Impact of tocilizumab on anti-CD19 chimeric antigen receptor T-cell therapy in B-cell acute lymphoblastic leukemia.

BACKGROUND: Tocilizumab is commonly used for the management of chimeric antigen receptor (CAR) T-cell therapy-associated cytokine release syndrome (CRS). However, it remains unknown whether tocilizumab or its dosage affects the efficacy and safety of CAR T-cell therapy. The objective of this multicenter retrospective study was to explore the impact of tocilizumab on CAR T-cell therapy. METHODS: In total, 93 patients with B-cell acute lymphoblastic leukemia (B-ALL) receiving humanized anti-CD19 CAR T cells were recruited from May 2016 to November 2022. Forty-five patients received tocilizumab (tocilizumab group), whereas 48 patients did not (nontocilizumab group). Thirteen patients received >1 dose of tocilizumab. The primary end point was the effect of tocilizumab on the efficacy and safety of CAR T cells. Additionally, proliferation, killing, and cytokine assays of CAR T cells were performed in vitro in the presence of tocilizumab. RESULTS: The median age of the patients was 33 years, with 47 males and 46 females. Patients in the tocilizumab group showed similar complete response (CR) rate, overall survival (OS), and event-free survival (EFS) compared with the nontocilizumab group. Compared with patients who received ≤1 dose of tocilizumab, receiving >1 dose of tocilizumab did not affect their CR rate, OS, or EFS. In the tocilizumab group, all patients experienced CRS and 26.7% experienced immune effector cell-associated neurotoxicity syndrome (ICANS). In the nontocilizumab group, 64.6% of patients experienced CRS and 8.3% experienced ICANS. Up to 75% of ICANS and 87.5% of grade ≥3 ICANS occurred in the tocilizumab group. In vitro, tocilizumab did not impair the proliferation and killing effects of CAR T cells. CONCLUSIONS: Tocilizumab does not affect the efficacy of CAR T cells but may increase the likelihood of ICANS.

Enhancement of liposomal properties of thyme essential oil using lysozyme modification: Physicochemical, storage, and antibacterial properties.

Thyme essential oil (TEO) is a natural food antimicrobial agent derived of spice, but suffers from volatility and poor water solubility, which problem can be effectively solved by the encapsulation of liposomes. On this basis, a safe and common natural antibacterial protein, LYZ was used to modify the TEO liposomes (TEO-lips) for gaining better properties. 2.5 mg/mL TEO and 0.05 % LYZ/S100 mass ratio were the best formula for the preparation of LYZ-TEO-lips. After LYZ modification, the particle size and PDI increased, and the zeta potential decreased slightly. The modification of LYZ not only improves the thermal stability of TEO-Lips, weakens the influence of acid and salt ions on liposomes, but also improves the antibacterial properties of TEO-Lips. In brief, LYZ has the potential to improve the overall properties of liposomes and can provide a reference for the development of antimicrobial liposomes.

Aggregation studies of alpha-lactalbumin induced by edible azo dyes with different sulfonyl group numbers: A comparative study.

As an opaque and complex colloidal mixture, milk is usually present as a positively charged colloid under acidic conditions. Adding negatively charged colloids can lead to protein aggregation in milk. Alpha-lactalbumin (α-La) is an essential component of whey protein and has good physicochemical properties for functional food development. We combined spectroscopy, computer simulations, and other techniques to comparative analyze the mechanisms and characteristics of isolated α-La aggregation induced by CI Acid Red 27 (C27)/CI Acid Red 14 (FB) containing different sulfonyl groups in vitro. The results showed that C27/FB (5.25 × 10-5 mol·L-1 to 3.15 × 10-4 mol·L-1) induced the formation of fibril-like aggregates under acidic conditions (pH 2.0 and 4.0) mainly benefit from hydrophobic and electrostatic forces. Weakening and redshift of α-La's characteristics negative peak were observed (208 nm to 218 nm) on circular dichroism. ß-Crosslinks self-assembly and reorganization of disulfide bonds occurred during protein fibrillation. Moreover, the different redshift intensity of Congo red binding to amyloid fibrils was observed to be induced by C27 (>551 nm) and FB (>536 nm), and the direct observation by TEM demonstrated the ability to induce protein fibrillation is C27 > FB. Edible azo dyes with more sulfonyl groups would possess a stronger ability to induce protein fibrillation.

