Sirolimus is effective for refractory/relapsed idiopathic multicentric Castleman disease: A single-center, retrospective study.

Refractory/relapsed idiopathic multicentric Castleman disease (R/R iMCD) has limited treatment options. With studies showing increased mTOR activation in iMCD patients, sirolimus becomes an attractive and promising therapy for R/R iMCD. Here we report the results of a retrospective study involving 26 R/R iMCD patients treated with sirolimus-containing regimen. The median age at sirolimus initiation was 40.5 years (23-60), with a median prior treatment line of 2 (1-5). 18 patients (69.2%) achieved symptomatic and biochemical response, with a median time to at least overall partial remission of 1.9 months (0.5-14.6). The median follow-up time from sirolimus initiation was 11.7 months (1.6-50.7) and the median time to next treatment (TTNT) was 46.2 months. No patients died at the end of follow-up. Most of the patients in the cohort are in ongoing responses and continue sirolimus therapy. Sirolimus is well tolerated with minor adverse effects. In conclusion, sirolimus is effective for R/R iMCD patients with good tolerance.

The Liquid-Fermentation Formulation of Sanghuangporus sanghuang Optimized by Response Surface Methodology and Evaluation of Biological Activity of Extracellular Polysaccharides.

Sanghuangporus sanghuang is a rare fungus growing on mulberry trees that has immense medicinal value. This study aimed to optimize the liquid-fermentation-media formulation and culture conditions for large-scale culturing of S. sanghuang by performing one-way testing and response surface methodology. The antioxidant and anticancer activities of the extracellular polysaccharides from S. sanghuang were also analyzed. The optimal formulation and growth conditions for S. sanghuang were as follows: glucose, 30.2 ± 0.37 g/L; yeast extract, 14.60 ± 0.05 g/L; dandelion powder, 1.24 ± 0.01 g/L; shaker speed, 150 r/min; and temperature, 25 °C. We obtained 13.99 ± 0.42 g/L of mycelium biomass by culturing S. sanghuang for 15 days with the optimized formulation. This was 2-fold higher than the mycelial mass obtained with the sub-optimal formulation. The extracellular fungal polysaccharides showed significant antioxidant activity against ABTS and DPPH free radicals, and significantly reduced the in vitro growth and survival of several cancer cell lines. The anticancer activity of the extracellular fungal polysaccharides was significantly higher in the human glioma cells than in other cancer cell lines. In summary, this study optimized the liquid media formulation and conditions for the large-scale culturing of S. sanghuang. Furthermore, the extracellular polysaccharides from S. sanghuang showed significant antioxidant and anticancer activities.

A prospective study of zanubrutinib, a Bruton tyrosine kinase inhibitor, in relapsed/refractory idiopathic multicentric Castleman disease.

Relapsed and refractory (R/R) idiopathic multicentric Castleman disease (iMCD) is a clinical challenge with no standard treatment. In this preliminary clinical trial, we investigated the efficacy and safety profiles of a Bruton tyrosine kinase inhibitor (BTKi), zanubrutinib, in patients with R/R iMCD. The primary endpoint was the overall response rate at Week 12 according to the Castleman Disease Collaborative Network (CDCN) response criteria. The trial was terminated early due to a lack of treatment response in the first enrolled 5 patients. Although 3 patients achieved symptomatic response, none of the 5 patients had an overall response by Week 12. One patient had progressive disease and the other 4 had stable disease. The study drug was well tolerated without grade 2 or higher adverse events. Our findings suggest that BTKi therapy is not effective for iMCD, and further attempts at single-agent therapy with zanubrutinib or other BTKis for iMCD should be considered with caution and probably avoided. This trial was registered at www.clinialtrials.gov as #NCT04743687.

Idiopathic multicentric Castleman disease (iMCD)-idiopathic plasmacytic lymphadenopathy: A distinct subtype of iMCD-not otherwise specified with different clinical features and better survival.

