Tyrosine phosphorylation and palmitoylation of TRPV2 ion channel tune microglial beta-amyloid peptide phagocytosis.

Alzheimer's disease (AD) is the leading form of dementia, characterized by the accumulation and aggregation of amyloid in brain. Transient receptor potential vanilloid 2 (TRPV2) is an ion channel involved in diverse physiopathological processes, including microglial phagocytosis. Previous studies suggested that cannabidiol (CBD), an activator of TRPV2, improves microglial amyloid-ß (Aß) phagocytosis by TRPV2 modulation. However, the molecular mechanism of TRPV2 in microglial Aß phagocytosis remains unknown. In this study, we aimed to investigate the involvement of TRPV2 channel in microglial Aß phagocytosis and the underlying mechanisms. Utilizing human datasets, mouse primary neuron and microglia cultures, and AD model mice, to evaluate TRPV2 expression and microglial Aß phagocytosis in both in vivo and in vitro. TRPV2 was expressed in cortex, hippocampus, and microglia.Cannabidiol (CBD) could activate and sensitize TRPV2 channel. Short-term CBD (1 week) injection intraperitoneally (i.p.) reduced the expression of neuroinflammation and microglial phagocytic receptors, but long-term CBD (3 week) administration (i.p.) induced neuroinflammation and suppressed the expression of microglial phagocytic receptors in APP/PS1 mice. Furthermore, the hyper-sensitivity of TRPV2 channel was mediated by tyrosine phosphorylation at the molecular sites Tyr(338), Tyr(466), and Tyr(520) by protein tyrosine kinase JAK1, and these sites mutation reduced the microglial Aß phagocytosis partially dependence on its localization. While TRPV2 was palmitoylated at Cys 277 site and blocking TRPV2 palmitoylation improved microglial Aß phagocytosis. Moreover, it was demonstrated that TRPV2 palmitoylation was dynamically regulated by ZDHHC21. Overall, our findings elucidated the intricate interplay between TRPV2 channel regulated by tyrosine phosphorylation/dephosphorylation and cysteine palmitoylation/depalmitoylation, which had divergent effects on microglial Aß phagocytosis. These findings provide valuable insights into the underlying mechanisms linking microglial phagocytosis and TRPV2 sensitivity, and offer potential therapeutic strategies for managing AD.

Nickel-catalyzed oxidative thiolation of α-amino carbonyl compounds with thiols.

An efficient oxidative thiolation of α-amino carbonyl compounds with thiols by the catalysis of an Earth-abundant nickel salt is disclosed for the first time. A variety of alkyl thiols and (hetero)aryl thiols underwent the reaction well with α-amino ketones and an α-amino ester to produce the desired α,α-aminothiocarbonyl compounds in good to excellent yields under ligand- and base-free conditions.

Comprehensive analysis revealed the immunoinflammatory targets of rheumatoid arthritis based on intestinal flora, miRNA, transcription factors, and RNA-binding proteins databases, GSEA and GSVA pathway observations, and immunoinfiltration typing.

OBJECTIVE: Rheumatoid arthritis (RA) is a chronic inflammatory arthritis. This study aimed to identify potential biomarkers and possible pathogenesis of RA using various bioinformatics analysis tools. METHODS: The GMrepo database provided a visual representation of the analysis of intestinal flora. We selected the GSE55235 and GSE55457 datasets from the Gene Expression Omnibus database to identify differentially expressed genes (DEGs) separately. With the intersection of these DEGs with the target genes associated with RA found in the GeneCards database, we obtained the DEGs targeted by RA (DERATGs). Subsequently, Disease Ontology, Gene Ontology, and the Kyoto Encyclopedia of Genes and Genomes were used to analyze DERATGs functionally. Gene Set Enrichment Analysis (GSEA) and Gene Set Variation Analysis (GSVA) were performed on the data from the gene expression matrix. Additionally, the protein-protein interaction network, transcription factor (TF)-targets, target-drug, microRNA (miRNA)-mRNA networks, and RNA-binding proteins (RBPs)-DERATGs correlation analyses were built. The CIBERSORT was used to evaluate the inflammatory immune state. The single-sample GSEA (ssGSEA) algorithm and differential analysis of DERATGs were used among the infiltration degree subtypes. RESULTS: There were some correlations between the abundance of gut flora and the prevalence of RA. A total of 54 DERATGs were identified, mainly related to immune and inflammatory responses and immunodeficiency diseases. Through GSEA and GSVA analysis, we found pathway alterations related to metabolic regulations, autoimmune diseases, and immunodeficiency-related disorders. We obtained 20 hub genes and 2 subnetworks. Additionally, we found that 39 TFs, 174 drugs, 2310 miRNAs, and several RBPs were related to DERATGs. Mast, plasma, and naive B cells differed during immune infiltration. We discovered DERATGs' differences among subtypes using the ssGSEA algorithm and subtype grouping. CONCLUSIONS: The findings of this study could help with RA diagnosis, prognosis, and targeted molecular treatment.

