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Abstract Letermovir (LTV) prophylaxis is effective in reducing the incidence of clinically significant cytomegalovirus (CMV) infection (cs CMVi) after allogeneic haematopoietic stem cell transplantation (allo-HSCT). Since our centre began administering LTV prophylaxis in June 2022, we have observed a certain increase in the incidence of Epstein–Barr virus (EBV) reactivation after haploidentical HSCT. We retrospectively analysed 230 consecutive patients who underwent haploidentical HSCT with rabbit anti-thymocyte globulin (ATG) from October 2022 to June 2023. The LTV group included 133 patients who received LTV prophylaxis, and the control group included 97 patients who did not receive LTV prophylaxis. At 1 year after HSCT, EBV reactivation was observed in 36 patients (27%) in the LTV group and 13 patients (13%) in the control group (p = 0.012). All patients with EBV reactivation had EBV-DNAemia, and one patient in each group developed EBV-associated posttransplantation lymphoproliferative disorder (PTLD). The proportion of patients with low EBV-DNA loads (> 5 × 102 to

Abstract Background Rhododendron delavayi is a natural shrub that is distributed at different elevations in the karst region of Bijie, China, and that has an important role in preventing land degradation in this region. In this study, we determined the soil mineral element contents and soil enzyme activities. The composition of the soil bacterial community of R. delavayi at three elevations (1448 m, 1643 m, and 1821 m) was analyzed by high-throughput sequencing, and the interrelationships among the soil bacterial communities, mineral elements, and enzyme activities were determined. Results The Shannon index of the soil bacterial community increased and then decreased with increasing elevation and was highest at 1643 m. Elevations increased the number of total nodes and edges of the soil bacterial community network, and more positive correlations at 1821 m suggested stronger intraspecific cooperation. Acidobacteria, Actinobacteria and Proteobacteria were the dominant phyla at all three elevations. The Mantel test and correlation analysis showed that Fe and soil urease significantly affected bacterial communities at 1448 m; interestingly, Chloroflexi was positively related to soil urease at 1448 m, and Actinobacteria was positively correlated with Ni and Zn at 1821 m. Fe and soil urease significantly influenced the bacterial communities at lower elevations, and high elevation (1821 m) enhanced the positive interactions of the soil bacteria, which might be a strategy for R. delavayi to adapt to high elevation environments. Conclusion Elevation significantly influenced the composition of soil bacterial communities by affecting the content of soil mineral elements and soil enzyme activity.

Abstract Objective To develop a nomogram based on tumor and peritumoral edema (PE) radiomics features extracted from preoperative multiparameter MRI for predicting brain invasion (BI) in atypical meningioma (AM). Methods In this retrospective study, according to the 2021 WHO classification criteria, a total of 469 patients with pathologically confirmed AM from three medical centres were enrolled and divided into training (n = 273), internal validation (n = 117) and external validation (n = 79) cohorts. BI was diagnosed based on the histopathological examination. Preoperative contrast-enhanced T1-weighted MR images (T1C) and T2-weighted MR images (T2) for extracting meningioma features and T2-fluid attenuated inversion recovery (FLAIR) sequences for extracting meningioma and PE features were obtained. The multiple logistic regression was applied to develop separate multiparameter radiomics models for comparison. A nomogram was developed by combining radiomics features and clinical risk factors, and the clinical usefulness of the nomogram was verified using decision curve analysis. Results Among the clinical factors, PE volume and PE/tumor volume ratio are the risk of BI in AM. The combined nomogram based on multiparameter MRI radiomics features of meningioma and PE and clinical indicators achieved the best performance in predicting BI in AM, with area under the curve values of 0.862 (95% CI, 0.819–0.905) in the training cohort, 0.834 (95% CI, 0.780–0.908) in the internal validation cohort and 0.867 (95% CI, 0.785–0.950) in the external validation cohort, respectively. Conclusions The nomogram based on tumor and PE radiomics features extracted from preoperative multiparameter MRI and clinical factors can predict the risk of BI in patients with AM.

Two‐dimensional polymers (2DPs) and their layer‐stacked 2D covalent organic frameworks have recently emerged as nonlinear optical (NLO) materials for potential applications in optics. However, the chemistry for designing third‐order NLO 2DP films with large nonlinear absorption coefficient (β) has remained a mystery. Herein, three highly crystalline porphyrin‐integrated 2D polyimines (named as 2DPI‐Zn‐Azo, 2DPI‐2H‐Azo, and 2DPI‐Zn), which are homogeneous films showing large lateral areas over cm2, uniform transparency, and thickness of tens of nanometers are reported. Particularly, the 2DPI‐Zn‐Azo film comprising zinc porphyrin and –NN– displays a large saturable absorption under 532 nm and the highest β (−1.88 × 105 cm GW−1) among the three 2D polyimines, that is also 2–5 orders of magnitude higher than the state‐of‐art performance of photoactive small molecules, porphyrin‐integrated 2DPs, and inorganic 2D materials. Control experiments in combination with theoretical calculation discover that the embedding of metal centers and –NN– results in highly delocalized π‐electrons and narrow bandgap in 2DPI‐Zn‐Azo, which enables fast transfer of the photogenerated electrons after the light‐excited charge separation, thus boosting the NLO performance. This work opens up a new path for the construction of highly efficient third‐order NLO film materials, and pushes the development of 2DPs for optics and optoelectronics.

