Paired comparisons of venetoclax concentration in cerebrospinal fluid, bone marrow, and plasma in acute leukemia patients.

Venetoclax, a small molecule inhibitor of BCL-2, has demonstrated efficacy in treating acute leukemias and has been recommended as one of the first-line anti-leukemia therapies. Although venetoclax has been suggested to probably possess the ability to penetrate the central nervous system (CNS), current data to elucidate the characteristics of venetoclax in cerebrospinal fluid (CSF), bone marrow (BM), and plasma are still lacking. This study investigated the real-world characteristics of venetoclax concentrations in CSF, BM, and plasma in acute leukemia patients. Thirteen acute leukemia patients treated with venetoclax were included, with paired samples of CSF, BM, and plasma collected and venetoclax concentrations measured using LC-MS/MS. With the results, the median venetoclax concentrations were 2030 ng/mL in plasma, 16.7 ng/mL in CSF, and 1390 ng/mL in BM. The percentages of CSF/plasma and BM/plasma were 0.74% and 70.37%, respectively. While no direct correlation was observed between CSF and plasma venetoclax levels, there was a trend toward an improved CSF/plasma percentage over time following the last administration of venetoclax. In contrast, a strong correlation was found between BM and plasma levels. This study demonstrated that venetoclax could reach its effective concentration in most patients, suggesting its potential clinical utility in the management of CNS involvement in acute leukemia.

Prediction of prognosis in supramalleolar osteotomy with or without additional fibula osteotomy by approaching a biomechanical study: a finite element analysis.

Supramalleolar osteotomy (SMO) is a representative procedure to restore a malalignment in the varus ankle deformity by shifting the concentrated pressure on the medial ankle joint to the lateral area. Additionally, fibula osteotomy (FO) is selectively selected and performed according to the surgeon's preference. However, it is controversial whether FO is effective in shifting the abnormal pressure from the medial to the lateral area on the ankle joint. Some cadaveric studies have been performed to prove this. However, it is difficult to consistently reconstruct amount of the varus ankle deformities angle in cadavers and to guarantee reliable contact pressure between the ankle joint. Thus, the aim of this study was predicted and quantitatively compared a peak pressure between single SMO and SMO with FO procedure by using a finite element analysis as a powerful biomechanical tool to those limitations of cadaveric study. This study reconstructed total 4 3D foot and ankle models including a normal and pre-op model and 2 post-op models. The pre-op model was modified by assigning 10° varus tilting corresponding to stage 3b in the classification of varus ankle osteoarthritis based on the validated normal model. Also, the post-op models were reconstructed by applying single SMO and SMO with FO, respectively. All of the models were assumed as one-leg standing position and to mimic smooth ankle joint motion. Peak contact pressure change was predicted at the medial ankle joint by using computational simulation. As a result, 2 post-op models showed a remarkably peak pressure reduction by up to 5.5 times on the medial tibiotalar joint. However, a comparison between single SMO and SMO with FO model showed no appreciable differences. In conclusion, this study predicted that single SMO may be as effective as SMO with FO in reducing peak contact pressure on the medial tibiotalar joint in varus ankle osteoarthritis.

Nitrogen-Doped Carbon Dots: A New Powerful Fluorescent Dye with Substantial Effect on Bacterial Cell Labeling.

Carbon dots (CDs)-minute carbon nanoparticles with remarkable luminescent properties, photostability, and low toxicity-show potential for various applications. CDs synthesized using citric acid and urea are the least toxic to biological environments. Here, we aimed to explore the effect of CDs synthesized using citric acid and urea at 50, 33, and 25% (CDs 1/1, 1/2, and 1/3, respectively) weight ratios in a microwave on bacterial cell fluorescence sensing and labeling. The nanoscale properties of CDs were investigated via transmission electron microscopy and dynamic light scattering particle size analysis. X-ray powder diffraction confirmed the graphitic structures of CDs. X-ray photoelectron spectroscopy revealed that the nitrogen content increased gradually with increasing urea ratios, indicating functional group changes. Transient photoluminescence decay periods demonstrated superior fluorescence intensity of CDs 1/3 under blue, green, and red lights. The use of CDs was notably more efficient than traditional methods in staining bacterial cells. Fluorescence microscopy of 10 g-positive and 10 g-negative bacteria revealed enhanced staining of Gram-positive strains, with CDs 1/3 presenting the best results. The CDs exhibited excellent photostability, maintaining poststaining fluorescence for 100 min, surpassing the performance of conventional dyes. CDs could serve as potential fluorescent dyes for the rapid discrimination of Gram-positive and Gram-negative bacteria.