Identification and assessment of the drift velocity of green tides using the maximum cross-correlation method in the Yellow Sea.

The green tides outbreak events seriously threaten the ecological balance of the coastal areas. Quickly and accurately obtaining the spatial distribution and drift state of green tides is key to early warning. Based on Landsat 8 (L8) and Sentinel-2 (S2) image pair, the green tides drift velocity was extracted using the maximum cross-correlation (MCC) method, and windage was calculated by combining ocean current and wind data. The results of the MCC method were validated. Ulva's drift in the Yellow Sea is shaped by both ocean currents and wind, closely aligning with the direction of the currents. Notably, the northward drift velocity of Ulva exhibits a clear boundary around 34°40'N. Windage shows similar characteristics with the Ulva drift velocity, as its values vary with time and space. This study will enhance our comprehension of the dynamic mechanism of green tides drift.

Establishment and health management application of a prediction model for high-risk complication combination of type 2 diabetes mellitus based on data mining.

In recent years, the prevalence of T2DM has been increasing annually, in particular, the personal and socioeconomic burden caused by multiple complications has become increasingly serious. This study aimed to screen out the high-risk complication combination of T2DM through various data mining methods, establish and evaluate a risk prediction model of the complication combination in patients with T2DM. Questionnaire surveys, physical examinations, and biochemical tests were conducted on 4,937 patients with T2DM, and 810 cases of sample data with complications were retained. The high-risk complication combination was screened by association rules based on the Apriori algorithm. Risk factors were screened using the LASSO regression model, random forest model, and support vector machine. A risk prediction model was established using logistic regression analysis, and a dynamic nomogram was constructed. Receiver operating characteristic (ROC) curves, harrell's concordance index (C-Index), calibration curves, decision curve analysis (DCA), and internal validation were used to evaluate the differentiation, calibration, and clinical applicability of the models. This study found that patients with T2DM had a high-risk combination of lower extremity vasculopathy, diabetic foot, and diabetic retinopathy. Based on this, body mass index, diastolic blood pressure, total cholesterol, triglyceride, 2-hour postprandial blood glucose and blood urea nitrogen levels were screened and used for the modeling analysis. The area under the ROC curves of the internal and external validations were 0.768 (95% CI, 0.744-0.792) and 0.745 (95% CI, 0.669-0.820), respectively, and the C-index and AUC value were consistent. The calibration plots showed good calibration, and the risk threshold for DCA was 30-54%. In this study, we developed and evaluated a predictive model for the development of a high-risk complication combination while uncovering the pattern of complications in patients with T2DM. This model has a practical guiding effect on the health management of patients with T2DM in community settings.

Machine Learning Electrocardiogram for Mobile Cardiac Pattern Extraction.

BACKGROUND: Internet-of-things technologies are reshaping healthcare applications. We take a special interest in long-term, out-of-clinic, electrocardiogram (ECG)-based heart health management and propose a machine learning framework to extract crucial patterns from noisy mobile ECG signals. METHODS: A three-stage hybrid machine learning framework is proposed for estimating heart-disease-related ECG QRS duration. First, raw heartbeats are recognized from the mobile ECG using a support vector machine (SVM). Then, the QRS boundaries are located using a novel pattern recognition approach, multiview dynamic time warping (MV-DTW). To enhance robustness with motion artifacts in the signal, the MV-DTW path distance is also used to quantize heartbeat-specific distortion conditions. Finally, a regression model is trained to transform the mobile ECG QRS duration into the commonly used standard chest ECG QRS durations. RESULTS: With the proposed framework, the performance of ECG QRS duration estimation is very encouraging, and the correlation coefficient, mean error/standard deviation, mean absolute error, and root mean absolute error are 91.2%, 0.4 ± 2.6, 1.7, and 2.6 ms, respectively, compared with the traditional chest ECG-based measurements. CONCLUSIONS: Promising experimental results are demonstrated to indicate the effectiveness of the framework. This study will greatly advance machine-learning-enabled ECG data mining towards smart medical decision support.

Genetically predicted ankylosing spondylitis is causally associated with psoriasis.