Abstract Metallic phthalocyanines are promising electrocatalysts for CO2 reduction reaction (CO2RR). However, their catalytic activity and stability (especially under high potential) are still unsatisfactory. Herein, we synthesized a covalent organic polymer (COP‐CoPc) by introducing charge‐switchable viologen ligands into cobalt phthalocyanine (CoPc). The COP‐CoPc exhibits great activity for CO2RR, including a high Faradaic efficiency over a wide potential window and the highest CO partial current density among all ligand‐tuned phthalocyanine catalysts reported in the H‐type cell. Particularly, COP‐CoPc also shows great potential for practical applications, for example, a FECO of >95% is realized at a large current density of 150 mA/cm2 in a two‐electrode membrane electrode assembly reactor. Ex situ and in situ X‐ray absorption fine structure spectroscopy measurements and theory calculations reveal that when the charge‐switchable viologen ligands switch to neutral‐state ones, they can act as electron donors to enrich the electron density of Co centers in COP‐CoPc and enhance the desorption of *CO, thus improving the CO selectivity. Moreover, the excellent reversible redox capability of viologen ligands and the increased Co–N bonding strength in the Co–N4 sites enable COP‐CoPc to possess outstanding stability under elevated potentials and currents, enriching the knowledge of charge‐switchable ligands tailored CO2RR performance.

The CBL (Casitas B-lineage lymphoma) family, as a class of ubiquitin ligases, can regulate signal transduction and activate receptor tyrosine kinases through various tyrosine kinase-dependent pathways. There are three members of the family: c-CBL, CBL-b, and CBL-c. Numerous studies have demonstrated the important role of CBL in various cellular pathways, particularly those involved in the occurrence and progression of cancer, hematopoietic development, and regulation of T cell receptors. Therefore, the purpose of this review is to comprehensively summarize the function and regulatory role of CBL family proteins in different human tumors, as well as the progress of drug research targeting CBL family, so as to provide a broader clinical measurement strategy for the treatment of tumors.

The anomalies of cadmium (Cd) in karst region pose a severe threat to plant growth and development. In this study, the responses of Rhododendron decorum to Cd stress were investigated at physiological, molecular, and endophytic microbial levels, and the potential correlation among these responses was assessed. The Cd stress impeded R. decorum growth and led to an increase in malondialdehyde (MDA) and hydrogen peroxide (H2O2) levels, as well as enhanced superoxide dismutase (SOD) and catalase (CAT) activities. Meanwhile, Cd stress increased the Cd (up to 80 times compared to the control), sodium (Na), aluminum (Al), and zinc (Zn) contents, while decreased the magnesium (Mg) and manganese (Mn) contents in R. decorum leaves. Transcriptome suggested that Cd significantly regulated the pathways including “protein repair”, “hormone-mediated signaling pathway”, and “ATP-binding cassette (ABC) transporters”. Additionally, q-PCR analysis showed that Cd stress significantly up-regulated the expressions of ABCB19-like and pleiotropic drug resistance, while down-regulated the expressions of indole-3-acetic acid-amido synthetase and cytokinin dehydrogenase. The Cd stress influenced the composition of endophytic microbial communities in R. decorum leaves and enhanced the interspecific bacterial associations. Furthermore, the bacterial genera Achromobacter, Aureimonas and fungal genus Vishniacozyma exhibited a high degree of connectivity with other nodes in networks constructed by the metal element contents, differentially expressed genes (DEGs), and microbial communities, respectively. These findings provide a comprehensive insight into the response of R. decorum to Cd-induced stress, which might facilitate the breeding of the Cd-tolerant R. decorum.

Abstract Background Emerging evidence has shown interferon-induced protein with tetratricopeptide repeats 3 (IFIT3) may be predicted to be a candidate oncogene and involved in the onset and progression of cancer, but IFIT3’s potential role in cancer, particularly in head and neck squamous cell carcinoma (HNSC), is not well recognized. This study aims to reveal the role of IFIT3 in HNSC and the underlying molecular mechanism. Methods Bioinformatics analysis, immunohistochemical staining, RT-PCR, and Western blotting analysis were used to detect IFIT3 expression in HNSC. CCK-8 assays, colony formation assays, wound-healing assays, transwell assays, and sphere formation were used to explore proliferative, migratory, and invasive activities and cancer stemness of HNSC cells after IFIT3 knockdown and over-expressed. The alterations of EMT markers and PI3K/AKT pathway were detected by Western blotting. Animal studies were performed to analyze the effect of IFIT3 on tumor growth and metastasis of HNSC in vivo. Results In this study, we observed that IFIT3 was highly expressed in HNSC, and its higher expression contributed to poorer survival of patients with clinical stage IV or grade 3. Function assay indicated that IFIT3 promoted malignant behaviors in vitro, as well as tumor growth and lung metastasis in vivo. Meanwhile, PD-L1 knockdown or over-expressed reversed cancer cell stemness, migration, invasion, and PI3K/AKT signaling pathway which were regulated by IFIT3. Conclusions Our results reveal that IFIT3 promotes EMT and cancer stemness by targeting PD-L1 to activate PI3K/AKT signaling pathway in HNSC, and targeting IFIT3 may be a novel strategy for the treatment of patients with HNSC.