Chromosome 1q21 Aberrations Are Poor Prognostic Factors for Newly Diagnosed Multiple Myeloma Patients.

BACKGROUND: Chromosome 1q21 aberrations are one of the most common cytogenetic abnormalities in patients with multiple myeloma (MM). However, the prognostic value remains controversial. This study aimed to determine the prognostic value of numerical abnormalities of chromosome 1q21 for newly diagnosed patients with MM patients in Chinese population. METHODS: We retrospectively analyzed 629 patients with newly diagnosed MM who received the detection of chromosome 1q21 by fluorescence in situ hybridization in China. RESULTS: Among 629 patients, 309 (49.1%) had 1q21 abnormalities, of which 187 (29.7%) had three copies and 122 (19.4%) had four or more copies. Patients with two copies of 1q21 had a significantly longer median overall survival (OS) than those with three copies or ≥4 copies and also had longer progression-free survival (PFS). However, patients with three or ≥4 copies had similar OS and PFS. Univariate Cox proportional hazards regression analyses determined that 1q21 aberrations are associated with shorter OS and PFS. 1q21 aberrations are also independent poor prognostic factors for OS and PFS in multivariable analyses. Del(17p), t(4;14), and t(14;16) are common high-risk cytogenetic abnormalities (HRCAs) in patients with MM. Patients with 1q21+ alone or 1q21+ combined with HRCAs had shorter OS and PFS than patients without cytogenetic abnormalities. Patients with 1q21+ and t(11;14) also had shorter PFS but had similar OS than patients without cytogenetic abnormalities. CONCLUSION: Our study showed that chromosome 1q21 aberrations are poor prognostic factors for newly diagnosed patients with MM.

Structural and Mutational Analyses of Trehalose Synthase from Deinococcus radiodurans Reveal the Interconversion of Maltose-Trehalose Mechanism.

Trehalose synthase (TreS) catalyzes the reversible interconversion of maltose to trehalose, playing a vital role in trehalose production. Understanding the catalytic mechanism of TreS is crucial for optimizing the enzyme activity and enhancing its suitability for industrial applications. Here, we report the crystal structures of both the wild type and the E324D mutant of Deinococcus radiodurans trehalose synthase in complex with the trehalose analogue, validoxylamine A. By employing structure-guided mutagenesis, we identified N253, E320, and E324 as crucial residues within the +1 subsite for isomerase activity. Based on these complex structures, we propose the catalytic mechanism underlying the reversible interconversion of maltose to trehalose. These findings significantly advance our comprehension of the reaction mechanism of TreS.

NLRP3 Inflammasome Deficiency Alleviates Inflammation and Oxidative Stress by Promoting PINK1/Parkin-Mediated Mitophagy in Allergic Rhinitis Mice and Nasal Epithelial Cells.