Background: Previous observational studies have reported the striking association between ankylosing spondylitis (AS) and psoriasis, but the causal relationship between the two diseases remains unclear. Methods: Two-sample Mendelian randomization (MR) analysis with methods of inverse-variance weighted, MR-Egger regression, weighted median, and weighted mode was conducted to evaluate the bidirectional causal associations between AS and psoriasis. Effective single-nucleotide polymorphisms (SNPs) from genome-wide association studies (GWAS) were selected as instrumental variables (IVs). Sensitivity analyses were also applied to verify whether heterogeneity and pleiotropy can bias the results. Result: We found positive causal effects of genetically increased AS risk on psoriasis (IVW: OR = 1.009, 95% CI = 1.005-1.012, p = 8.07E-07). Comparable outcomes were acquired by MR-Egger regression, weighted median, and weighted mode approaches. Nevertheless, we did not find significant causal effects of psoriasis on AS (IVW: OR = 1.183, 95% CI = 0.137-10.199, p = 0.879). The sensitivity analyses showed that the horizontal pleiotropy was unlikely to skew the causality. The leave-one-out analysis demonstrated that no single SNP can drive the MR estimates. No evidence of heterogeneity was found between the selected IVs. Conclusion: Our findings provide evidence that AS has positive causal effects on the risk of psoriasis in the European population.

Anti-G Protein-Coupled Receptor, Class C Group 5 Member D Chimeric Antigen Receptor T Cells in Patients With Relapsed or Refractory Multiple Myeloma: A Single-Arm, Phase â ¡ Trial.

PURPOSE: G protein-coupled receptor, class C group 5 member D (GPRC5D) is considered to be a promising surface target for multiple myeloma (MM) immunotherapy. Here, we report the efficacy and safety of anti-GPRC5D chimeric antigen receptor (CAR) T cells in patients with relapsed or refractory (R/R) MM. METHODS: This phase Ⅱ, single-arm study enrolled patients (18-70 years) with R/R MM. Lymphodepletion was performed before patients received 2 × 106/kg anti-GPRC5D CAR T cells. The primary end point was the proportion of patients who achieved an overall response. Safety was also evaluated in eligible patients. RESULTS: From September 1, 2021, to March 23, 2022, 33 patients were infused with anti-GPRC5D CAR T cells. At a median follow-up of 5.2 months (range, 3.2-8.9), the overall response rate was 91% (95% CI, 76 to 98; 30 of 33 patients), including 11 (33%) stringent complete responses, 10 (30%) complete responses, four (12%) very good partial responses, and five (15%) partial responses. Partial responses or better were observed in nine (100%) of nine patients with previous anti-B-cell maturation antigen (BCMA) CAR T-cell therapy, including two patients who had received repeated anti-BCMA CAR T-cell infusions with no responses at the last time. Grade 3 or higher hematologic toxicities were neutropenia (33 [100%]), anemia (17 [52%]), and thrombocytopenia (15 [45%]). Cytokine release syndrome occurred in 25 (76%) of 33 patients (all were grade 1 or 2), and neurotoxicities in three patients (one grade 2 and one grade 3 ICANSs and one grade 3 headache). CONCLUSION: Anti-GPRC5D CAR T-cell therapy showed an encouraging clinical efficacy and manageable safety profile in patients with R/R MM. For patients with MM that progressed after anti-BCMA CAR T-cell therapy or that is refractory to anti-BCMA CAR T cell, anti-GPRC5D CAR T-cell therapy might be a potential alternative option.

Associations of granulocyte colony-stimulating factor with toxicities and efficacy of chimeric antigen receptor T-cell therapy in relapsed or refractory multiple myeloma.