Idiopathic multicentric Castleman disease (iMCD) is subclassified into iMCD-thrombocytopenia, anasarca, reticulin fibrosis, renal dysfunction, organomegaly (TAFRO) and iMCD-not otherwise specified (NOS) according to the Castleman Disease Collaborative Network (CDCN) consensus criteria. With a deeper understanding of iMCD, a group of patients with iMCD-NOS characterised by polyclonal hypergammaglobulinaemia, plasmacytic/mixed-type lymph node histopathology and thrombocytosis has attracted attention. This group of patients has been previously described as having idiopathic plasmacytic lymphadenopathy (IPL). Whether these patients should be excluded from the current classification system lacks sufficient evidence. This retrospective analysis of 228 patients with iMCD-NOS identified 103 (45.2%) patients with iMCD-IPL. The clinical features and outcomes of patients with iMCD-IPL and iMCD-NOS without IPL were compared. Patients with iMCD-IPL showed a significantly higher inflammatory state but longer overall survival. No significant difference in overall survival was observed between severe and non-severe patients in the iMCD-IPL group according to the CDCN severity classification. Compared with lymphoma-like treatments, multiple myeloma-like and IL-6-blocking treatment approaches in the iMCD-IPL group resulted in significantly higher response rates and longer time to the next treatment. These findings highlight the particularities of iMCD-IPL and suggest that it should be considered a new subtype of iMCD-NOS.

Self-Report Amphiphilic Polymer-Based Drug Delivery System with ROS-Triggered Drug Release for Osteoarthritis Therapy.

The development of drug delivery systems with real-time cargo release monitoring capabilities is imperative for optimizing nanomedicine performance. Herein, we report an innovative self-reporting drug delivery platform based on a ROS-responsive random copolymer (P1) capable of visualizing cargo release kinetics via the activation of an integrated fluorophore. P1 was synthesized by copolymerization of pinacol boronate, PEG, and naphthalimide monomers to impart ROS-sensitivity, hydrophilicity, and fluorescence signaling, respectively. Detailed characterization verified that P1 self-assembles into 11 nm micelles with 10 µg mL-1 CMC and can encapsulate hydrophobic curcumin with 79% efficiency. Fluorescence assays demonstrated H2O2-triggered disassembly and curcumin release with concurrent polymer fluorescence turn-on. Both in vitro and in vivo studies validated the real-time visualization of drug release and ROS scavenging, as well as the therapeutic effect on osteoarthritis (OA). Overall, this nanotheranostic polymeric micelle system enables quantitative monitoring of drug release kinetics for enhanced treatment optimization across oxidative stress-related diseases.

Treatment Response Assessment in Multiple Myeloma: Histogram Analysis of Total Tumor Apparent Diffusion Coefficient based on Whole-body Diffusion-weighted MR Imaging.

BACKGROUND: The International Myeloma Working Group (IMWG) consensus criteria for response assessment in multiple myeloma (MM) has methodological limitations. Whole-body diffusion-weighted imaging (DWI) with apparent diffusion coefficient (ADC) histogram analysis may be complementary to response assessment of MM. PURPOSE: To explore the role of histogram analysis of the ADC based on the total tumor volume (ttADC) in response assessment in patients with newly diagnosed MM (NDMM). STUDY TYPE: Retrospective. POPULATION: Thirty-six patients with NDMM. FIELD STRENGTH/SEQUENCE: 3.0T/single-shot DWI echo planar imaging (EPI) sequence with an integrated slice-by-slice shimming (iShim) technique. ASSESSMENT: Baseline (median: 1 day before treatment) and post-treatment (median: five cycles of therapy) whole-body DWI were analyzed. A region of interest (ROI) containing lesions on every section of baseline image was drawn to derive the per-patient total tumor data. Post-treatment image analysis was based on the same ROI as the corresponding baseline. Histogram metrics were extracted from both ROIs. Patients were categorized into the very good partial response or better (VGPR+) group and the less than VGPR group per the IMWG response criteria for response assessment. Progression-free survival (PFS) was also calculated. STATISTICAL TESTS: Mann-Whitney test and Fisher's exact or Chi-squared tests, Receiver operating characteristic (ROC) analysis and DeLong test, Kaplan-Meier analysis and Cox proportional hazards model. A two-tailed P-value <0.05 was considered statistically significant. RESULTS: Thirty patients were categorized into the VGPR+ group and six into the less than VGPR group. The ttADC histogram changes between post-treatment and baseline metrics (ΔttADC) revealed significant differences in all percentile values between the VGPR+ and less than VGPR groups. For distinguishing VGPR+, ΔttADC_5th percentile had the largest area under the curve (AUC) (0.950, 95% CI 0.821-0.995). Patients with lower ΔttADC_5th percentile values (cutoff point, 188.193) showed significantly longer PFS (HR = 34.911, 95% CI 6.392-190.677). DATA CONCLUSION: ttADC histogram may facilitate response assessment in patients with NDMM. LEVEL OF EVIDENCE: 3 TECHNICAL EFFICACY: Stage 4.