Abstract Background The possibility of adverse effects of medical treatment (AEMT) is increasing worldwide, but little is known about AEMT in China. This study analyzed the health burden of AEMT in China in recent years through the Global Burden of Disease Study (GBD) 2019 and compared it with the worldwide average level and those in different sociodemographic index (SDI) regions. Methods We calculated the age-standardized rate (ASR) of deaths, disability-adjusted life years (DALYs), years of life lost (YLLs), years lived with disability (YLDs), incidence and prevalence attributed to AEMT in China, worldwide and countries with different sociodemographic indices during 1990–2019 using the latest data and methods from the GBD 2019. Results From 1990 to 2019, the global age-standardized death rate (ASDR), DALYs, and YLLs for AEMT showed a significant downward trend and were negatively associated with the SDI. By 2040, the ASDR is expected to reach approximately 1.58 (95% UI: 1.33–1.80). From 1990 to 2019, there was no significant change in the global incidence of AEMT. The occurrence of AEMT was related to sex, and the incidence of AEMT was greater among females. In addition, the incidence of AEMT-related injuries and burdens, such as ASR of DALYs, ASR of YLLs and ASR of YLDs, was greater among women than among men. Very old and very young people were more likely to be exposed to AEMT. Conclusions From 1990 to 2019, progress was made worldwide in reducing the harm caused by AEMT. However, the incidence and prevalence of AEMT did not change significantly overall during this period. Therefore, the health sector should pay more attention to AEMT and take effective measures to reduce AEMT.

Abstract Adverse‐risk acute myeloid leukemia (AML) has a dismal prognosis. We aimed to investigate the activity and tolerability of venetoclax combined with homoharringtonine (HHT) plus cytarabine (VHA) regimen for de novo adverse‐risk AML. Thirteen de novo AML patients with adverse‐risk factors were treated with venetoclax (100 mg day 1, 200 mg day 2, 400 mg days 3‐21), HHT (1 mg/m2 days 1‐5) and cytarabine (100 mg/m2 days 1‐5) (VHA regimen). Complete remission (CR) was achieved in 11/13 patient (84.6%), all of CR responders were measurable residual disease (MRD) negative detected by multi‐parameter flow cytometry (MFC). Grade 3‐4 neutropenia, anaemia, and thrombocytopenia occurred in most patients. Grade 3‐4 non haematological adverse events (AEs) included febrile neutropenia (4/13, 30.8%). With a median follow‐up of 10 months (range 4‐19), median overall survival and event‐free survival were not reached. VHA may be a promising and well‐tolerated regimen in de novo adverse‐risk AML.

Vascular regeneration and patency maintenance, without anticoagulant administration, represent key developmental trends to enhance small-diameter vascular grafts (SDVG) performance. In vivo engineered autologous biotubes have emerged as SDVG candidates with pro-regenerative properties. However, mechanical failure coupled with thrombus formation hinder translational prospects of biotubes as SDVGs. Previously fabricated poly(ε-caprolactone) skeleton-reinforced biotubes (PBs) circumvented mechanical issues and achieved vascular regeneration, but orally administered anticoagulants were required. Here, highly efficient and biocompatible functional modifications were introduced to living cells on PB lumens. The 1,2-dimyristoyl-sn-glycero-3-phosphoethanolamine-N-methoxy (DMPE)-PEG-conjugated anti-coagulant bivalirudin (DPB) and DMPE-PEG-conjugated endothelial progenitor cell (EPC)-binding TPS-peptide (DPT) modifications possessed functionality conducive to promoting vascular graft patency. Co-modification of DPB and DPT swiftly attained luminal saturation without influencing cell viability. DPB repellent of non-specific proteins, DPB inhibition of thrombus formation, and DPB protection against functional masking of DPT's EPC-capture by blood components, which promoted patency and rapid endothelialization in rat and canine artery implantation models without anticoagulant administration. This strategy offers a safe, facile, and fast technical approach to convey additional functionalization to living cells within tissue-engineered constructs.

Pancreatic cancer (PC) represents a group of malignant tumours originating from pancreatic duct epithelial cells and acinar cells, and the 5-year survival rate of PC patients is only approximately 12%. Molecular targeted drugs are specific drugs designed to target and block oncogenes, and they have become promising strategies for the treatment of PC. Compared to traditional chemotherapy drugs, molecular targeted drugs have greater targeting precision, and they have significant therapeutic effects and minimal side effects. This article reviews several molecular targeted drugs that are currently in the experimental stage for the treatment of PC; these include antibody-drug conjugates (ADCs), aptamer-drug conjugates (ApDCs) and peptide-drug conjugates (PDCs). ADCs can specifically recognize cell surface antigens and reduce systemic exposure and toxicity of chemotherapy drugs. By delivering nucleic acid drugs to target cells, the targeting RNA of ApDCs can inhibit the expression or translation of mutated genes, thereby inhibiting tumour development. Moreover, PDCs can effectively penetrate tumour cells, and the peptide groups in PDCs preferentially target tumour cells with minimal side effects. In the targeted therapy of PC, molecular targeted drugs have very broad prospects, which provides new hope for the clinical treatment of PC patients and is worth further research.

