Myelofibrosis (MF) is a chronic myeloproliferative neoplasm characterized by splenomegaly, systemic symptoms, and anemia, the latter being strongly associated with poor survival and reduced quality of life. Current Janus kinase (JAK) inhibitors improve symptoms and spleen size but often exacerbate anemia, leaving a significant unmet clinical need. Momelotinib, a JAK1/JAK2 and activin A receptor type 1 (ACVR1) inhibitor, has been proposed to address both splenomegaly and anemia through hepcidin suppression. This study critically evaluates the clinical benefit of momelotinib using the European Society for Medical Oncology Magnitude of Clinical Benefit Scale for Hematological Malignancies (ESMO-MCBS:H), focusing on the phase 3 trials SIMPLIFY-1 and MOMENTUM. In SIMPLIFY-1, momelotinib demonstrated non-inferiority to ruxolitinib in terms of spleen volume reduction (SVR35 26.5% vs 29.0%) and did not evaluated quality of life as a prespecified outcome, resulting in an ESMO-MCBS:H score indicating no evaluable benefit (NEB). In contrast, in MOMENTUM, conducted in symptomatic, anemic patients previously treated with JAK inhibitors, momelotinib was superior to danazol for MFSAF total symptom score response (≥50% reduction from baseline 25% vs 9%). As no improvement in global health status was observed, MOMENTUM was scored as Grade 1. Interpretation of hematologic benefits remains limited by trial design, as the anemia related outcomes were not primary endpoints and studies were not powered to robustly assess them. Furthermore, the negative SIMPLIFY-2 trial underscores uncertainty in pretreated populations. In conclusion, momelotinib demonstrates a differentiated clinical profile with consistent spleen control and potential hematologic benefits, particularly in anemic patients. However, superiority over other improved JAK inhibitors has not been demonstrated in the pivotal phase 3 trials evaluated. Future trials incorporating anemia-focused primary endpoints and biomarker stratification are warranted to better define its role in myelofibrosis management.

Sleep disorders present major public health issues because of their associations with chronic diseases. Despite extensive research efforts, the underlying biological mechanisms remain inadequately understood. We performed bidirectional two-sample Mendelian randomization (MR) to investigate relationships between sleep disorders and common brain diseases, followed by summary-data-based Mendelian randomization (SMR), heterogeneity in dependent instruments (HEIDI), and colocalization analyses integrating protein quantitative trait locus (pQTL) and expression quantitative trait locus (eQTL) data to prioritize genetically supported candidate genes. Compound-gene associations were subsequently evaluated, and selected clinically used compounds underwent exploratory molecular docking and molecular dynamics simulation. Two-step MR mediation analyses and MR phenome-wide association study (MR-PheWAS) were used to investigate potential mediating traits and broader phenotypic associations. Multi-omic genetic analyses prioritized six candidate genes-BCAN, HDGF, MEPE, PAM, PRR4, and IGLON5-with BCAN, HDGF, and MEPE showing the strongest genetic support. Compound prioritization retained four clinically used drugs associated with the candidate genes for structure-based assessment. Exploratory molecular docking yielded the most favorable predicted Vina score for the BCAN-danazol pair, and molecular dynamics simulation showed persistent local BCAN-danazol contacts despite substantial global conformational rearrangement of BCAN during the trajectory. Mediation analyses identified several risk factors, cerebrospinal fluid metabolites, and structural connectivity measures showing statistical evidence consistent with partial mediation of selected gene/protein-sleep disorder associations. MR-PheWAS further characterized broader phenotypic associations of the genetically supported genes. Integrating genetic and multi-omic evidence identified candidate molecular targets and compound-gene associations relevant to sleep disorders. These findings provide hypotheses for subsequent functional and pharmacological validation.