Self-calibrating dual-sensing electrochemical sensors for accurate detection of carbon dioxide in blood.

A paper-based electrochemical dual-function biosensor capable of determining pH and TCO2 was synthesized for the first time using an iridium oxide pH electrode and an all-solid-state ion electrode (ASIE). In the study, to obtain highly reliable results, the biosensor was equipped with a real-time pH correction function before TCO2 measurements. Compared to traditional liquid-filling carbon dioxide detection sensors, the utilization of ferrocene endows our novel sensor with abundant positive sites, and thus greatly improves its performance. Conversely, the introduction of MXene with conductivity close to that of metals reduces electrode resistance, which is beneficial for accelerating the electrochemical reaction of the sensor and reducing LOD. After optimization, the detection range of TCO2 is 0.095 nM-0.66 M, with a detection limit of as low as 0.023 nM. In addition, the sensor was used in real serum sample-spiked recovery experiments and comparison experiments with existing clinical blood gas analyzers, which confirmed the effectiveness of its clinical application. This study provides a method for the rational design of paper-based electrochemical biosensors and a new approach for the clinical detection of blood carbon dioxide.

First detection of cutavirus DNA in stools of patients with rheumatic diseases in Guangzhou, China.

Cutavirus (CuV) is a novel protoparvovirus possibly associated with diarrhea and cutaneous T-cell lymphomas. Patients with rheumatic disease are immunosuppressed and may be more vulnerable to pathogenic viruses. A descriptive study was conducted among hospitalized patients with rheumatic diseases and individuals undergoing medical health check-ups between June 2019 and June 2022 in Guangzhou, China. Stool samples of subjects were tested for CuV DNA. Demographic and fecal examination data of patients were obtained from electronic medical records. A total of 505 patients with rheumatic diseases and 244 individuals who underwent medical health check-ups were included in the study. Of the patients with rheumatic disease, 5.74% [95% confidence interval (CI): 4.03%-8.12%] were positive for CuV DNA, while no individual in the medical health check-up group was positive, indicating a close correlation between CuV and rheumatic disease. Men and patients with rheumatoid arthritis or ankylosing spondylitis, according to the disease classification, were more susceptible to being infected with CuV (P â€‹< â€‹0.01). After adjustments, being male remained the only significant factor, with an adjusted odd ratio (OR) of 4.4 (95% CI: 1.7-11.4, P â€‹= â€‹0.002). Phylogenetic analysis of the CuV VP2 sequences showed three diverse clades, one of which was segregated to be a single branching independent of previously known sequences, which is possible a new genotype.

Drivers and mechanisms of spontaneous plant community succession in abandoned PbZn mining areas in Yunnan, China.

The drivers and mechanisms underlying succession and the spontaneous formation of plant communities in mining wasteland remain largely unknown. This study investigated the use of nature-based restoration to facilitate the recovery of viable plant communities in mining wasteland. It was found that scientific analyses of spontaneously formed plant communities in abandoned mining areas can provide insights for nature-based restoration. A chronosequence ("space for time") approach was used to establish sites representing three successional periods with six successional stages, and 90 quadrats were constructed to investigate changes in plant species and functional diversity during succession in abandoned PbZn mining areas. A total of 140 soil samples were collected to identify changes in soil properties, including plant nutrient and heavy metal concentrations. Then, this paper used structural equation models to analyze the mechanisms that drive succession. It was found that the functional diversity of plant communities fluctuated substantially during succession. Species had similar functional traits in early and mid-succession, but traits tended to diverge during late succession. Soil bulk density and soil organic matter gradually increased during succession. Total nitrogen (N), pH, and soil Zn concentrations first increased and then decreased during succession. Concentrations of Mn and Cd gradually decreased during succession. During early succession, soil organic matter was the key factor driving plant colonization and succession. During mid-succession, soil Zn functioned as an environmental filter factor limiting the rates of succession in mining wasteland communities. During late succession, soil bulk density and competition for nutrient resources contributed to more balanced differentiation among plant species. This thesis proposed that a nature-based strategy for the stabilization of abandoned mining lands could facilitate effective plant community restoration that promotes ecosystem services and functioning.