PurposeTo predict chromosome 7 gain and chromosome 10 loss (+7/-10) in IDH wild-type (IDH-wt) histologically low-grade gliomas (LGG) by machine learning models based on MRI radiomics and semantic features.MethodsA total of 122 patients diagnosed as IDH-wt histologically LGG were retrospectively included in this study. The patients were randomly divided into a training group and a test group in a ratio of 7:3. The radiomics features were extracted from axial T1WI, T2WI, FLAIR and CET1 sequences, respectively. The distance correlation (DC) and least absolute shrinkage and selection operator (LASSO) were used to select the radiomics signatures. Three machine learning algorithms including neural network (NN), support vector machine (SVM), and linear discriminant analysis (LDA) were used to construct radiomics models. In addition, a nomogram was developed by combining the optimal radiomics signature with clinical risk factors, and the potential clinical utility of the nomogram was evaluated using decision curve analysis.ResultsThe LDA+DC model was identified as the optimal classifier among the six radiomics models. Necrosis was determined as a risk factor for +7/-10 in IDH-wt histologically LGG. The nomogram achieved the best performance, with an AUC of 0.854 and an accuracy of 0.778 in the independent test group. The decision curve of the nomogram confirmed its clinical usefulness in a wide range of thresholds.ConclusionThe nomogram combining radiomics and semantic features can predict the +7/-10 status effectively, which may contribute to the risk stratification and individualized treatment planning of patients with IDH-wt histologically LGG.

High-rise buildings (HRBs) are prone to high fire hazards due to their high occupant density, limited evacuation routes, and high fire load. The indicator system method, as a systematic evaluation method, is widely applied to assess HRB fire risk. However, the method is subjective because the determination of the indicator weights mainly relies on expert experience. In order to reduce the subjectivity of the indicator system method in assessing the fire risk of HRBs, this study proposes a new assessment method by combining the spatial Markov chain model and the indicator system method. In this new method, fire occurrence probability is calculated by the spatial Markov chain model using historical HRB fire accident data. An indicator system is built to characterize the fire consequence by the structure entropy weight method. Subsequently, HRBs in Beijing are used as a case to illustrate the practicality of this approach. Firstly, the spatial Markov chain model is trained and validated using the chi-square goodness-of-fit test based on fire accident data from 2018 to 2023 in Beijing. It was found that the best performance was achieved with the monthly period and the four-state. Then, the distribution of regional fire occurrence probability in April was predicted based on fire accident data in March 2023 in Beijing. It showed that areas with higher fire occurrence probability are mainly located in the central region, especially in the I District. Then, the indicator system was used to evaluate the HRB fire consequence in the I District. The assessment results showed that the areas with more severe fire consequences are mainly located in the II and IV Districts, due to the poor performance of the fire system or the absence of fire protection systems. Coupling the fire occurrence probability and its consequences shows that HRBs with higher fire risk are mainly located in area II and should be carefully supervised for fire management. This developed method can provide some insights into the fire safety management of HRBs and the layout of the fire stations.

Abstract With a wide range of applications in autonomous driving and robotics, semantic segmentation for large‐scale outdoor point clouds is a critical and challenging issue. Due to the large number and irregular arrangement of point clouds, it is difficult to balance the efficiency and effectiveness. In this paper, we propose LessNet, a lightweight and efficient voxel‐based method for LiDAR‐only semantic segmentation, taking advantage of cylindrical partition and intra‐voxel feature fusion. Specifically, we use a cylindrical partition method to distribute the outdoor point clouds more evenly in voxels. To better encode the voxel features, we adopt an intra‐voxel aggregation method without querying neighbours. The voxel features are further input into a lightweight and effective 3D U‐net to aggregate local features and dilate the receptive field. Extensive experiments prove the satisfied semantic segmentation performance and the improvement of each component in our proposed framework. Our method is capable of processing more than one million point clouds at a time while retaining low latency and few parameters. Moreover, our method achieves comparable performance with state‐of‐the‐art approaches and outperforms all projection‐based methods on the SemanticKITTI benchmark.