The impact of dynamic linking on cooperation on complex networks.

In complex social systems, individual relationships and the surrounding environment are constantly changing, allowing individuals to interact on dynamic networks. This study aims to investigate how individuals in a dynamic network engaged in a prisoner's dilemma game adapt their competitive environment through random edge breaks and reconnections when faced with incomplete information and adverse local conditions, thereby influencing the evolution of cooperative behavior. We find that random edge breaks and reconnections in dynamic networks can disrupt cooperative clusters, significantly hindering the development of cooperation. This negative impact becomes more pronounced over larger time scales. However, we also observe that nodes with higher degrees of connectivity exhibit greater resilience to this cooperation disruption. Our research reveals the profound impact of dynamic network structures on the evolution of cooperation and provides new insights into the mechanisms of cooperation in complex systems.

Virulence Variability and Genetic Diversity in Blumeria graminis f. sp. hordei in Southeastern and Southwestern China.

Powdery mildew is a key airborne foliar disease of barley in southeastern and southwestern China. Barley varieties usually partially or wholly lose resistance to the pathogen Blumeria graminis (DC.) f. sp. hordei 3 to 5 years after release due to the frequent acquirements of new virulences in the pathogen population. However, no B. graminis f. sp. hordei virulence detection has been carried out in the recent decade and, thus, no information is available on the present virulence components and major pathotypes in epidemic regions. Twenty-one near-isogenic lines of Pallas were selected to detect B. graminis f. sp. hordei virulence variation, with 97 pathotypes identified from the isolates collected from 2015 to 2019. The virulence complexities ranged from 1 to 12, with 1.5 isolates on average assigned per pathotype, suggesting a natural trait of high pathotype diversity and low virulence complexity in the Chinese B. graminis f. sp. hordei populations. Eleven high-virulence pathotypes were detected in the traditional barley-growing regions in Yunnan and Zhejiang. Six virulent pathotypes to resistance gene mlo-5 were detected only in the two traditional epidemic regions, with a virulence frequency (VF) of 4.8% (7 of 147). Compared with the results from a decade ago, VFs for resistance alleles Mla3, mlo-5, Mla6 + Mla14, Mla7 + Mlk, Mlg + MlCP, and Mla13 + MlRu3 + MlaRu4 increased from 0 to 0.7 to 25.8%. Isolates from Yunnan and Zhejiang had similar virulence profiles, which differed from those identified in Tibet. In addition, genetic diversities differed in the isolate groups collected from Tibet, Yunnan, and Zhejiang.

ATM inhibitor KU-55933 induces apoptosis and inhibits motility by blocking GLUT1-mediated glucose uptake in aggressive cancer cells with sustained activation of Akt.

Enhanced glucose uptake is coupled with elevated aerobic glycolysis (the Warburg effect) in cancer cells and is closely correlated with increased tumor aggressiveness and poor prognosis. We previously discovered that ATM, a protein kinase deficient in Ataxia-telangiectasia (A-T) disease, is an insulin-responsive protein that participates in insulin-mediated glucose uptake in muscle cells by stimulating glucose transporter 4 (GLUT4) translocation. However, the role of ATM in glucose uptake and tumorigenesis of cancer cells is unclear. In the present study, we found that aggressive breast and prostate cancer cell lines with overactivated Akt activity exhibit enhanced glucose uptake and GLUT1 translocation upon insulin treatment, and KU-55933, a specific inhibitor of ATM, inhibits insulin-mediated glucose uptake by blocking translocation of GLUT1 to the cell surface. KU-55933 also inhibits aerobic glycolysis and ATP production in these cells. Moreover, KU-55933 induces apoptosis and inhibits motility of cancer cells by inhibiting glucose uptake. Our results showed that while high concentration of glucose and insulin promote the expression of a mesenchymal biomarker (vimentin) in these cancer cells, KU-55933 strongly inhibits its expression as well as epithelial to mesenchymal transition. The roles of ATM in stimulating glucose uptake, glycolysis, motility, and proliferation of cancer cells were demonstrated by knocking-down ATM in these cells. KU-55933 treatment also inhibits tumor growth and metastasis in vivo in mouse mammary tumors through inhibition of GLUT1 translocation and vimentin expression. These results suggest that ATM acts as a promoter of tumorigenesis in cancer cells with overactivated Akt, and KU-55933 induces apoptosis and inhibits motility by blocking GLUT1-mediated glucose uptake and glycolysis in these cancer cells, which may lead to the use of KU-55933 and its analogs as new preventive or therapeutic agents against cancer.