Effects of Heavy Metals on Stomata in Plants: A Review.

Stomata are one of the important structures for plants to alleviate metal stress and improve plant resistance. Therefore, a study on the effects and mechanisms of heavy metal toxicity to stomata is indispensable in clarifying the adaptation mechanism of plants to heavy metals. With the rapid pace of industrialization and urbanization, heavy metal pollution has been an environmental issue of global concern. Stomata, a special physiological structure of plants, play an important role in maintaining plant physiological and ecological functions. Recent studies have shown that heavy metals can affect the structure and function of stomata, leading to changes in plant physiology and ecology. However, although the scientific community has accumulated some data on the effects of heavy metals on plant stomata, the systematic understanding of the effects of heavy metals on plant stomata remains limited. Therefore, in this review, we present the sources and migration pathways of heavy metals in plant stomata, analyze systematically the physiological and ecological responses of stomata on heavy metal exposure, and summarize the current mechanisms of heavy metal toxicity on stomata. Finally, the future research perspectives of the effects of heavy metals on plant stomata are identified. This paper can serve as a reference for the ecological assessment of heavy metals and the protection of plant resources.

Novel Mn4+-Activated K2Nb1-xMoxF7 (0 ≤ x ≤ 0.15) Solid Solution Red Phosphors with Superior Moisture Resistance and Good Thermal Stability.

Nowadays, Mn4+-activated fluoride red phosphors with excellent luminescence properties have triggered tremendous attentions for enhancing the performance of white light-emitting diodes (WLEDs). Nonetheless, the poor moisture resistance of these phosphors impedes their commercialization. Herein, we proposed the dual strategies of "solid solution design" and "charge compensation" to design K2Nb1-xMoxF7 novel fluoride solid solution system, and synthesized the Mn4+-activated K2Nb1-xMoxF7 (0 ≤ x ≤ 0.15, x represents the mol % of Mo6+ in the initial solution) red phosphors via co-precipitation method. The doping of Mo6+ not only significantly improve the moisture resistance of the K2NbF7: Mn4+ phosphor without any passivation and surface coating, but also effectively enhance the luminescence properties and thermal stability. In particular, the obtained K2Nb1-xMoxF7: Mn4+ (x = 0.05) phosphor possesses the quantum yield of 47.22% and retains 69.95% of its initial emission intensity at 353 K. Notably, the normalized intensity of the red emission peak (627 nm) for the K2Nb1-xMoxF7: Mn4+ (x = 0.05) phosphor is 86.37% of its initial intensity after immersion for 1440 min, prominently higher than that of the K2NbF7: Mn4+ phosphor. Moreover, a high-performance WLED with high CRI of 88 and low CCT of 3979 K is fabricated by combining blue chip (InGaN), yellow phosphor (Y3Al5O12: Ce3+) and the K2Nb1-xMoxF7: Mn4+ (x = 0.05) red phosphor. Our findings convincingly demonstrate that the K2Nb1-xMoxF7: Mn4+ phosphors have a good practical application in WLEDs.

The PRAK-NRF2 axis promotes the differentiation of Th17 cells by mediating the redox homeostasis and glycolysis.