Tree peony (Paeonia suffruticosa) is a well-known Chinese ornamental plant with showy flower color. However, the color fading problem during vase time seriously blocks its development in the cut flower market. In this study, we found that exogenous glucose supply improved the color quality of P. suffruticosa ‘Tai Yang’ cut flowers with increased total soluble sugar and anthocyanin contents of petals. Besides, the promotion effect of glucose was better than the osmotic control of 3-O-methylglucose (3OMG) treatment and the glucose analog mannose treatment. The structural genes, including PsF3H, PsF3′H, PsDFR, PsAOMT, and PsUF5GT, were remarkably upregulated under glucose treatment. Meanwhile, the regulatory genes, including PsbHLH1, PsbHLH3, PsMYB2, PsWD40-1, and PsWD40-2, also showed a strong response to glucose treatment. Among these five regulatory genes, PsMYB2 showed less response to 3OMG treatment but was highly expressed under glucose and mannose treatments, indicating that PsMYB2 may have an important role in the glucose signal pathway. Ectopic overexpression of PsMYB2 in Nicotiana tabacum resulted in a strong pigmentation in petals and stamens of tobacco flowers accompanied with multiple anthocyanin biosynthetic genes upregulated. More importantly, the overexpression of PsMYB2 enhanced the ability of glucose-induced anthocyanin accumulation in Arabidopsis thaliana seedlings since PsMYB2-overexpressing Arabidopsis showed higher expression levels of AtPAL1, AtCHS, AtF3H, AtF3′H, AtDFR, and AtLDOX than those of wild type under glucose treatment. In summary, we suggested that glucose supply promoted petal coloration of P. suffruticosa ‘Tai Yang’ cut flower through the signal pathway, and PsMYB2 was a key component in this process. Our research made a further understanding of the mechanism that glucose-induced anthocyanin biosynthesis of P. suffruticosa cut flowers during postharvest development, laying a foundation for color retention technology development of cut flowers.

Over the years, probabilistic nature of renewable energy sources (RES) and its influence on power system adequacy have been well studied. However, rather less attention has been paid to the impact of RES unit itself's and its power conversion system's (PCS') reliability, as well as their various connection topologies. This paper devises a comprehensive sensitivity study on how each of these elements can affect overall generating system reliability. given the plethora of RES configurations and components, it is of import to identify the most vulnerable element in RES. In this work, component importance is extended, for the first time, to generating capacity adequacy assessment (HLI). Measurement index is the centerpiece in reliability importance. New indices have to be introduced to facilitate the study. While the physical meaning of previously developed indices is lost, in this study indices are proposed based on traditional importance measures, of which the physical meaning are strictly retained and consistent with the definitions. With the proposed assessment technique, components in various RES configuration can be ranked according to their reliability importance. It is found in the numerical study that different importance measures (such as risk-achievement based measures and risk-reduction based measures) can result in different rankings. Studies on contributing factors of the reliability importance are also performed. As more and more RES gaining foothold in generating systems, the proposed technique assist to achieve targeted reliability level of the system, by easily identifying and prioritizing reliability improvement tasks among various units/components in the increasing complex system.

The subject of optimal secondary control of power-electronic-interfaced distributed energy resources (DERs) in droop-controlled microgrids has garnered significant research attention in recent years. While the feasibility of optimal secondary control based on non-linear power flow has been proven, the power flow algorithm is essentially iterative in nature. This work proposes an optimal secondary control with non-iterative power flow to regulate multi-bus voltages and DERs’ reactive powers. The control scheme incorporates a modified Decoupled Linearized Power Flow that is known to be superior in terms of reactive power and bus voltage magnitude estimation, as compared to classical DC power flow, into a constrained quadratic programming. Q-V droop is integrated into the linear power flow in place of the slack bus. The proposed optimal scheme is provably accurate for maintaining reactive power sharing while regulating multiple load-bus voltages. The additional degrees of freedom enabled by the weighting factors significantly improve the control flexibility of the secondary controller. The allowable bus voltages and DER kVar capacity limits have also been considered by the control algorithm. The work is proven through an accurate co-simulation study comprising an 18-bus network and a full primary control models in PowerFactory, interfaced through industrial communication tool MatrikonOPC.

Increasing evidence has shown that mammaglobin, GATA-binding protein 3 (GATA3), and epithelial growth factor receptor (EGFR) have unique clinical implications for breast cancer subtyping and classification, as well as for breast cancer targeted therapy. It is particularly important to clarify the correlation between their expression and different molecular breast carcinoma subtypes to better understand the molecular basis of the subtypes and to identify effective therapeutic targets for the disease. This study aimed to evaluate mammaglobin, GATA3, and EGFR expression in different breast cancer subtypes, as well as their clinical significance. Subjects of the study included 228 patients with breast cancer at The First Affiliated Hospital of University of Science and Technology of China. They were divided into triple negative (TN), Luminal A, Luminal B, and HER-2 positive (HER-2.P) breast cancer groups based on molecular classification. Immunohistochemical methods were used to detect mammaglobin, GATA3, and EGFR expression in cases of different molecular subtypes before determining the correlation between protein expression and subtype. Mammaglobin and GATA3 expression levels were found to significantly vary with respect to histopathological grade, lymph node status, and molecular subtype; EGFR expression was significantly correlated with breast cancer histopathological grade and molecular subtype. For breast cancer, the expression levels of mammaglobin and GATA3, as well as mammaglobin and EGFR, were significantly correlated. In addition, there was a significantly negative correlation between the expression levels of GATA3 and EGFR in breast cancer tissue samples, especially in HER-2.P samples. These findings provide a theoretical basis for assessing breast cancer clinical prognosis based on the cancer subtype, and hence, have significant practical value.