Cannabidiol Enhances Microglial Beta-Amyloid Peptide Phagocytosis and Clearance via Vanilloid Family Type 2 Channel Activation.

Alzheimer's disease (AD) is associated with the accumulation and aggregation of amyloid in the brain. The cation channel TRPV2 may mediate the pathological changes in mild cognitive impairment. A high-affinity agonist of TRPV2 named cannabidiol is one of the candidate drugs for AD. However, the molecular mechanism of cannabidiol via TRPV2 in AD remains unknown. The present study investigated whether cannabidiol enhances the phagocytosis and clearance of microglial Aß via the TRPV2 channel. We used a human dataset, mouse primary neuron and microglia cultures, and AD model mice to evaluate TRPV2 expression and the ability of microglial amyloid-ß phagocytosis in vivo and in vitro. The results revealed that TRPV2 expression was reduced in the cortex and hippocampus of AD model mice and AD patients. Cannabidiol enhanced microglial amyloid-ß phagocytosis through TRPV2 activation, which increased the mRNA expression of the phagocytosis-related receptors, but knockdown of TRPV2 or Trem2 rescued the expression. TRPV2-mediated effects were also dependent on PDK1/Akt signaling, a pathway in which autophagy was indispensable. Furthermore, cannabidiol treatment successfully attenuated neuroinflammation while simultaneously improving mitochondrial function and ATP production via TRPV2 activation. Therefore, TRPV2 is proposed as a potential therapeutic target in AD, while CBD is a promising drug candidate for AD.

Formulation and evaluation of a topical liposomal gel containing a combination of zedoary turmeric oil and tretinoin for psoriasis activity.

This study was to develop a combination of zedoary turmeric oil (ZTO) and tretinoin (TRE)-loaded liposomal gel as a topical drug delivery system. We used a combination of single-factor experiment and orthogonal experiment to systematically optimize encapsulation process of the compound liposomes. The optimized liposome vesicles were incorporated into Carbopol gel matrix and studied by continuous in vitro (skin penetration and retention) and in vivo (anti-psoriatic activity using mouse vaginal model and mouse tail model) experiments. The optimized liposomes had an entrapment efficiency (EE) of ZTO was (64.63 ± 1.00)%, EE of TRE was (90.33 ± 0.72)%, drug loading (DL) of ZTO was (9.09 ± 0.14)%, DL of TRE was (1.43 ± 0.02)%, particle size of 257.41 ± 7.58 nm, polydispersity index (PDI) of 0.10 ± 0.04 and zeta potential of -38.77 ± 0.81 mV. Transmission electron microscopy showed liposomes had a regular spherical surface. After 1-month storage at (4 ± 2)°C, the optimized liposome preparations maintained its stability. In vitro study indicated that liposome formulations could significantly prolong the penetration of drugs into the hair follicles of mice and keep more drugs in the skin compared with conventional gel formulations. In vivo study showed that liposomal gel was more effective than conventional gel in treating psoriasis and had a significant dose-dependent effect on psoriasis. In summary, liposomal gel is expected to be an ideal carrier for topical drug delivery systems of ZTO and TRE.

Uniquely confining Cu2S nanoparticles in graphitized carbon fibers for enhanced oxygen evolution reaction.