Oxidative stress is a key feature in both chronic inflammation and cancer. P38 regulated/activated protein kinase (PRAK) deficiency can cause functional disorders in neutrophils and macrophages under high oxidative stress, but the precise mechanisms by which PRAK regulates reactive oxygen species (ROS) elimination and its potential impact on CD4+ T helper subset function are unclear. The present study reveals that the PRAK-NF-E2-related factor 2(NRF2) axis is essential for maintaining the intracellular redox homeostasis of T helper 17(Th17) cells, thereby promoting Th17 cell differentiation and antitumor effects. Through mechanistic analysis, we identify NRF2 as a novel protein substrate of PRAK and find that PRAK enhances the stability of the NRF2 protein through phosphorylation NRF2 Serine(S) 558 independent of protein ubiquitination. High accumulation of cellular ROS caused by loss of PRAK disrupts both glycolysis and PKM2-dependent phosphorylation of STAT3, which subsequently impairs the differentiation of Th17 cells. As a result, Prak knockout (KO) mice display significant resistance to experimental autoimmune encephalomyelitis (EAE) but impaired antitumor immunity in a MC38 tumor model. This work reveals that the PRAK-NRF2-mediated antioxidant pathway is a metabolic checkpoint that controls Th17-cell glycolysis and differentiation. Targeting PRAK is a promising strategy for maintaining an active ROS scavenging system and may lead to potent Th17 cell antitumor immunity.

Hydrazone-Based Amphiphilic Brush Polymer for Fast Endocytosis and ROS-Active Drug Release.

Due to the high reactivity of reactive oxygen species (ROS), it is essential to sweep them away in time. In this study, ClO--responsible amphiphilic brush polymers were prepared by free radical polymerization using two monomers consisting of polyethylene glycol as the hydrophilic part, and an alkyl chain connected by hydrazone as the hydrophobic part. The macromolecules assemble into particles with nanoscaled dimensions in a neutral buffer, which ensures quick cellular internalization. The polymer has a low critical micellization concentration and can encapsulate hydrophobic drug molecules up to 19% wt. The micelles formed by the polymer disassemble in a ClO--rich environment and release 80% of their cargo within 2 h, which possesses a faster release rate compared to the previous systems. The relatively small size and the quick response of hydrazone toward ClO- ensure a quick uptake and elimination of ROS in vitro and in vivo.

Cholesterol metabolism: Towards a therapeutic approach for multiple sclerosis.

Growing evidence points to the importance of cholesterol in preserving brain homeostasis. Cholesterol makes up the main component of myelin in the brain, and myelin integrity is vital in demyelinating diseases such as multiple sclerosis. Because of the connection between myelin and cholesterol, the interest in cholesterol in the central nervous system increased during the last decade. In this review, we provide a detailed overview on brain cholesterol metabolism in multiple sclerosis and its role in promoting oligodendrocyte precursor cell differentiation and remyelination.

AutoDeconJ: a GPU-accelerated ImageJ plugin for 3D light-field deconvolution with optimal iteration numbers predicting.

MOTIVATION: Light-field microscopy (LFM) is a compact solution to high-speed 3D fluorescence imaging. Usually, we need to do 3D deconvolution to the captured raw data. Although there are deep neural network methods that can accelerate the reconstruction process, the model is not universally applicable for all system parameters. Here, we develop AutoDeconJ, a GPU-accelerated ImageJ plugin for 4.4× faster and more accurate deconvolution of LFM data. We further propose an image quality metric for the deconvolution process, aiding in automatically determining the optimal number of iterations with higher reconstruction accuracy and fewer artifacts. RESULTS: Our proposed method outperforms state-of-the-art light-field deconvolution methods in reconstruction time and optimal iteration numbers prediction capability. It shows better universality of different light-field point spread function (PSF) parameters than the deep learning method. The fast, accurate and general reconstruction performance for different PSF parameters suggests its potential for mass 3D reconstruction of LFM data. AVAILABILITY AND IMPLEMENTATION: The codes, the documentation and example data are available on an open source at: https://github.com/Onetism/AutoDeconJ.git. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Global and national trends in years of life lost and years lived with disability caused by three common gastrointestinal cancers from 1990 to 2019.