Purpose: Accumulating evidence indicates that oxidative stress and inflammation are the pathological basis of allergic diseases. Inhibition of NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome could ameliorate allergic rhinitis (AR). Here, we explored the effects and mechanisms that underlie NLRP3 inhibition on oxidative stress and inflammation in AR. Methods: Ovalbumin (OVA)-induced AR murine model was established using wild-type (WT) and NLRP3-deficient mice. HNEpCs were stimulated with interleukin (IL)-13 with MCC950 pretreatment or PTEN-induced putative kinase 1 (PINK1) siRNA. The indicators of oxidative stress, inflammation, apoptosis, and mitophagy were determined both in vivo and in vitro. Results: NLRP3 knockout (KO) reduced the frequency of nasal rubbing and sneezing, the infiltration of eosinophils, the number of mast cells, and the accumulation of goblet cells in AR mice after OVA stimulation. The NLRP3 KO AR mice exhibited the increased concentrations of OVA-specific immunoglobulin E (OVA-sIgE), IL-1ß, IL-4, IL-13, IL-6, TNF-α, and the upregulated level of IFN-γ. NLRP3 KO significantly inhibited oxidative stress, and also markedly decreased apoptosis in the nasal mucosa of AR mice. Moreover, evaluated protein expressions of PINK1, enzyme 3 (E3) ubiquitin ligase PRKN (Parkin), and LC3 II, decreased expression of TOM20, as well as the increased colocalization of LC3 with mitochondria were observed in NLRP3 KO AR mice. In vitro, IL-13 exposure increased the levels of NLRP3 and IL-1ß. Inhibition of NLRP3 using MCC950 enhanced PINK1/Parkin-mediated mitophagy but attenuated inflammation, oxidative stress, and apoptosis. However, PINK1 knockdown abrogated mitophagy and also reversed the protective effects of MCC950 on inflammation, oxidative stress, and apoptosis in HNEpCs stimulated with IL-13. Conclusion: Inhibition of NLRP3 inflammasome exerts the protective effects on AR by facilitating mitophagy regulated by PINK1/Parkin signaling pathway.

Development of a clinical prognostic model for primary plasma cell leukemia patients treated with novel agents: a multicenter retrospective cohort study.

The prognosis of primary plasma cell leukemia (pPCL) is poor, and the relevant prognostic factors are incompletely understood. We aimed to explore the prognostic factors and develop a validated prognostic prediction model for pPCL patients in the new era. This multicenter retrospective study was conducted across 16 hospitals in China. Cox proportional hazards regression analysis was used to develop a prediction model. The predictive performance of the model was assessed using multiple metrics. Internal validation was conducted using bootstrap resampling. A total of 102 pPCL patients were included in this study, and 57 (55.9%) were male. The 12-month, 24-month, and 36-month OS rates for pPCL patients were 75.4%, 58.3%, and 47.6%, respectively. An overall survival prognostic nomogram for pPCL patients was established by integrating independent prognostic factors, including age, B2MG, and del17p. The nomogram exhibited good performance, with a C-index of 0.720 (95% CI 0.642-0.797) and an AUC of 0.653. Bootstrap validation yielded a C-index of 0.721 (95% CI 0.629-0.787) and an AUC of 0.653 (95% CI 0.546-0.759), indicating a relatively good fit of the calibration curve. A nomogram incorporating age, B2MG grade, and del17p were developed and validated to accurately and consistently predict the prognosis of pPCL patients.

Quantitative analysis of sagittal curvatures of the tibial plafond by computed tomography.

Background: Although the talar morphology has been well understood, studies on the corresponding tibial plafond are still lacking. Based on computed tomography (CT) data, this quantitative study divided the tibial plafond into anterior and posterior regions on five sagittal sections. The objectives of this study were (I) to determine whether the sagittal curvatures of the tibial plafond can be quantitatively and accurately described using the double-diameter method; (II) to compare the difference between the anterior and posterior diameters on five sagittal sections. Methods: In this study, CT data were collected from 100 adult ankles, and the three-dimensional (3D) ankle joint model was reconstructed using CT images. An anatomical coordinate system of the 3D ankle joint model was created to establish the standard coronal and sagittal planes. The measurement outcomes of sagittal curvatures included: the anterior and posterior diameters, the distal tibial arc length (TiAL) and the distal tibial mortise depth (TMD) on five sagittal sections (the most medial, medial 1/4, middle, lateral 1/4 and the most lateral section). Subgroup analysis was performed to compare the differences between males and females. Results: Analysis of the sagittal curvatures showed that the anterior diameter of tibial plafond was significantly smaller than the posterior diameter on five sagittal sections with a mean difference ranging from 3.9 to 6.8 mm (P<0.001). For the anterior diameters, the anteromedial curve had the smallest diameter (35.3±5.3 mm), and the anterolateral curve had the largest diameter (38.0±5.8 mm). For the posterior diameter, the posteromedial curve had the smallest diameter (39.2±6.4 mm), and the posterolateral 1/4 curve had the largest diameter (43.5±6.9 mm). One-way analysis of variance (ANOVA) revealed significant differences in the anterior and posterior diameters among five groups (P<0.012). Subgroup analysis showed that gender partly affected the results of sagittal curvature measurements. Conclusions: The sagittal curvatures of the tibial plafond can be described quantitatively and accurately using anterior and posterior diameters. Our study showed that there were significant differences between the anterior and posterior diameters, and gender was an important factor influencing the sagittal curvatures of the tibial plafond.