Telomere biology disorders (TBDs) are inherited conditions that can present in adulthood with pancytopenia and liver disease. We describe a case of a 45-year-old man with a high body mass index (BMI), long-standing macrocytic pancytopenia, and biopsy-proven steatohepatitis who was found to have markedly short telomeres and a heterozygous telomerase reverse transcriptase (TERT)variant. The patient had a clear hematologic response to danazol but developed progressive cirrhosis with portal hypertension, ultimately requiring orthotopic liver transplantation with sleeve gastrectomy; after transplant, liver chemistries normalized, but cytopenias recurred under tacrolimus-based immunosuppression. This case highlights the need to consider TBDs in adults with unexplained macrocytic cytopenias and progressive liver disease, and to recognize that liver transplantation corrects hepatic failure but not the underlying bone marrow disorder.

This study aims to investigate the clinical characteristics and outcomes of Paroxysmal Nocturnal Hemoglobinuria (PNH) patients in a tertiary care center in South India, where access to C5 inhibitors is limited. A retrospective observational study was conducted between January 2018 and July 2024. Data from 45 PNH patients, diagnosed with flow cytometry, were collected from electronic medical records. Clinical information, laboratory results, treatment details, and follow-up data were analyzed using appropriate statistical methods, including Kaplan-Meier survival analysis. The median age at symptom onset was 35 years. Common presentations included pancytopenia (59%), thrombosis (13.3%), and hemoglobinuria (11.1%). The mean time to diagnosis was 1.88 years. Most patients had hypocellular marrow (74%). The mean Hemoglobin was 7.3 ± 2.3gm/dL. Patients received supportive care, including transfusions (66.67%), steroids (28.8%), calcineurin inhibitors (42.2%), and danazol (64.4%). The 5-year overall survival was 57.6%. Infections and hemorrhage were the leading causes of death. PNH in this resource-limited setting is characterized by delayed diagnosis, significant morbidity, and high mortality. Pancytopenia and thrombosis were common. Supportive care, in the absence of C5 inhibitors, is associated with poor outcomes, highlighting the need for improved access to standard of care treatments.

This multicenter, randomized, controlled study was conducted to explore the safety and efficacy of low-dose baricitinib plus danazol for ITP patients who had failed corticosteroids and at least one recommended subsequent treatment. Participants were randomly assigned to receive baricitinib plus danazol (n = 108) or danazol alone (n = 108) by a central, interactive web-based system. Patients and caregivers were not blinded to group assignment. Efficacy assessments were performed in the intention-to-treat population by investigators blinded to group assignment. The primary endpoint was 6-month durable response. Forty-nine (45.4%) patients in the combination arm and 22 (20.4%) patients in the monotherapy arm achieved 6-month durable response (P < 0.001). The safety analysis set included patients who received at least one dose of study medication (n = 108 in the combination arm and n = 105 in the monotherapy arm). Fifty-two (48.1%) patients receiving baricitinib plus danazol and 47 (44.7%) patients receiving danazol alone reported at least one adverse event. Each arm reported two patients who developed an adverse event causing study discontinuation and one patient who developed a grade 3 or more severe adverse event. Low-dose baricitinib plus danazol might be a novel option for difficult-to-treat ITP. Funding: National Key Research and Development Program of China (No. 2023YFC2507800), National Natural Science Foundation of China (No. 82230004, No. 82430006, No. 82400157), Capital Health Development and Research of Special (No. 2022-1-4082), and Beijing Natural Science Foundation (No. 7242154 and No. 7232188). ClinicalTrials.gov identifier: NCT05852847.