Abstract Background Mixed phenotype acute leukemia (MPAL) is a rare leukemia and is regarded as a high-risk entity with a poor prognosis. Induction therapy of an acute lymphoblastic leukemia type or hybrid regimen and hematopoietic stem cell transplantation has been recommended for MPAL. However, the optimal therapies for relapsed or refractory MPAL remain unclear, especially for relapse after stem cell transplantation. Donor-derived chimeric antigen receptor T (CAR-T) cell therapy may be a promising therapeutic option for patients with MPAL who express target antigens and have relapsed after stem cell transplantation. However, recurrence remains a challenge, and reinfusion of CAR-T cells is not always effective. An infusion of secondary donor-derived humanized CD19-modified CAR-T cells may be effective in inducing remission. Case presentation We report a case of MPAL with CD19 expression. The patient was treated with acute lymphoblastic leukemia-like induction and consolidation therapies but remained positive for SET-NUP214 fusion gene transcript. He subsequently underwent a haploidentical stem cell transplantation but relapsed within 6 months. He then underwent donor-derived CD19-targeted CAR-T cell therapy and achieved a sustained, complete molecular remission. Unfortunately, he developed a CD19-positive relapse after 2 years. Donor-derived humanized CD19-directed CAR-T cells induced a second complete molecular remission without severe cytokine release syndrome or acute graft-versus-host disease. Conclusion This case demonstrated the efficacy and safety of humanized donor-derived CD19-modified CAR-T cell infusion for treating the recurrence of MPAL previously exposed to murine-derived CD19-directed CAR-T cells.

Variant acute promyelocytic leukemia (APL) showed quite different aspects, and the current treatments remained challenged at present. Venetoclax, a selective inhibitor of B-cell lymphoma 2 (BCL-2), is a small molecule that has been studied in several hematologic malignancies as both monotherapy and in combination with other agents. However, there is little of its use in the treatment of APL or variant APL. In this report, we identified THRAP3 as novel RARA fusion in resembling APL, which was resistant to all-trans retinoic acid (ATRA) combined arsenic trioxide (ATO) chemotherapy. Then, the patient was salvaged by low-dose venetoclax and decitabine. The treatment in this case demonstrates the potential ability of venetoclax in variant APL, thus providing a new treatment option for all kinds of APL.

Simple, rapid, and accurate detection of myoinositol (MI) concentration in blood is crucial in diagnosing polycystic ovary syndrome, neurological disorders, and cancer. A novel electrochemical detection (IED) method was established to quantify MI in human serum using a disposable unmodified screen-printed carbon electrode (SPCE) for the first time. MI was detected indirectly by the reaction product of myoinositol dehydrogenase (IDH) and cofactor β-nicotinamide adenine dinucleotide (NAD+). Good linear calibration curves were obtained at the concentration range from 5.0 μM to 500.0 μM (R2 = 0.9981) with the lower limits of detection (LOD) and quantification (LOQ) of 1.0 μM and 2.5 μM, respectively. Recoveries were calculated at three spiked concentrations, and the values were between 90.3 and 106%, with relative standard deviation values of 3.2–6.2% for intraday precision and 7.1–9.0% for interday precision. The SPCE-electrochemical biosensor is simple, accurate, and without modification, showing great potential for point-of-care testing (POCT) of serum MI in clinical samples.

Objective: To investigate the ability of a MRI-based radiomics-clinicopathological model to predict pituitary macroadenoma (PMA) recurrence within 5 years.Materials and Methods: We recruited 74 recurrent and 94 non-recurrent subjects, following first surgery with 5-year follow-up data. Univariate and multivariate analyses were conducted to identify independent clinicopathological risk factors. Two independent and blinded neuroradiologists used 3D-Slicer software to manually delineate whole tumors using preoperative axial contrast-enhanced T1WI (CE-T1WI) images. 3D-Slicer was then used to extract radiomics features from segmented tumors. Dimensionality reduction was carried out by the least absolute shrinkage and selection operator (LASSO). Two multilayer perceptron (MLP) models were established, including independent clinicopathological risk factors (Model 1) and a combination of screened radiomics features and independent clinicopathological markers (Model 2). The predictive performance of these models was evaluated by receiver operator characteristic (ROC) curve analysis.Results: In total, 1,130 features were identified, and 4 of these were selected by LASSO. In the test set, the area under the curve (AUC) of Model 2 was superior to Model 1 {0.783, [95% confidence interval (CI): 0.718—.860] vs. 0.739, (95% CI: 0.665–0.818)}. Model 2 also yielded the higher accuracy (0.808 vs. 0.692), sensitivity (0.826 vs. 0.652), and specificity (0.793 vs. 0.724) than Model 1.Conclusions: The integrated classifier was superior to a clinical classifier and may facilitate the prediction of individualized prognosis and therapy.