Asymmetric Organocatalytic 1,3-Dipolar Cycloaddition of Azomethine Ylides with ß-Substituted Cyclic Enones.

The enantioselective and diastereoselective control of 1,3-dipolar cycloaddition reactions to ß-substituted cyclic enones has been developed. The 1,3-dipolar cycloaddition of phthalazinium dicyanomethanides with cyclic dienones affords chiral tetrahydropyrrolo[2,1-a]phthalazine derivatives 3 through vinylogous iminium ion activation by combining a cinchona-based primary amine C3 and a chiral camphorsulfonic acid additive. Conversely, with a weaker 3,5-bis(trifluoromethyl)benzoic acid additive, the 1,3-dipolar cycloaddition of phthalazinium dicyanomethanides with ß-substituted cyclic enones leads to chiral hexahydroisoindolo[1,2-a]phthalazin-10(8H)-one derivatives 4 with excellent stereocontrol via endo-dienamine activation.

2,2',4,4'-Tetrabromodiphenyl Ether (BDE-47) at Environmental Levels Influenced Photosynthesis in the Mangrove Species Kandelia obovata.

2,2',4,4'-tetra-bromodiphenytol ether (BDE-47) is one of the ubiquitous organic pollutants in mangrove sediments. To reveal the toxic effects of BDE-47 on mangrove plants, the mangrove species Kandelia obovate was used to investigate the photosynthetic capacity effects and the molecular mechanisms involved after BDE-47 exposure at environment-related levels (50, 500, and 5000 ng g-1 dw). After a 60-day exposure, the photosynthetic capacity was inhibited in K. obovata seedlings, and a decrease in the stomatal density and damage in the chloroplast ultrastructure in the leaves were found. Transcriptome sequencing showed that, following exposure to BDE-47, gene expression in photosynthesis-related pathways was predominantly suppressed in the leaves. The bioinformatics analysis indicated that BDE-47 exerts toxicity by inhibiting photosystem I activity and chlorophyll a/b-binding protein-related genes in the leaves of K. obovata. Thus, this study provides preliminary theoretical evidence for the toxic mechanism effect of BDE-47 on photosynthesis in mangrove species.

Bioequivalence of Recombinant Human Teriparatide Injection in Healthy Adult Female Subjects in the Fasting State.

A single-center, randomized, open, 2-period, self-crossover, single-dose trial was conducted to evaluate the bioequivalence of the test (T) and reference (R) preparations in healthy adult female subjects under fasting conditions. Seventy-six subjects were enrolled in the study, and subjects were randomly divided into 2 groups at a 1:1 ratio and were administered once per period, with a 4-day washout period. In each period, plasma drug concentrations, blood calcium changes, and antibodies were determined for pharmacokinetics, pharmacodynamics, and immunogenicity analysis, respectively, and adverse events were recorded for safety analysis. The 90% confidence intervals for the geometric mean ratios (T:R) of maximum plasma concentration, area under the plasma concentration-time curve from time 0 to the last measurable concentration, and area under the plasma concentration-time curve from time 0 to infinity were within the predefined bioequivalence criterion of 80%-125%, indicating bioequivalence between the T and R preparations under fasting conditions. Comparable serum calcium levels demonstrated pharmacodynamics similarity, and no differences were found in immunogenicity profiles. Additionally, the incidence of adverse reactions to the T preparation was 18.4% lower than that of the R preparation (31.6%). This study confirmed the bioequivalence of the T and R preparations under fasting conditions, along with comparable immunogenicity profiles and good safety.