BACKGROUND: Gastrointestinal cancers are a critical global cancer burden, and tracking their trends would inform the health policies. METHODS: Trends of years of life lost (YLLs) and years lived with disability (YLDs) caused by three common gastrointestinal cancers were estimated using annual percentage change (EAPC) and age-standardized rate (ASR). Data was extracted from the Global Burden of Disease study 2019. RESULTS: The ASR per 100,000 population-year of YLLs caused by esophageal cancer, stomach cancer, and colorectal cancer were 137.98, 264.15, and 282.51 in 2019, respectively. Their overall trends of YLLs declined during 1990-2019, with the respective EAPCs being - 1.42 (95% Confidence Interval [CI]: - 1.71 to - 1.13), - 2.13 (95%CI: - 2.29 to - 1.96), and - 0.25 (95%CI: - 0.30 to - 0.19). Meanwhile, decreasing trends of YLDs caused by esophageal cancer and stomach cancer were observed, in which the EAPCs were - 0.67 (95%: - 0.94 to - 0.40) and - 0.85 (95%CI: - 0.97 to - 0.73), respectively. However, an increasing trend was seen in that of colorectal cancer (EAPC = 0.83, 95%CI: 0.77 to 0.89). Among countries, the largest decrease in trend of YLLs was that of stomacher cancer in the Republic of Korea (EAPC = - 5.88, 95%CI: - 6.07 to - 5.69). However, pronounced increasing trend of YLDs caused by colorectal cancer occurred in China (EAPC = 4.40, 95%CI: 4.07 to 4.72). CONCLUSIONS: Decreasing trends in YLLs and YLDs caused by esophageal cancer, stomach cancer, and colorectal cancer were observed in most countries and regions, indicating that the great progress had been achieved over the past decades. However, the cancer burden was geographical heterogeneity, and cost-effective measures were still required to decline the burden caused by gastrointestinal cancers.

A novel immune prognostic model of non-M3 acute myeloid leukemia.

Acute myeloid leukemia (AML) is a common hematological malignancy in adults. AML patients exhibit clinical heterogeneity with complications of molecular basis. The leukemogenesis of AML involves immune escape, and the immunosuppression status of the patient might have great impact on AML treatment outcome. In this study, we established an immune prognostic model of AML using bioinformatics tools. With the data in the TCGA and GTEx datasets, we analyzed differentially expressed genes (DEGs) in non-M3 AML and identified 420 immune-related DEGs. Among which, 49 genes' expression was found to be related to AML prognosis based on univariate Cox regression analysis. Next, we established a prognostic model with these 49 genes in AML by LASSO regression and multivariate Cox regression analyses. In our model, the expressions of 5 immune genes, MIF, DEF6, OSM, MPO, AVPR1B, were used to stratify non-M3 AML patients' treatment outcome. A patient's risk score could be calculated as Risk Score=0.40081 × MIF (MIF expression) - 0.15201 × MPO + 0.78073 × DEF6 - 0.45192 × AVPR1B + 0.25912 × OSM. The area under the curve of the risk score signature was 0.8, 0.8, and 0.96 at 1 year, 3 years, and 5 years, respectively. The prognostic model was then validated internally by TCGA data and externally by GEO data. At last, the result of single-sample gene-set enrichment analysis demonstrated that compared with healthy samples, the abundance of non-turmeric immune cells was significantly repressed in AML. To summarize, we presented an immune-related 5-gene signature prognostic model in AML.

ISG20L2 suppresses bortezomib antimyeloma activity by attenuating bortezomib binding to PSMB5.

The proteasome inhibitors (PIs) bortezomib and carfilzomib, which target proteasome 20S subunit beta 5 (PSMB5) in cells, are widely used in multiple myeloma (MM) treatment. In this study, we demonstrated the role of interferon-stimulated 20 kDa exonuclease-like 2 (ISG20L2) in MM PI resistance. Gain- and loss-of-function studies showed that ISG20L2 suppressed MM cell sensitivity to PIs in vitro and in vivo. Patients with ISG20L2lo MM had a better response to PIs and a longer overall survival than patients with ISG20L2hi MM. Biotinylated bortezomib pull-down assays showed that ISG20L2 competed with PSMB5 in binding to bortezomib. The surface plasmon resonance assay confirmed the direct binding of bortezomib to ISG20L2. In ISG20L2hi MM cells, ISG20L2 attenuated the binding of bortezomib to PSMB5, resulting in lower inhibition of proteasome activity and therefore less bortezomib-induced cell death. Overall, we identified a potentially novel mechanism by which ISG20L2 conferred bortezomib resistance on MM. The expression of ISG20L2 correlated with MM PI responses and patient treatment outcomes.

Correction: Effect of the "Art Coloring" Online Coloring Game on Subjective Well-Being Increase and Anxiety Reduction During the COVID-19 Pandemic: Development and Evaluation.

[This corrects the article DOI: 10.2196/37026.].