BACKGROUND AIMS: Few studies have reported the associations of granulocyte colony-stimulating factor (G-CSF) with cytokine release syndrome (CRS), neurotoxic events (NEs) and efficacy after chimeric antigen receptor (CAR) T-cell therapy for relapsed or refractory (R/R) multiple myeloma (MM). We present a retrospective study performed on 113 patients with R/R MM who received single anti-BCMA CAR T-cell, combined with anti-CD19 CAR T-cell or anti-CD138 CAR T-cell therapy. METHODS: Eight patients were given G-CSF after successful management of CRS, and no CRS re-occurred thereafter. Of the remaining 105 patients that were finally analyzed, 72 (68.6%) received G-CSF (G-CSF group), and 33 (31.4%) did not (non G-CSF group). We mainly analyzed the incidence and severity of CRS or NEs in two groups of patients, as well as the associations of G-CSF timing, cumulative dose and cumulative time with CRS, NEs and efficacy of CAR T-cell therapy. RESULTS: Both groups of patients had similar duration of grade 3-4 neutropenia, and the incidence and severity of CRS or NEs.There were also no differences in the incidence and severity of CRS or NEs between patients with the timing of G-CSF administration ≤3 days and those >3 days after CAR T-cell infusion. The incidence of CRS was greater in patients receiving cumulative doses of G-CSF >1500 µg or cumulative time of G-CSF administration >5 days. Among patients with CRS, there was no difference in the severity of CRS between patients who used G-CSF and those who did not. The duration of CRS in anti-BCMA and anti-CD19 CAR T-cell-treated patients was prolonged after G-CSF administration. There were no significant differences in the overall response rate at 1 and 3 months between the G-CSF group and the non-G-CSF group. CONCLUSIONS: Our results showed that low-dose or short-time use of G-CSF was not associated with the incidence or severity of CRS or NEs, and G-CSF administration did not influence the antitumor activity of CAR T-cell therapy.

Comparative analysis of the interaction between alpha-lactalbumin and two edible azo colorants equipped with different sulfonyl group numbers.

Alpha-lactalbumin (α-La) is a crucial active component in whey protein. It would be mixed with edible azo pigments during processing. Spectroscopic analyses and computer simulations were used here to characterize the interaction between acid red 27 (C27) /acidic red B (FB) and α-La. Fluorescence, thermodynamics, and energy transfer showed the binding mechanism is a static quenching with a medium affinity. This binding process occurred spontaneously and was mainly driven by hydrophobic forces. Conformation analysis showed FB led to a greater change in the secondary structure of α-La compared with C27. C27 increased and FB decreased the surface hydrophobicity of α-La. The spatial structures of complexes were visualized with computer aid. The azo colorant binds to α-La easily and deeply with a smaller space volume and dipole moment and thereby affecting the α-La conformation and functionality. This study provides a theoretical basis for the application of edible azo pigments.

Factors associated with infection events after chimeric antigen receptor T-cell therapy for relapsed or refractory multiple myeloma.

OBJECTIVES: Chimeric antigen receptor (CAR) T-cell therapy is a new and effective method in relapsed or refractory (R/R) multiple myeloma (MM). This study was aimed to explore the risk factors of infection events. METHODS: We retrospectively analyzed 68 patients with R/R MM who received CAR T-cell therapy at the Affiliated Hospital of Xuzhou Medical University from June 2017 to June 2021.35 patients received anti-CD19 combined with anti-BCMA CAR T-cell therapy and 33 patients received anti-BCMA CAR T-cell therapy alone. RESULTS: Infection events in patients who received ≥4 prior lines of treatment or with grade 3-5 cytokines released syndrome (CRS) mainly occurred within 4 months after CAR T-cell infusion(CTI). The duration of infection-free survival was positively correlated with progression-free survival of patients with R/R MM (R2 = 0.962, p < 0.001) and the first infection event was closely accompanied by the disease relapse or progression. Treatment lines (p = 0.05), duration of ANC<500 cells/mm3 after CTI (p = 0.036), CRS grade (p = 0.007) and treatment response (p < 0.001) were the independent risk factors associated with infection for a multivariable model. The infection incidence was higher in patients with dual CAR T-cell therapy than with mono CAR T-cell therapy18 months after CTI although no statistic differences were observed within 18 months. CONCLUSIONS: Infections after CTI were closely associated with more lines of prior treatment, longer duration of ANC<500 cells/mm3, higher grade CRS and poor treatment response. Infections tended to occur in the early stage after CTI in patients with more lines of prior treatment and higher grade CRS.

Cooling effect of the pocket park in the built-up block of a city: a case study in Xi'an, China.