Health economics study of paliperidone palmitate in the treatment of schizophrenia: a 12-month cohort study.

BACKGROUND: To analyze the economic benefits of paliperidone palmitate in the treatment of schizophrenia. METHODS: We collected 546 patients who met the diagnostic criteria for schizophrenia according to the 《International Statistical Classification of Diseases and Related Health Problems,10th》(ICD-10). We gathered general population data such as gender, age, marital status, and education level, then initiated treatment with paliperidone palmitate. Then Follow-up evaluations were conducted at 1, 3, 6, 9, and 12 months after the start of treatment to assess clinical efficacy, adverse reactions, and injection doses. We also collected information on the economic burden before and after 12 months of treatment, as well as the number of outpatient visits and hospitalizations in the past year to analyze economic benefits. RESULTS: The baseline patients totaled 546, with 239 still receiving treatment with paliperidone palmitate 12 months later. After 12 months of treatment, the number of outpatient visits per year increased compared to before (4 (2,10) vs. 12 (4,12), Z=-5.949, P < 0.001), while the number of hospitalizations decreased (1 (1,3) vs. 1 (1,2), Z = 5.625, P < 0.001). The inpatient costs in the direct medical expenses of patients after 12 months of treatment decreased compared to before (5000(2000,12000) vs. 3000 (1000,8050), P < 0.05), while there was no significant change in outpatient expenses and direct non-medical expenses (transportation, accommodation, meal, and family accompanying expenses, etc.) (P > 0.05); the indirect costs of patients after 12 months of treatment (lost productivity costs for patients and families, economic costs due to destructive behavior, costs of seeking non-medical assistance) decreased compared to before (300(150,600) vs. 150(100,200), P < 0.05). CONCLUSION: Palmatine palmitate reduces the number of hospitalizations for patients, as well as their direct and indirect economic burdens, and has good economic benefits.

[Clinical Significance of USP5 Expression Level in Acute Myeloid Leukemia and Its Regulatory Effects on AKT/mTOR/4EBP1 Signaling Pathway].

OBJECTIVE: To investigate the clinical significance, functional role and potential downstream mechanism of USP5 in acute myeloid leukemia (AML). METHODS: The expression of USP5 in AML and normal tissues and its correlation with patients' survival were analyzed based on TCGA database. USP5 was knocked down and overexpressed in Jurkat and HL-60 cells using lentivirus. USP5 mRNA and protein expression were detected by RT-qPCR and Western blot, respectively. Cell proliferation and growth were measured by CCK-8 and methylcellulose colony-forming assay. Flow cytometry was used to analyze cell cycle and apoptosis. RESULTS: USP5 was highly expression in AML compared with normal tissues. Up-regulation of USP5 was negatively correlated with the survival of AML patients. USP5 knockdown and overexpression inhibited and promoted the proliferation and colony growth of AML cells, respectively. Cell cycle arrest and apoptosis were induced in USP5 knockdown Jurkat and HL-60 cells. Furthermore, USP5 knockdown inhibited the phosphrylation of AKT, mTOR and 4EBP1. CONCLUSION: Overexpression of USP5 predicts poor survival of AML patients. Targeting USP5 suppresses AKT/mTOR/4EBP1 signaling and reduces the proliferation and growth of AML cells.

The prognostic value of ubiquitin/ubiquitin-like-related genes along with immune cell infiltration and clinicopathological features in osteosarcoma.