Abstract Background Lignocellulosic biomass is one of the most abundant materials for biochemicals production. However, efficient co-utilization of glucose and xylose from the lignocellulosic biomass is a challenge due to the glucose repression in microorganisms. Kluyveromyces marxianus is a thermotolerant and efficient xylose-utilizing yeast. To realize the glucose–xylose co-utilization, analyzing the glucose repression of xylose utilization in K. marxianus is necessary. In addition, a glucose–xylose co-utilization platform strain will facilitate the construction of lignocellulosic biomass-utilizing strains. Results Through gene disruption, hexokinase 1 (KmHXK1) and sucrose non-fermenting 1 (KmSNF1) were proved to be involved in the glucose repression of xylose utilization while disruption of the downstream genes of cyclic AMP-protein kinase A (cAMP-PKA) signaling pathway or sucrose non-fermenting 3 (SNF3) glucose-sensing pathway did not alleviate the repression. Furthermore, disruption of the gene of multicopy inhibitor of GAL gene expression (KmMIG1) alleviated the glucose repression on some nonglucose sugars (galactose, sucrose, and raffinose) but still kept glucose repression of xylose utilization. Real-time PCR analysis of the xylose utilization related genes transcription confirmed these results, and besides, revealed that xylitol dehydrogenase gene (KmXYL2) was the critical gene for xylose utilization and stringently regulated by glucose repression. Many other genes of candidate targets interacting with SNF1 were also evaluated by disruption, but none proved to be the key regulator in the pathway of the glucose repression on xylose utilization. Therefore, there may exist other signaling pathway(s) for glucose repression on xylose consumption. Based on these results, a thermotolerant xylose–glucose co-consumption platform strain of K. marxianus was constructed. Then, exogenous xylose reductase and xylose-specific transporter genes were overexpressed in the platform strain to obtain YHY013. The YHY013 could efficiently co-utilized the glucose and xylose from corncob hydrolysate or xylose mother liquor for xylitol production (> 100 g/L) even with inexpensive organic nitrogen sources. Conclusions The analysis of the glucose repression in K. marxianus laid the foundation for construction of the glucose–xylose co-utilizing platform strain. The efficient xylitol production strain further verified the potential of the platform strain in exploitation of lignocellulosic biomass.

Multi-drug resistance (MDR) and hypervirulence (hv) were exhibited by different well-separated Klebsiella pneumoniae lineages in the past, but their convergence clones—MDR-hypervirulent K. pneumoniae (HvKPs)—both highly pathogenic and resistant to most available antibiotics, have increasingly been reported. In light of the clonal lineages and molecular characteristics of the studied MDR-HvKP strains found in the literature since 2014, this review discusses the epidemiology of MDR-HvKPs, in particular summarizing the three general aspects of plasmids-associated mechanisms underlying the formation of MDR-HvKPs clones: MDR-classic K. pneumoniae (cKPs) acquiring hv plasmids, hvKPs obtaining MDR plasmids, and the acquisition of hybrid plasmids harboring virulence and resistance determinants. A deeper understanding of epidemiological characteristics and possible formation mechanisms of MDR-HvKPs is greatly needed for the proper surveillance and management of this potential threat.

The purpose of this study was to design an innovative topical ointment containing betamethasone dipropionate loaded nanostructured lipid carrier (BD-NLC) for the treatment of atopic dermatitis (AD). BD-loaded NLC was produced with precirol ATO 5 and oleic oil (OA) by melt emulsification method. Effects of surfactant concentration, amount of solid lipid and liquid lipid on skin retention and skin penetration were investigated by in vitro percutaneous permeation experiment. The optimized BD-NLC showed a homogeneous particle size of 169.1 nm (with PI = 0.195), negatively charged surface (−23.4 mV) and high encapsulation efficiency (85%). Particle morphology assessed by TEM revealed a spherical shape. In vitro skin permeation study was carried out to investigate the percutaneous behaviors of W/O ointment with BD-NLC and Carbopol emulgel ointment with BD-NLC. W/O ointment with BD-NLC showed high skin retention (35.43 µg/g) and low penetration (0.87 µg/ml). In vitro drug release studies were carried out to demonstrate the drug releasing properties of the two ointments. W/O ointment with BD-NLC showed an advantage for skin retention as it was better for drug release. The tissue distribution test suggested that BD distribution was skin > muscle > blood. Self-made topical ointment in mice showed no skin irritation. The animal experiments indicated that BD-loaded NLC ointment was effective and safe for topical use.

The phosphoinositide 3-kinase pathway is one of the most commonly altered pathways in human cancers. The serum/glucocorticoid-regulated kinase (SGK) family of serine/threonine kinases consists of three isoforms, SGK1, SGK2, and SGK3. This family of kinases is highly homologous to the AKT kinase family, sharing similar upstream activators and downstream targets. Few studies have investigated the role of SGK2 in hepatocellular carcinoma. Here, we report that SGK2 expression levels were upregulated in hepatocellular carcinoma tissues and human hepatoma cell lines compared to the adjacent normal liver tissues and a normal hepatocyte line, respectively. We found that downregulated SGK2 inhibits cell migration and invasive potential of hepatocellular carcinoma cell lines (SMMC-7721 and Huh-7).We also found that downregulated SGK2 suppressed the expression level of unphosphorylated (activated) glycogen synthase kinase 3 beta. In addition, SGK2 downregulation decreased the dephosphorylation (activation) of β-catenin by preventing its proteasomal degradation in the hepatocellular carcinoma cell lines. These findings suggest that SGK2 promotes hepatocellular carcinoma progression and mediates glycogen synthase kinase 3 beta/β-catenin signaling in hepatocellular carcinoma cells.

