial with blinded outcome assessment and hierarchical hypothesis testing. Secondary and tertiary care hospitals across 39 centres in China. 1000 adults aged 18-64 years with a diagnosis of migraine for more than one year, experiencing at least four migraine days per month, and with PFO confirmed by echocardiography. All participants completed a 12 week screening period before randomisation during which eligibility was confirmed and baseline headache data were prospectively recorded. Participants with previous stroke, transient ischaemic attack, intracranial haemorrhage, non-PFO right-to-left shunt, or contraindications to study drugs were excluded. Of the randomised participants, 984 (75.1% female) were included in the full analysis set. After the screening phase, participants were randomised in a 1:1:1:1 ratio to receive aspirin (300 mg once daily), clopidogrel (75 mg once daily), rivaroxaban (20 mg once daily), or metoprolol (25 mg twice daily) for 12 weeks. No additional preventive migraine treatments were permitted during the intervention period. The primary outcome was the proportion of participants achieving a ≥50% reduction in monthly migraine days or attacks from baseline to weeks 9-12. Safety outcomes included bleeding and other adverse events. For the primary endpoint, aspirin, clopidogrel, and rivaroxaban were all non-inferior to metoprolol. Responder rates were 61.7% (148/240) with aspirin, 66.8% (157/235) with clopidogrel, 78.4% (185/236) with rivaroxaban, and 61.8% (144/233) with metoprolol. Rivaroxaban further showed a statistically higher responder rate than metoprolol, with an absolute difference of 16.2% (98.33% confidence interval 6.0 to 26.4; P<0.001). Among secondary endpoints, rivaroxaban was associated with greater reductions in migraine days and attacks, higher rates of complete migraine cessation, and greater improvements in migraine specific quality-of-life scores than metoprolol. No major bleeding events occurred. The antithrombotic agents evaluated in this trial (aspirin, clopidogrel, and rivaroxaban) were all non-inferior to metoprolol for responder rate in participants with PFO and migraine. Rivaroxaban also showed superior responder rates over metoprolol without an increase in major bleeding events. ClinicalTrials.gov NCT05546320.
Large-cell neuroendocrine carcinomas (LCNECs) of the lung are rare tumours with poor prognosis. A platinum-based regimen is currently the recommended first-line treatment for advanced LCNECs. Retrospective studies suggest potential benefit from immune checkpoint inhibitors (ICIs) but prospective data is lacking. The ongoing phase II FIRST-NEC (First-line treatment for NeuroEndocrine Carcinoma) externally-controlled trial evaluates the efficacy and safety of durvalumab combined with platinum-etoposide as first-line treatment in locally advanced, ineligible for local therapy or patients with metastatic LCNEC. Histopathological diagnosis is centrally confirmed. All patients receive four induction cycles once every 3 weeks with durvalumab 1500 mg and platinum-etoposide. Durvalumab is maintained once every four weeks for up to 24 additional cycles. The primary endpoint is the 12-month progression-free rate (12M-PFR) as per central radiological review. Secondary endpoints include progression-free survival (PFS), overall survival (OS) and safety. Efficacy is assessed every 10 patients using a Bayesian approach, with a futility rule stopping the trial if the probability that 12M-PFR ≤15% exceeds 80%. Based on an A'Hern-Fleming design, 51 evaluable patients are required. Given the rarity of LCNEC, we developed an innovative approach based on target trial emulation to compare the survival outcomes of ICI plus chemotherapy (PFS and OS) to an external control arm (real-world PFS and OS), using real-world data from the Epidemiological Strategy and Medical Economics-Advanced and Metastatic Lung Cancer database. This clinical trial received approval from the competent authorities on 14 March 2024. The results from the final clinical report will be published in medical journals. V.2.0 dated 11 December 2024. NCT06393816.
To examine the association between early rasburicase treatment and acute kidney injury requiring kidney replacement therapy or death among patients with tumour lysis syndrome (TLS). Emulated target trial. 36 US hospitals. 1276 adults (≥18 years) admitted to hospital between 2014 and 2023 with active haematological malignancy or solid tumour with metastases, high tumour burden, or laboratory findings and clinical features consistent with TLS. The primary outcome was a composite of acute kidney injury requiring kidney replacement therapy or death during the index hospital admission. A key secondary outcome was 90 day mortality. Outcomes were compared between patients who received rasburicase within 12 hours after TLS onset and those who did not, using logistic regression with inverse probability of treatment weighting to adjust for confounding. Among 1276 patients included in the analysis, 705 (55.3%) received rasburicase within 12 hours after TLS onset. Among patients treated within 12 hours of TLS onset, rasburicase was administered at a median of 5.0 hours (interquartile range 3.1-7.5 hours). Patients who received rasburicase had higher uric acid concentrations than those who did not (median 0.71 v 0.59 mmol/L (11.9 v 9.9 mg/dL)); however, severity of illness was well balanced after applying inverse probability of treatment weighting. Early rasburicase treatment was associated with a lower risk of acute kidney injury requiring kidney replacement therapy or death (32.7% v 42.0%; adjusted odds ratio 0.67, 95% confidence interval 0.52 to 0.88; P<0.001). Results were consistent across multiple sensitivity analyses and for 90 day mortality (adjusted odds ratio 0.71, 0.54 to 0.94). Among adults with TLS, early rasburicase treatment for TLS was associated with about one third lower risk of acute kidney injury requiring kidney replacement therapy or death compared with delayed or no rasburicase treatment.
Bersiporocin is a first-in-class prolyl-tRNA-synthetase inhibitor under clinical development for the treatment of idiopathic pulmonary fibrosis. In a prior first-in-human study, the incidence of gastrointestinal (GI) adverse events (AEs) differed across prandial conditions. This study aimed to evaluate the effect of food on the pharmacokinetics (PKs) and safety profile of bersiporocin. This randomized, open-label, single-dose, three-period crossover study enrolled 36 healthy Korean participants. Each participant received a single oral dose of bersiporocin 200 mg under three conditions: fasted (A), 30 minutes after a high-fat meal (B), and 2 hours after a high-fat meal (C), with a 7-day washout between periods. Plasma concentrations of bersiporocin and its active metabolite M8 were quantified using a validated LC-MS/MS assay, and PK parameters were determined by non-compartmental analysis. Safety was evaluated by monitoring AEs, clinical laboratory tests, vital signs, and electrocardiograms. A high-fat meal delayed the absorption of bersiporocin and M8. The median Tmax for bersiporocin increased from 3 hours under condition A to 6 hours under conditions B and C. However, systemic exposure, as assessed by AUClast, was comparable across conditions, with geometric mean ratios (90% confidence intervals) of 0.9380 (0.8500-1.0351) and 0.9944 (0.9000-1.0988) for B and C relative to A, respectively. Similar PK trends were observed for M8. A higher incidence of GI AEs was observed in condition B (45.7%) than in conditions A (25.7%) or C (24.2%). Systemic exposure did not differ between participants with and without vomiting. A high-fat meal delayed the oral absorption rate of bersiporocin but did not have a clinically significant effect on systemic exposure to bersiporocin or M8. Given the increased incidence of GI AEs under early postprandial conditions, administration under fasted conditions or at least 2 hours postprandially may be appropriate for future clinical studies.