BACKGROUND: Ubiquitin/ubiquitin-like (Ub/UBL)-related genes have been reported to be associated with the survival of osteosarcoma patients but have not yet been systematically explored. METHODS: The prognostic value of Ub/UBL-related genes, immune cell infiltration and clinicopathological features of patients were explored by Cox and LASSO regression analyses. A prognostic model was established and then validated in the GSE21257 dataset. The differential expression of hub genes in osteosarcoma was confirmed by qRT-PCR, western blotting and immunohistochemistry. RESULTS: Tripartite Motif Containing 8 (TRIM8) and Ubiquitin Like With PHD And Ring Finger Domains 2 (UHRF2) were screened as genes with prognostic value in osteosarcoma. Kaplan-Meier analysis and scatter plots indicated that patients in the high gene significance score group tended to have a worse prognosis. The concordance index, calibration analysis and receiver operating characteristic analysis suggested that the model had good prediction accuracy and high sensitivity and specificity. Decision curve analysis revealed that patients could obtain greater net benefit from this model. Functional analyses of the differentially expressed genes indicated that they were involved in important functions and pathways. TRIM8 and UHRF2 were confirmed to be highly expressed in osteosarcoma cell lines and tissues. CONCLUSIONS: TRIM8 and UHRF2 are potential prognostic genes in osteosarcoma, and these results provide insights into the roles of these genes and their implications for patient outcomes.

Complete genome sequence of Sphingomonas sp. strain R1, a bacterium isolated from tomato (Solanum lycopersicum).

Sphingomonas sp. strain R1 was isolated from the stem of a tomato plant and exhibited antagonism with Agrobacterium. The complete genome sequence of this bacterium consists of one 3,874,532 bp circular chromosome and two plasmids.

Environmental pollution of paraben needs attention: A study of methylparaben and butylparaben co-exposure trigger neurobehavioral toxicity in zebrafish.

Parabens (PBs) are commonly utilized as preservatives in various commodities. Of all the PBs, methylparaben (MeP) and butylparaben (BuP) are usually found together at similar levels in the aqueous environment. Although a few studies have demonstrated that PBs are neurotoxic when present alone, the neurobehavioral toxic effects and mechanisms of coexisting MeP and BuP at environmental levels has not been determined. Neurobehavior is a sensitive indicator for identifying neurotoxicity of environmental pollutants. Therefore, adult female zebrafish (Danio rerio) were chronic co-exposure of MeP and BuP at environmental levels (5, 50, and 500 ng/L) for 60 d to investigate the effects on neurobehavior, histopathology, oxidative stress, mitochondrial function, neurotransmitters and gene expression. The results demonstrated that chronic co-exposure of MeP and BuP interfered with several behaviors (learning-memory, anxiety, fear, aggressive and shoaling behavior) in addition to known mechanisms of producing oxidative stress and disrupting energy. More intriguingly, chronic co-exposure of MeP and BuP caused retinal vacuolization and apoptosis in the optic tectum zone. It even has further effects on the phototransduction pathway, impairing optesthesia and leading to neurotransmitters dysregulation. These are critical underlying mechanisms resulting in neurobehavioral abnormalities. This study confirms that the pollution of multiple PBs by chronic co-exposure in aquatic environments can result neurobehavioral toxicity. It also suggests that the prolonged effects of PBs on aquatic ecosystems and health require close attention.

Dynamic Microcirculation Characteristics of Plantar Skin Under Metatarsal Head of Human Foot in Response to Life-Like Pressure Stimulus.