Up to now, the literature on Cu2S with specific morphology applied to oxygen evolution reaction (OER) in the electrocatalytic field has been limited. In this work, unique peapod-like Cu2S/C exhibiting superb electrocatalytic performance toward OER is successfully synthesized, by employing Cu(OH)2 nanorods as the template and nontoxic glucose as the carbon source and then annealing with sublimed sulfur. It can be seen that this work explores a new application area for Cu2S. More precisely, the novel morphology contributes to increasing the electrochemical active surface area effectively and promoting contact between the Cu2S nanoparticles and the electrolyte. During electrochemical measurements, the peapod-like Cu2S/C shows enhanced electrocatalytic activity with a low overpotential of 401 mV at the current density of 10 mA cm-2 and a Tafel slope of 52 mV dec-1. More importantly, our material is able to maintain stability for at least 8 h at constant potential and the current loss is negligible after 2000 cycles. Obviously, these striking properties fully demonstrate that the peapod-like Cu2S/C as an efficient catalyst shows great promise for OER.

The neutrophil-to-lymphocyte ratio on admission is a good predictor for all-cause mortality in hypertensive patients over 80 years of age.

BACKGROUND: Immuno-inflammation plays a major role in the process of hypertension. We aimed to evaluate the association between inflammatory markers, neutrophil-to-lymphocyte ratio (NLR), red cell distribution width (RDW) and all-cause mortality in elderly patients with hypertension. METHODS: A total of 341 hypertensive patients over 80 years of age were included to this study. The NLR and RDW were measured on admission and all the selected patients were followed up for up to 90 days. Kaplan-Meier curves were plotted to evaluate the association between the NLR and the all-cause mortality at follow-up. Using Cox regression models, we investigated the prognostic value of NLR and RDW for all-cause mortality. RESULTS: Patients with higher quartile of NLR linked to high mortality in hypertensive patients at 90 day after admission (16.47%,13.25%,1.14%,1.17% respectively; χ2 = 20.581,P = 0.000). Surviving patients had lower RDW (13.61 ± 1.37 VS 14.18 ± 1.38, p = 0.041) and NLR (4.97 ± 5.72 VS 7.95 ± 6.88,p = 0.011). The receiver operating curve (ROC) of the NLR for all-cause mortality had an area under the curve (AUC) =0.714 (95%CI: 0.629-0.798, P = 0.000), with acritical value of 2.97, with sensitivity of 92.6%, and a specificity of 52.5%. The ROC of the RDW to predict all-cause mortality, had an AUC =0.654 (95%CI:0.548-0.761, P = 0.008), with acritical value of 13.2%.The Kaplan-Meier curve showed a significant difference between different NLR levels (p = 0.002). Multivariate Cox proportional hazard analysis shown 3rd quartile of NLR(RR = 9.646, 95% CI 1.302-34.457, P = 0.041) and 4th quartiles(RR = 16.451, 95% CI 2.137-66.643, P = 0.007) were found to independently predict all-cause death in hypertensive patients over 80 years of age. Higher rank of NLR was link to higher incidence of all-cause death for such patients. CONCLUSION: The findings of the present study demonstrate the potential utility of NLR in risk stratification of elderly patients with hypertension to provide information for clinical treatment strategies.

Quantitative assessment of the association between MTHFR rs1801131 polymorphism and risk of liver cancer.

Methylenetetrahydrofolate reductase (MTHFR) is one of the most important enzymes for folate metabolism which plays a key role in cell metabolism. MTHFR rs1801131 (A1298C) polymorphism can decrease in vitro MTHFR enzyme activity and has been hypothesized to be associated with liver cancer risk. This study aimed to quantify the strength of the association between MTHFR rs1801131 polymorphism and liver cancer risk by performing a meta-analysis. We searched the PubMed and Wanfang databases for studies relating on the association between MTHFR rs1801131 polymorphism and risk of liver cancer. Seven studies with 2,030 cases of liver cancer and 3,096 controls were finally included into the meta-analysis. Meta-analysis of a total of seven studies showed that the homozygote genotype CC of MTHFR rs1801131 polymorphism was significantly associated with decreased risk of liver cancer (for CC versus AA: odds ratio (OR) = 0.65, 95% confidence interval (CI) 0.47-0.89, P = 0.007; for CC versus AA + AC: OR = 0.65, 95% CI 0.48-0.89, P = 0.006). Subgroup by race showed that the homozygote genotype CC of MTHFR rs1801131 polymorphism was significantly associated with decreased risk of liver cancer in Asians (CC versus AA: OR = 0.64, 95% CI 0.46-0.90, P = 0.010; for CC versus AA + AC: OR = 0.63, 95% CI 0.45-0.88, P = 0.007). However, the association in Caucasians was still unclear owing to the limited data available now. Thus, Asian individuals with the homozygote genotype CC of MTHFR rs1801131 polymorphism are significantly associated with decreased risk of liver cancer. The association in Caucasians needs further studies.