Colorectal cancer (CRC) is a leading cause of cancer mortality, with treatment efficacy limited by tumor heterogeneity and chemotherapy resistance. Drug repositioning can accelerate discovery using FDA-approved agents. Here, we introduce a multi-omics repositioning framework integrating bulk and single-cell data with network pharmacology, structural modeling, and validation and apply it for the first time in CRC. Bulk RNA-seq identified 3480 upregulated and 3816 downregulated genes in TCGA-COADREAD, and 602 upregulated and 744 downregulated in GSE103512. Single-cell RNA-seq revealed 1227 upregulated and 728 downregulated in GSE231559, and 1628 upregulated and 850 downregulated in GSE144735. Integration with cMap and ASGARD yielded 20 candidates; four FDA-approved drugs (rifapentine, danazol, tolbutamide, and triamcinolone) had not been linked to CRC. DepMap PRISM data supported inhibitory activity. Docking and 200 ns molecular dynamics showed stable binding of all four in the HSP90α ATP-binding pocket, with hydrogen bonding and favorable MM/GBSA free energies (-30.59 kcal/mol for danazol to -37.37 kcal/mol for rifapentine; reference NVP-AUY922 -47.99 kcal/mol). Independent triplicate simulations of the reference and top-ranked candidate complexes confirmed the statistical reliability and reproducibility of these structural and energetic descriptors (reference ΔGtotal = -47.90 ± 0.08 kcal/mol). Direct binding of all four compounds to HSP90α was further confirmed by surface plasmon resonance. In vitro, the drugs suppressed proliferation and induced apoptosis in HCT116, LoVo, and HCT-15 cells, with IC₅₀ values of 2.60-13.15 μM. These results identify unreported HSP90AA1 inhibitors in CRC and establish a generalizable repositioning framework.

Doping in sports, particularly using danazol (DZ), a steroid prohibited by the World Anti-Doping Agency (WADA), can lead to serious health risks due to its unregulated use. Current detection methods are costly and performed in specialized laboratories. In this work, we developed a low-cost electrochemical screening platform based on the direct electrochemical reduction of graphene oxide (GO) onto a glassy carbon electrode (GCE), without the use of chemical reductants or multi-step functionalization. The GCE/ErGO electrode was characterized by cyclic voltammetry (CV) using the redox probe [Fe(CN)6]3-/4- and by double-layer capacitance measurements in Britton-Robinson buffer (pH 3.0), confirming the improved performance of the modified surface. The net current observed in the presence of DZ increases almost three times when ErGO modifies the electrode surface. Based on the response obtained for DZ detection using Square-Wave Adsorptive Stripping Voltammetry (SWAdSV), chemical and electrochemical parameters were optimized. The optimal conditions were Britton-Robinson buffer at pH 3.0, an accumulation potential (Eacc) of -0.4 V, and an accumulation time (tacc) of 300 s. Under these conditions, the calibration curve yielded limits of detection and quantification of 7.0 and 20.0 µg L-1, respectively. Spiked water, synthetic urine and synthetic saliva samples were analyzed using the standard addition method, achieving satisfactory recoveries. The sensor maintained a measurable DZ signal in the presence of cortisol, urea, and nandrolone, with no anti-fouling or carryover observed. In mechanistic terms, 1H-NMR spectra of electrolyzed DZ supported hydroxylation at the allylic position, delivering 6-hydroxy-4,5-dihydro-DZ as the main oxidation product.

The distinctive flavor and desirable texture of Qiandongnan Xiaoxiang chicken meat make it an ideal model for studying the formation of chicken meat quality traits. This study investigated age-related changes in meat quality, gut microbiota, and the underlying molecular mechanisms in Qiandongnan Xiaoxiang chickens. By integrating multi-omics data, we systematically examined the alterations and interrelationships among serum biochemical indices, gut microbial composition, breast muscle metabolome, and transcriptome in chickens at different ages (60-180 days). The results showed that increasing age significantly affected physiological metabolism, muscle development, and meat quality formation. As age increased, breast muscle pH, shear force, and redness (a*) increased, whereas yellowness (b*) decreased. Serum lipidomic profiling revealed elevated levels of triglycerides, cholesterol, and free fatty acids, accompanied by a reduction in high-density lipoprotein cholesterol. Flavor precursors such as sucrose, arbutin, acylcarnitines, lipid-derived substrates, and bile acid-related metabolites may participate in the maillard reaction, lipid oxidation, or undergo further transformation during processing, thereby promoting aroma formation. With increasing age, lipid metabolism-related signaling pathways, including adipocytokine signaling, fatty acid biosynthesis, fatty acid metabolism, linoleic acid metabolism, glycerophospholipid metabolism, and regulation of lipolysis in adipocytes, were significantly enriched. Transcriptomic analysis identified the key lipid-related gene PLA1A, whose expression pattern was consistent with the observed metabolic changes. Multi-omics analysis identified gut microorganisms (Bifidobacterium, Lachnospiraceae NK4A136 group, and Christensenellaceae R7 group) that were negatively correlated with the PLA1A gene and flavor metabolites such as 4‑aminovaleric acid betaine, danazol, and hetisine. Collectively, these findings elucidate the microbial-metabolic-genetic network underlying meat quality development and provide new insights for optimizing poultry production.