OBJECTIVE: Diabetic foot ulcer (DFU) is a severe complication with high mortality. High plantar pressure and poor microcirculation are considered main causes of DFU. The specific aims were to provide a novel technique for real-time measurement of plantar skin blood flow (SBF) under walking-like pressure stimulus and delineate the first plantar metatarsal head dynamic microcirculation characteristics because of life-like loading conditions in healthy individuals. METHODS: Twenty young healthy participants (14 male and 6 female) were recruited. The baseline (i.e., unloaded) SBF of soft tissue under the first metatarsal head were measured using laser Doppler flowmetry (LDF). A custom-made machine was utilized to replicate daily walking pressure exertion for 5 min. The exerted plantar force was adjusted from 10 N (127.3 kPa) to 40 N (509.3 kPa) at an increase of 5 N (63.7 kPa). Real-time SBF was acquired using the LDF. After each pressure exertion, postload SBF was measured for comparative purposes. Statistical analysis was performed using the R software. RESULTS: All levels of immediate-load and postload SBF increased significantly compared with baseline values. As the exerted load increased, the postload and immediate-load SBF tended to increase until the exerted load reached 35 N (445.6 kPa). However, in immediate-load data, the increasing trend tended to level off as the exerted pressure increased from 15 N (191.0 kPa) to 25 N (318.3 kPa). For postload and immediate-load SBF, they both peaked at 35 N (445.6 kPa). However, when the exerted force exceeds 35 N (445.6 kPa), both the immediate-load and postload SBF values started to decrease. CONCLUSIONS: Our study offered a novel real-time plantar soft tissue microcirculation measurement technique under dynamic conditions. For the first metatarsal head of healthy people, 20 N (254.6 kPa)-plantar pressure has a fair microcirculation stimulus compared with higher pressure. There might be a pressure threshold at 35 N (445.6 kPa) for the first metatarsal head, and soft tissue microcirculation may decrease when local pressure exceeds it.

Efficacy and safety of sovleplenib (HMPL-523) in adult patients with chronic primary immune thrombocytopenia in China (ESLIM-01): a randomised, double-blind, placebo-controlled, phase 3 study.

BACKGROUND: Sovleplenib, a novel spleen tyrosine kinase (SYK) inhibitor, showed promising safety and activity in patients with primary immune thrombocytopenia in a phase 1b/2 trial. We aimed to evaluate the efficacy and safety of sovleplenib in patients with chronic primary immune thrombocytopenia. METHODS: This randomised, double-blind, placebo-controlled, phase 3 trial (ESLIM-01) was done in 34 clinical centres in China. Eligible patients, aged 18-75 years, had chronic primary immune thrombocytopenia, an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, and received one or more previous treatments. Patients were randomly assigned (2:1) to receive oral sovleplenib or placebo, 300 mg once daily, for 24 weeks. Randomisation was stratified by baseline platelet counts, previous splenectomy, and concomitant treatment for anti-immune thrombocytopenia at baseline. The primary endpoint was durable response rate (proportion of patients with a platelet count of ≥50 × 109/L on at least four of six scheduled visits between weeks 14 and 24, not affected by rescue treatment) assessed by intention-to-treat. The trial is registered with ClinicalTrials.gov, NCT05029635, and the extension, open-label phase is ongoing. FINDINGS: Between Sept 29, 2021, and Dec 31, 2022, 188 patients were randomly assigned to receive sovleplenib (n=126) or placebo (n=62). 124 (66%) were female, 64 (34%) were male, and all were of Asian ethnicity. Median previous lines of immune thrombocytopenia therapy were 4·0, and 134 (71%) of 188 patients had received previous thrombopoietin or thrombopoietin receptor agonist. The primary endpoint was met; durable response rate was 48% (61/126) with sovleplenib compared with zero with placebo (difference 48% [95% CI 40-57]; p<0·0001). The median time to response was 8 days with sovleplenib compared with 30 days with placebo. 125 (99%) of 126 patients in the sovleplenib group and 53 (85%) of 62 in the placebo group reported treatment-emergent adverse events (TEAEs), and most events were mild or moderate. Frequent TEAEs of grade 3 or higher for sovleplenib versus placebo were platelet count decreased (7% [9/126] vs 10% [6/62]), neutrophil count decreased (3% [4/126] vs 0% [0/62]), and hypertension (3% [4/126] vs 0% [0/62]). Incidences of serious TEAEs were 21% (26/126) in the sovleplenib group and 18% (11/62) in the placebo group. There were no deaths in the study. INTERPRETATION: Sovleplenib showed a clinically meaningful sustained platelet response in patients with chronic primary immune thrombocytopenia, with a tolerable safety profile and improvement in quality of life. Sovleplenib could be a potential treatment option for patients with immune thrombocytopenia who received one or more previous therapy. FUNDING: HUTCHMED and Science and Technology Commission of Shanghai Municipality.