Technical note: MR image-based synthesis CT for CyberKnife robotic stereotactic radiosurgery.

The purpose of this study is to investigate whether deep learning-based sCT images enable accurate dose calculation in CK robotic stereotactic radiosurgery. A U-net convolutional neural network was trained using 2446 MR-CT pairs and used it to translate 551 MR images to sCT images for testing. The sCT of CK patient was encapsulated into a quality assurance (QA) validation phantom for dose verification. The CT value difference between CT and sCT was evaluated using mean absolute error (MAE) and the statistical significance of dose differences between CT and sCT was tested using the Wilcoxon signed rank test. For all CK patients, the MAE value of the whole brain region did not exceed 25 HU. The percentage dose difference between CT and sCT was less than ±0.4% on GTV (D2(Gy), -0.29%, D95(Gy), -0.09%), PTV (D2(Gy), -0.25%, D95(Gy), -0.10%), and brainstem (max dose(Gy), 0.31%). The percentage dose difference between CT and sCT for most regions of interest (ROIs) was no more than ±0.04%. This study extended MR-based sCT prediction to CK robotic stereotactic radiosurgery, expanding the application scenarios of MR-only radiation therapy. The results demonstrated the remarkable accuracy of dose calculation on sCT for patients treated with CK robotic stereotactic radiosurgery.

Nerolidol, Bioactive Compound Suppress Growth of HCT-116 Colorectal Cancer Cells Through Cell Cycle Arrest and Induction of Apoptosis.

Colon cancer is the most prevalent cancer and causes the highest cancer-associated mortality in both men and women globally. It has a high incidence and fatality rate, which places a significant burden on the healthcare system. The current work was performed to understand the beneficial roles of nerolidol on the viability and cytotoxic mechanisms in the colon cancer HCT-116 cells. The MTT cytotoxicity assay was done to investigate the effect of nerolidol at different doses (5-100 µM) on the HCT-116 cell viability. The impacts of nerolidol on ROS accumulation and apoptosis were investigated using DCFH-DA, DAPI, and dual staining assays, respectively. The flow cytometry analysis was performed to study the influence of nerolidol on the cell cycle arrest in the HCT-116 cells. The outcomes of the MTT assay demonstrated that nerolidol at different doses (5-100 µM) substantially inhibited the HCT-116 cell viability with an IC50 level of 25 µM. The treatment with nerolidol appreciably boosted the ROS level in the HCT-116 cells. The findings of DAPI and dual staining revealed higher apoptotic incidences in the nerolidol-exposed HCT-116 cells, which supports its ability to stimulate apoptosis. The flow cytometry analysis demonstrated the considerable inhibition in cell cycle at the G0/G1 phase in the nerolidol-exposed HCT-116 cells. Our research showed that nerolidol can inhibit the cell cycle, increase ROS accumulation, and activate apoptosis in HCT-116 cells. In light of this, it may prove to be a potent and salutary candidate to treat colon cancer.

Trends in the mobility of primary healthcare human resources in underdeveloped regions of western China from 2000 to 2021: Evidence from Nanning.

OBJECTIVE: This research aimed to identify the fundamental and geographic characteristics of the primary healthcare personnel mobility in Nanning from 2000 to 2021 and clarify the determinants that affect their transition to non-primary healthcare institutions. METHODS: Through utilizing the Primary Healthcare Personnel Database (PHPD) for 2000-2021, the study conducts descriptive statistical analysis on demographic, economic, and professional aspects of healthcare personnel mobility across healthcare reform phases. Geographic Information Systems (QGIS) were used to map mobility patterns, and R software was employed to calculate spatial autocorrelation (Moran's I). Logistic regression identified factors that influenced the transition to non-primary institutions. RESULTS: Primary healthcare personnel mobility is divided into four phases: initial (2000-2008), turning point (2009-2011), rapid development (2012-2020), and decline (2021). The rapid development stage saw increased mobility with no spatial clustering in inflow and outflow. From 2016 to 2020, primary healthcare worker mobility reached its peak, in which the most significant movement occurred between township health centers and other institutions. Aside from their transition to primary medical institutions, the primary movement of grassroots health personnel predominantly directs towards secondary general hospitals, tertiary general hospitals, and secondary specialized hospitals. Since 2012, the number and mobility distance of primary healthcare workers have become noticeably larger and remained at a higher level from 2016 to 2020. The main migration of primary healthcare personnel occurred in their districts (counties). Key transition factors include gender, education, ethnicity, professional category, general practice registration, and administrative division. CONCLUSIONS: This study provides evidence of the features of primary healthcare personnel mobility in the less developed western regions of China, in which Nanning was taken as a case study. It uncovers the factors that impact the flow of primary healthcare personnel to non-primary healthcare institutions. These findings are helpful to policy refinement and support the retention of primary healthcare workers.