Urate oxidase is a key enzyme in purine metabolism and catalyzes the oxidation of uric acid to allantoin. It is used to treat hyperuricemia and gout, and also in a diagnostic kit. In this study, error-prone polymerase chain reaction and staggered extension process was used to generate a mutant urate oxidase with improved enzyme activity from Bacillus subtilis. After several rounds of mutagenesis and screening, two mutants 6E9 and 8E279 were obtained which exhibited 2.99 and 3.43 times higher catalytic efficiency, respectively. They also exhibited lower optimal reaction temperature and higher thermo-stability. D44V, Q268R and K285Q were identified as the three most beneficial amino acid substitutions introduced by site-directed mutagenesis. D44V/Q268R, which was obtained through random combination of the three mutants, displayed the highest catalytic activity. The Km, kcat/Km and enzyme activity of D44V/Q268R increased by 68%, 83% and 129% respectively, compared with that of wild-type urate oxidase. Structural modeling indicated that mutations far from the active site can have significant effects on activity. For many of them, the underlying mechanisms are still difficult to explain from the static structural model. We also compared the effects of the same set of single point mutations on the wild type and on the final mutant. The results indicate strong effects of epistasis, which may imply that the mutations affect catalysis through influences on protein dynamics besides equilibrium structures.

The aim of this study was to design a compound transdermal patch containing diclofenac (DA) and teriflunomide (TEF) for the treatment of rheumatoid arthritis (RA). The various organic amines salts of DA were prepared and their forming was confirmed using DSC and FTIR. The percutaneous permeation of organic amines salt of DA was investigated in vitro using a two-chamber diffusion cell with excised rabbit skin as transdermal barrier. The formulation of the patch was optimized in terms of the concentration of percutaneous permeation enhancer and the loading dose of drugs. The pharmacokinetic behavior of the optimal formulation was studies in rabbits and the anti-inflammatory and analgesic effects of the optimal patch were evaluated with the adjuvant arthritis model in rats and the pain model in mice, respectively. The result showed that skin penetration of diclofenac-triethylamine (DA-TEtA) salt was better than other organic amine salts. Based on previous study of our laboratory, teriflunomide-triethylamine (TEF-TEtA) significantly enhanced the skin permeation of TEF. 10% of azone (AZ) was the best enhancer for the two drugs. The optimal patch formulation was composed of 2% of TEF-TEtA, 6% of DA-TEtA and 10% of AZ. The cumulative permeated amount of DA-TEtA in vitro was comparable with that of the commercial diclofenac-diethylamine (DA-DEtA) patch. The absolute bioavailability of TEF-TEtA was 42%, which could achieve the therapeutic drug levels. In animal study, the optimized compound patch containing DA-TEtA and TEF-TEtA displayed significant anti-inflammatory and analgesic effect, which indicated the potential of the compound patch.

BackgroundAlthough access to dental care has improved over time, many children still face difficulty in obtaining services. One strategy to increase access is through mobile dental services, often in collaboration with schools, Head Start programs, and school-based health centers. This study evaluates a large mobile dental care program based in Minnesota.MethodsThematic analysis of interview data collected during a 2-day site visit and multivariate regression analysis of electronic records of patients (adults and children) that received care from 2000 through 2015, representing 84,279 unique patients.ResultsThe number of patients increased from 5558 in 2000 to 13,863 in 2015. There was a decline in the share of preventive procedures over this period, from 45.7% to 29.4%, and an increase in the share of patients seen at fixed sites. The interview data revealed that program growth relied on relationships with school leaders, expanded scope of practice for dental assistants and dental therapists, and high Medicaid reimbursement.ConclusionsMobile dental care programs can increase both preventive and restorative dental care for individuals who otherwise would not easily access oral health care services; mobile dental programs could be an option in many other communities and schools.

Itepekimab, a monoclonal antibody against interleukin‐33, has demonstrated clinical utility in previous studies in patients with asthma and chronic obstructive pulmonary disease. An autoinjector (AI) has been developed for administering itepekimab to facilitate further development. This study compared pharmacokinetics of single 300‐mg itepekimab subcutaneous administration via an AI versus a prefilled syringe (PFS). Of 90 healthy volunteers enrolled in this Phase 1, parallel‐design, randomized study and stratified by body weight (50 to <70 kg, ≥70 to <80 kg, ≥80 to 100 kg) and injection site (abdomen, thigh, or arm), 84 completed the study. Systemic exposure of itepekimab was similar for both groups. Point estimates for geometric mean ratios of pharmacokinetic parameters for AI versus PFS groups were 1.01 for maximum serum concentration, 1.06 for area under the serum concentration‐time curve to the last quantifiable concentration, and 1.04 for area under the serum concentration‐time curve extrapolated to infinity. The exposure was similar for both devices in each body weight and injection site subgroup. Overall, systemic exposure of 300‐mg single‐dose itepekimab in healthy participants was comparable when administered subcutaneously via an AI device and PFS, with an acceptable safety profile in both device groups. [ABSTRACT FROM AUTHOR]