Pocket parks, the green infrastructures with small sizes and flexible layouts, are suitable for thermal environment improvement in the urban built-up block with limited green space. To quantify the relationship between pocket parks and the thermal environment in western China, two parks in the built-up block of Xi'an were selected. By field measurement, the cooling effect could be extended 100 m from the park boundary, connecting two parks. Furthermore, the road and greening within the block demonstrate significant influence on the cooling diffusion by regression analysis. Based on ENVI-met simulation, the ratio of the tree and the grass, the layout of the tree and the grass, and the layout of the paving were analyzed at different proportions of greening and paving of the park. Finally, a combination of the daytime physiological equivalent temperature (PET) and nighttime air temperature (AT) was proposed to choose the optimum layouts: the trees concentrated in the center and the pavement with more roads. Results can provide insights for designing pocket parks based on the thermal environment improvement.

The renew plans of urban thermal environment optimization for traditional districts in Xi'an, China.

During the process of the high-speed urbanization in Chinese cities, the social, economic, and political status and the interaction between each factor have been more focused on urban traditional district renewal. However, the effects on urban microclimate and the residential living conditions in traditional districts are not well discussed, which is strongly related to the living comfort and citizens' well-being. In this study, two typical traditional districts in Xi'an are selected. According to the original situation of building functions and the community characteristics, two renewal plans are proposed by adding vegetation in open spaces (V), and adding vegetation combined with building redevelopment (V&B), in order to balance the living convenience and thermal environment. Via ENVI-met simulation, the effects of the district renewal plans on thermal environment including wind speed, air temperature, and mean radiant temperature are evaluated. This study provides method of environmental evaluation for traditional district renewal, which contributes to sustainable urban planning in historical districts, and provides recommendations for related policy development.

Influencing factors of the thermal environment of urban green space.

Several heat records have been broken in recent years and decades. Extreme high temperature not only damages human health, but also increases the risk of wildfires. As a common urban infrastructure, urban green space has been proved to have a cooling effect. In this study, the physical indicators and temperature data of 36 green spaces in Xi'an were collected, and the influence of different physical indicators of green spaces on their thermal environment was explored through correlation analysis. The results suggest that the area of green space should be between 0.6-0.7 square kilometers or the perimeter should range from 4000 to 4500 m in order to obtain the lowest internal temperature. When the area of water body in the green space is between 0.3-0.4 square kilometers or the perimeter is about 5000 m, its internal temperature is the lowest. Indicators of green space in the conclusion can be directly understood and referred by urban planners and policy makers. Results of this study thus have implications for improving urban thermal comfort by controlling the physical indicators of green space.

Cellular Senescence and Periodontitis: Mechanisms and Therapeutics.

Periodontitis is a chronic inflammatory disease which increases in prevalence and severity in the older population. Aging is a leading risk factor for periodontitis, which exacerbates alveolar bone loss and results in tooth loss in the elderly. However, the mechanism by which aging affects periodontitis is not well understood. There is considerable evidence to suggest that targeting cellular senescence could slow down the fundamental aging process, and thus alleviate a series of age-related pathological conditions, likely including alveolar bone loss. Recently, it has been discovered that the senescent cells accumulate in the alveolar bone and promote a senescence-associated secretory phenotype (SASP). Senescent cells interacting with bacteria, together with secreted SASP components altering the local microenvironment and inducing paracrine effects in neighboring cells, exacerbate the chronic inflammation in periodontal tissue and lead to more alveolar bone loss. This review will probe into mechanisms underlying excessive alveolar bone loss in periodontitis with aging and discuss potential therapeutics for the treatment of alveolar bone loss targeting cellular senescence and the SASP. Inspecting the relationship between cellular senescence and periodontitis will lead to new avenues of research in this field and contribute to developing potential translatable clinical interventions to mitigate or even reverse the harmful effects of aging on oral health.

An Improved Two-Step Floating Catchment Area (2SFCA) Method for Measuring Spatial Accessibility to Elderly Care Facilities in Xi'an, China.