Tirzepatide shows neuroprotective effects via regulating brain glucose metabolism in APP/PS1 mice.

Tirzepatide (LY3298176), a GLP-1 and GIP receptor agonist, is fatty-acid-modified and 39-amino acid linear peptide, which ameliorates learning and memory impairment in diabetic rats. However, the specific molecular mechanism remains unknown. In the present study, we investigated the role of tirzepatide in the neuroprotective effects in Alzheimer's disease (AD) model mice. Tirzepatide was administrated intraperitoneal (i.p.) APP/PS1 mice for 8 weeks with at 10 nmol/kg once-weekly, it significantly decreased the levels of GLP-1R, and GFAP protein expression and amyloid plaques in the cortex, it also lowered neuronal apoptosis induced by amyloid-ß (Aß), but did not affect the anxiety and cognitive function in APP/PS1 mice. Moreover, tirzepatide reduced the blood glucose levels and increased the mRNA expression of GLP-1R, SACF1, ATF4, Glu2A, and Glu2B in the hypothalamus of APP/PS1 mice. Tirzepatide increased the mRNA expression of glucose transporter 1, hexokinase, glucose-6-phosphate dehydrogenase, and phosphofructokinase in the cortex. Lastly, tirzepatide improved the energetic metabolism by regulated reactive oxygen species production and mitochondrial membrane potential caused by Aß, thereby decreasing mitochondrial function and ATP levels in astrocytes through GLP-1R. These results provide valuable insights into the mechanism of brain glucose metabolism and mitochondrial function of tirzepatide, presenting potential strategies for AD treatment.

Neuronostatin regulates neuronal function and energetic metabolism in Alzheimer's disease in a GPR107-dependent manner.

Alzheimer's disease (AD) is the most prevalent neurodegenerative disease, which is characterized by the accumulation and aggregation of amyloid in brain. Neuronostatin (NST) is an endogenous peptide hormone that participates in many fundamental neuronal processes. However, the metabolism and function of NST in neurons of AD mice are not known. In this study, by combining the structural analyses, primary cultures, knockout cells, and various assessments, the behavior, histopathology, brain-wide expression and cellular signaling pathways in the APP/PS1 mice were investigated. It was found that NST directly bound to GPR107, which was primarily expressed in neurons. NST modulated the neuronal survivability and neurite outgrowth induced by Aß via GPR107 in neurons. Intracerebroventricular (i.c.v.) administration of NST attenuated learning and memory abilities, reduced the synaptic protein levels of hippocampus, but improved amyloid plaques in the cortex and hippocampus of APP/PS1 mice. NST modulated glucose metabolism of hypothalamus-hippocampus-cortex axis in APP/PS1 mice and decreased ATP levels via the regulation of reactive oxygen species (ROS) and mitochondrial membrane potential (MMP) in response to Aß, suppressed energetic metabolism, and mitochondrial function in neurons via GPR107/protein kinase A (PKA) signaling pathway. In summary, our findings suggest that NST regulates neuronal function and brain energetic metabolism in AD mice via the GPR107/PKA signaling pathway, which can be a promising target for the treatment of AD.

Safety of a 90-min duration of intravenous infusion of obinutuzumab in patients with B-cell non-Hodgkin's lymphoma in a tertiary hospital in China: a prospective, open-label, exploratory clinical trial.