Idiopathic dyskeratosis congenita (DC) is a disorder characterized by mucocutaneous alterations, bone-marrow failure, immune deficiency, liver cirrhosis, and other morbidities, due to alterations in telomere maintenance, which, in most cases, lead to short telomeres and poor tissue regeneration and function. The main cause of mortality is bone-marrow failure. A non-local diffusion-advection model with zero-flux boundary conditions is used to simulate the generational and temporal evolution of a hematopoietic stem cell (HSC) population in order to investigate the progression of DC. Blood-cell production from progenitor cells that had exited the HSC compartment was quantified. The influence of variations in initial proliferation potential ([Formula: see text]) and telomerase activity (s) on the onset of pancytopenia was examined. Age-and weight-dependent blood cell demands are modeled for both sexes, establishing a physiological baseline against which DC-related deficiencies are compared. Simulations revealed that lower [Formula: see text] values and reduced telomerase activity accelerate stem cell exhaustion, resulting in early pancytopenia, sometimes before age of 2 years. In contrast, patients with moderately higher [Formula: see text] values developed pancytopenia later in life, with onset delayed until the third or fourth decade. Treatment simulations demonstrated that a two-year course of danazol, a synthetic androgen, can slow telomere attrition. These findings suggest that pharmacological intervention may delay hematopoietic failure and possibly improve the production of oocytes with better-preserved telomeres in female DC patients. Our model provides a valuable framework for assessing (or understanding, or both) disease progression and evaluating therapeutic strategies in telomeropathy-associated bone marrow failure.

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare acquired hematopoietic disorder requiring careful therapeutic management. In resource-limited settings, traditional treatments may carry significant risks. A 32-year-old female with PNH developed acute pancreatitis 10 months after initiation of danazol and deflazacort therapy. Initial presentation included typical hemoglobinuria, pancytopenia, and indirect hyperbilirubinemia. Flow cytometry confirmed PNH clones despite a negative Ham's test. Treatment with danazol 200 mg twice daily and deflazacort 30 mg daily initially provided clinical improvement. Subsequently, the patient developed pigment nephropathy requiring dialysis, followed by severe acute pancreatitis with markedly elevated pancreatic enzymes (amylase: 3370 U/L and lipase: 12,478 U/L). Ultrasonography revealed a bulky pancreatic head with heterogeneous echotexture. Other causes of pancreatitis were excluded. Both medications were discontinued, and conservative management led to clinical recovery. This case represents drug-induced pancreatitis, a rare but serious complication of PNH therapy. Both danazol and corticosteroids have been independently associated with acute pancreatitis in the literature, though reports remain sparse. The concurrent use of these agents may have contributed synergistically to pancreatic inflammation. The patient's clinical course, including androgenic side effects and temporal relationship with drug exposure, supports the causal association. Healthcare providers managing PNH in African settings must remain vigilant for drug-induced pancreatitis when using traditional therapies. Enhanced monitoring protocols and improved access to safer complement inhibitors are essential for optimizing patient outcomes while minimizing treatment-related complications in resource-limited environments.