With the continuous aging of society, the demand among elderly citizens for care facilities is increasing. The accessibility of elderly care facilities is a significant indicator for evaluating whether the layout of urban elderly care facilities is reasonable, and research on the spatial accessibility of related facilities has become an important academic issue in recent years. In this paper, based on the lack of accurate measurement in calculating the spatial accessibility of existing elderly care facilities, we improve the mathematical model based on the two-step floating catchment area method (2SFCA) and introduce the probability function of the elderly population's choice, taking into account the influence of institutional capacity and service quality. In terms of the catchment radius, the calculation accuracy is improved by using the shortest distance along the route combined with the real road network instead of choosing the Euclidean distance. In addition, specific travel thresholds are set for the travel characteristics of the elderly. An evaluation model of the accessibility of urban elderly care facilities is constructed with the help of ArcGIS software to evaluate and analyze the accessibility of the current layout of urban elderly care facilities in Xi'an, China. The results show that the improved 2SFCA model is more effective in evaluating the spatial accessibility of elderly care facilities and has higher accuracy than the previous calculation model, which provides a methodological basis and academic reference for the specific planning of urban elderly care facilities.

Near-surface wind profile test based on accuracy verification of UAV anemometer lifting height in an urban fringe built-up area.

Multirotor UAVs (unmanned aerial vehicles) have been widely used in urban vertical wind environment testing, whereas less attention has been given to the accuracy of wind speed captured by anemometers as drones fly. This paper aims to identify the ideal location of the anemometer on the UAV to obtain more accurate wind speeds and to assess the variation characteristics of wind speed in different spatial types in urban fringe areas. Accuracy verification of the lifting height of the anemometer in the UAV and wind profile test was carried out at three locations (a tennis court, a residential area, and a green park) on the iHarbour campus of Xi'an Jiaotong University. The following results were obtained: (1) the background wind speed was captured more accurately (R = 0.727, P = 0.001) when the lifting height of the anemometer was 0.00 m (as the height of the anemometer was the same as the rotors) and when the multirotor UAV was hovering in the air. However, this optimal lifting height lost 29.6% of the accuracy for capturing the background wind speed. Interestingly, when the lifting height was 0.75 m, the anemometer captured by the anemometer on the drone showed a significant negative correlation (R = - 0.682, P = 0.005) with the background wind speed. (2) The wind speed at an altitude of 1.5 m in the residential area was significantly lower than that noted at other heights, and the wind speed at 24 m was significantly lower than that at 100 m. (3) In addition, a sudden increase in wind speeds was always observed near the surface of 12 m inside the campus, which may be due to the interaction of hot surface air in this newly built-up area with the cool rural winds around it. The study presents methods and quantitative references for the application of multirotor UAVs in urban vertical wind environment testing and the evaluation of ventilation performance at different heights inside high-rise houses in urban fringe areas.

Multidimensional Gene Regulatory Landscape of Motor Organ Pulvinus in the Model Legume Medicago truncatula.

Nyctinastic leaf movement of Fabaceae is driven by the tiny motor organ pulvinus located at the base of the leaf or leaflet. Despite the increased understanding of the essential role of ELONGATED PETIOLULE1 (ELP1)/PETIOLE LIKE PULVINUS (PLP) orthologs in determining pulvinus identity in legumes, key regulatory components and molecular mechanisms underlying this movement remain largely unclear. Here, we used WT pulvinus and the equivalent tissue in the elp1 mutant to carry out transcriptome and proteome experiments. The omics data indicated that there are multiple cell biological processes altered at the gene expression and protein abundance level during the pulvinus development. In addition, comparative analysis of different leaf tissues provided clues to illuminate the possible common primordium between pulvinus and petiole, as well as the function of ELP1. Furthermore, the auxin pathway, cell wall composition and chloroplast distribution were altered in elp1 mutants, verifying their important roles in pulvinus development. This study provides a comprehensive insight into the motor organ of the model legume Medicago truncatula and further supplies a rich dataset to facilitate the identification of novel players involved in nyctinastic movement.

Retro Baeyer-Villiger reaction: thermal conversion of the [60]fullerene-fused lactones to ketones.

The conversion of the [60]fullerene-fused lactones to ketones with triflic anhydride as an unusual reductant under aerobic conditions has been achieved in excellent yields. The present thermal retro Baeyer-Villiger reaction from lactones to ketones has no precedents. In addition, the unique ring-opened peroxy [60]fullerene derivatives can be obtained by the electrochemical reactions of the synthesized [60]fullerene-fused ketones.