This study aimed to analyze the safety and applicability of a 90-min duration of infusion (SDI) of obinutuzumab in patients with B-cell non-Hodgkin's lymphoma (NHL) in a tertiary hospital in China. This exploratory clinical trial was performed at Jiangsu Province Hospital. All patients were treated with the standard infusion regimen for the first infusion. If no grade ≥3 infusion-related reactions (IRRs) occurred, the subsequent infusions were given as SDI. The primary endpoint was the incidence of IRR during the standard infusion (3-4 h) and 90-min SDI regimens. This study enrolled 208 patients and all completed cycle 1. Forty-one patients (19.71%) had IRRs: five (2.40%) with grade 1, twenty-eight (13.46%) with grade 2, and eight (3.85%) with grade 3. The 41 patients had 71 IRRs, mainly fever (40.85%), chest pain/tightness (12.68%), and dyspnea (9.86%). The occurrence of IRRs in the first infusion was significantly lower in patients who received oral acetaminophen prophylaxis than those who did not (10.72% vs 30.21%, P<0.001). For the subsequent cycles with 90-min SDI, only two (0.25%) IRRs occurred among 814 infusions (one grade 1 hand numbness and one grade 2 chill/fever). The 90-min obinutuzumab SDI might be safe and feasible in patients with B-cell NHL in China.

IL-22-Induced Ubiquitin-Specific Protease 15 Promotes Proliferation and Inflammation of Keratinocytes through Stabilization of Squamous Cell Carcinoma Antigen 2.

Ubiquitin-specific protease 15 (USP15) plays a significant role in regulating various biological processes in several autoimmune diseases and cancers. However, its role in psoriatic keratinocytes (KCs) has not been extensively studied. In this study, we described that USP15 promotes proliferation and inflammation in KCs by stabilizing squamous cell carcinoma antigen 2. We discovered that the expression of USP15 and squamous cell carcinoma antigen 2 was elevated in lesions from patients with clinical psoriasis and an imiquimod-induced psoriatic dermatitis mouse model. USP15 was able to bind, deubiquitinate, and stabilize squamous cell carcinoma antigen 2. Knocking down USP15 resulted in reduced KC inflammation and impaired KC viability and clonogenicity. Topically applying USP15 small interfering RNA significantly ameliorated imiquimod-induced psoriatic dermatitis and reduced the infiltration of T cells and neutrophils. In addition, we determined that IL-22 was a key cytokine that upregulated the expression of USP15. These findings provide insights regarding the mechanisms involved in the proliferation and inflammation of KCs mediated by IL-22, suggesting a potential IL-22-USP15-squamous cell carcinoma antigen 2 axis in the pathogenesis of psoriatic KCs.

Prediction of dose deposition matrix using voxel features driven machine learning approach.

OBJECTIVES: A dose deposition matrix (DDM) prediction method using several voxel features and a machine learning (ML) approach is proposed for plan optimization in radiation therapy. METHODS: Head and lung cases with the inhomogeneous medium are used as training and testing data. The prediction model is a cascade forward backprop neural network where the input is the features of the voxel, including 1) voxel to body surface distance along the beamlet axis, 2) voxel to beamlet axis distance, 3) voxel density, 4) heterogeneity corrected voxel to body surface distance, 5) heterogeneity corrected voxel to beamlet axis, and (6) the dose of voxel obtained from the pencil beam (PB) algorithm. The output is the predicted voxel dose corresponding to a beamlet. The predicted DDM was used for plan optimization (ML method) and compared with the dose of MC-based plan optimization (MC method) and the dose of pencil beam-based plan optimization (PB method). The mean absolute error (MAE) value was calculated for full volume relative to the dose of the MC method to evaluate the overall dose performance of the final plan. RESULTS: For patient with head tumor, the ML method achieves MAE value 0.49 × 10-4 and PB has MAE 1.86 × 10-4. For patient with lung tumor, the ML method has MAE 1.42 × 10-4 and PB has MAE 3.72 × 10-4. The maximum percentage difference in PTV dose coverage (D98) between ML and MC methods is no more than 1.2% for patient with head tumor, while the difference is larger than 10% using the PB method. For patient with lung tumor, the maximum percentage difference in PTV dose coverage (D98) between ML and MC methods is no more than 2.1%, while the difference is larger than 16% using the PB method. CONCLUSIONS: In this work, a reliable DDM prediction method is established for plan optimization by applying several voxel features and the ML approach. The results show that the ML method based on voxel features can obtain plans comparable to the MC method and is better than the PB method in achieving accurate dose to the patient, which is helpful for rapid plan optimization and accurate dose calculation. ADVANCES IN KNOWLEDGE: Establishment of a new machine learning method based on the relationship between the voxel and beamlet features for dose deposition matrix prediction in radiation therapy.