The establishment of a multiple myeloma clinical registry in the Asia-Pacific region: The Asia-Pacific Myeloma and Related Diseases Registry (APAC MRDR).

BACKGROUND: Multiple myeloma (MM) is the second most common haematological cancer worldwide. Along with related diseases including monoclonal gammopathy of undetermined significance (MGUS), plasma cell leukaemia (PCL) and plasmacytoma, MM incidence is rising, yet it remains incurable and represents a significant disease burden. Clinical registries can provide important information on management and outcomes, and are vital platforms for clinical trials and other research. The Asia-Pacific Myeloma and Related Diseases Registry (APAC MRDR) was developed to monitor and explore variation in epidemiology, treatment regimens and their impact on clinical outcomes across this region. Here we describe the registry's design and development, initial data, progress and future plans. METHODS: The APAC MRDR was established in 2018 as a multicentre collaboration across the Asia-Pacific, collecting prospective data on patients newly diagnosed with MM, MGUS, PCL and plasmacytoma in Korea, Singapore, Malaysia and Taiwan, with China recently joining. Development of the registry required a multidisciplinary team of clinicians, researchers, legal and information technology support, and financial resources, as well as local clinical context from key opinion leaders in the APAC region. Written informed consent is obtained and data are routinely collected throughout treatment by hospital staff. Data are stored securely, meeting all local privacy and ethics requirements. Data were collected from October 2018 to March 2024. RESULTS: Over 1700 patients from 24 hospitals have been enrolled onto the APAC MRDR to date, with the majority (86%) being newly diagnosed with MM. Bortezomib with an immunomodulatory drug was most frequently used in first-line MM therapy, and lenalidomide-based therapy was most common in second-line. Establishment and implementation challenges include regulatory and a range of operational issues. CONCLUSION: The APAC MRDR is providing 'real-world' data to participating sites, clinicians and policy-makers to explore factors influencing outcomes and survival, and to support high quality studies. It is already a valuable resource that will continue to grow and support research and clinical collaboration in MM and related diseases across the APAC region.

Manganese Oxides with Different Morphologies In Situ Anchored onto Ti3C2Tx Nanosheets: Highly Effective Decontamination toward Sulfur Mustard Simulants.

Manganese oxides with porous structure and abundant active sites show potential in degrading sulfur mustard (HD). However, there is an interface effect between the oily liquid HD and nano oxides, and the powder is prone to agglomeration, which leads to incomplete contact and limited degradation ability. Here, we demonstrate a simple hydrothermal method for preparing MnO2/Ti3C2 composites to address this problem. The influence of morphology and crystal structure on performance are examined. Herein, flower-like MnO2 is loaded onto the surface or interlayer of Ti3C2-MXene nanosheets during in situ formation, significantly expanding the specific surface area. It also provides abundant acid-base sites and oxygen vacancies for the degradation of simulants 2-chloro-ethyl-ethyl thioether (2-CEES) without external energy, resulting in a reaction half-life as fast as 12.5 min. The relationship between structure and performance is clearly elaborated through temperature-programmed desorption (TPD), X-ray photoelectron spectroscopy (XPS), and X-ray absorption fine structure (XAFS) analyses. Based on in situ attenuated total reflection-Fourier transform infrared (ATR-FTIR) analysis, gas chromatography-mass spectrometry (GC-MS) analysis, and density functional theory (DFT) calculation, the proposed degradation pathway of the 2-CEES molecule is a synergistic effect of hydrolysis, elimination, and oxidation. Furthermore, the products are nontoxic or low toxic. Metal oxide/MXene composites are first illustrated for their potential use in degrading sulfur mustard, suggesting new insights into these materials as novel decontamination for decomposing chemical warfare agents.