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.

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.

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.

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.

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.

Relationship between patient safety culture and safety performance in nursing: The role of safety behaviour.

AIM: The aim of this work is to test the mediator role of patient safety behaviour between safety culture and safety performance among nurses. METHODS: This cross-sectional study was carried out between September and December 2017 in the nursing units of 10 primary hospitals, two secondary hospitals and two tertiary hospitals in Anhui Province, China. RESULTS: The study participants comprised 79 RNs from primary hospitals, 147 RNs from secondary hospitals and 242 RNs from tertiary hospitals. Most were female (97.6%) and married (73.1%), and their ages ranged from less than 25 years to retirement age. The sample included nurses working in several departments, including medicine (27.1%), surgery (14.3%), emergency (11.5%) and ICU (9%). Structural equation model analysis results showed that espoused values directly affected safety performance, and practised values affected safety performance through safety behaviour. CONCLUSION: Our hypothetical model noted that safety behaviour is a positive mediating factor of practised safety values affecting safety performance, suggesting that Chinese nursing managers should construct a patient safety culture that is guided and driven by appropriate values, which will ultimately be externalized as nurses' daily behaviour.

Downregulation of long non-coding RNA TUG1 suppresses tumor growth by promoting ubiquitination of MET in diffuse large B-cell lymphoma.

Long non-coding RNAs (lncRNAs) can modulate gene expression through different mechanisms, but the fundamental molecular mechanism between lncRNAs and MET protein in diffuse large B-cell lymphoma (DLBCL) was poorly understood. The expression of lncRNA TUG1 and MET in DLBCL tissues and cell lines was determined by quantitative real-time PCR and western blotting. Cell proliferation, invasion and apoptosis were determined by cell counting kit-8 assay, transwell assay and flow cytometer. The animal xenograft model was established by the injection of DLBCL cells carrying si-TUG1. The expression of TUG1 and MET was upregulated in DLBCL tissues and cells. We demonstrated that MET was altered in the TUG1 knockdown DLBCL cells, and confirmed the interaction between TUG1 and MET by RNA pull-down and RNA immunoprecipitation. Furthermore, knockdown of TUG1 reduced MET protein level by promoting ubiquitination, and suppressed tumor growth in vitro and in vivo. Our findings demonstrated that TUG1 exerted its oncogenic function in DLBCL by inhibiting the ubiquitination and the subsequent degradation of MET. Knockdown of TUG1 through MET downregulation suppressed DLBCL cell proliferation and tumor growth.

A parsimonious approach for screening moderate-to-profound hearing loss in a community-dwelling geriatric population based on a decision tree analysis.

BACKGROUND: Hearing loss is one of the most common modifiable factors associated with cognitive and functional decline in geriatric populations. An accurate, easy-to-apply, and inexpensive hearing screening method is needed to detect hearing loss in community-dwelling elderly people, intervene early and reduce the negative consequences and burden of untreated hearing loss on individuals, families and society. However, available hearing screening tools do not adequately meet the need for large-scale geriatric hearing detection due to several barriers, including time, personnel training and equipment costs. This study aimed to propose an efficient method that could potentially satisfy this need. METHODS: In total, 1793 participants (≥60 years) were recruited to undertake a standard audiometric air conduction pure tone test at 4 frequencies (0.5-4 kHz). Audiometric data from one community were used to train the decision tree model and generate a pure tone screening rule to classify people with or without moderate or more serious hearing impairment. Audiometric data from another community were used to validate the tree model. RESULTS: In the decision tree analysis, 2 kHz and 0.5 kHz were found to be the most important frequencies for hearing severity classification. The tree model suggested a simple two-step screening procedure in which a 42 dB HL tone at 2 kHz is presented first, followed by a 47 dB HL tone at 0.5 kHz, depending on the individual's response to the first tone. This approach achieved an accuracy of 91.20% (91.92%), a sensitivity of 95.35% (93.50%) and a specificity of 86.85% (90.56%) in the training dataset (testing dataset). CONCLUSIONS: A simple two-step screening procedure using the two tones (2 kHz and 0.5 kHz) selected by the decision tree analysis can be applied to screen moderate-to-profound hearing loss in a community-based geriatric population in Shanghai. The decision tree analysis is useful in determining the optimal hearing screening criteria for local elderly populations. Implanting the pair of tones into a well-calibrated sound generator may create a simple, practical and time-efficient screening tool with high accuracy that is readily available at healthcare centers of all levels, thereby facilitating the initiation of extensive nationwide hearing screening in older adults.

Highly wearable cuff-less blood pressure and heart rate monitoring with single-arm electrocardiogram and photoplethysmogram signals.

BACKGROUND: Long-term continuous systolic blood pressure (SBP) and heart rate (HR) monitors are of tremendous value to medical (cardiovascular, circulatory and cerebrovascular management), wellness (emotional and stress tracking) and fitness (performance monitoring) applications, but face several major impediments, such as poor wearability, lack of widely accepted robust SBP models and insufficient proofing of the generalization ability of calibrated models. METHODS: This paper proposes a wearable cuff-less electrocardiography (ECG) and photoplethysmogram (PPG)-based SBP and HR monitoring system and many efforts are made focusing on above challenges. Firstly, both ECG/PPG sensors are integrated into a single-arm band to provide a super wearability. A highly convenient but challenging single-lead configuration is proposed for weak single-arm-ECG acquisition, instead of placing the electrodes on the chest, or two wrists. Secondly, to identify heartbeats and estimate HR from the motion artifacts-sensitive weak arm-ECG, a machine learning-enabled framework is applied. Then ECG-PPG heartbeat pairs are determined for pulse transit time (PTT) measurement. Thirdly, a PTT&HR-SBP model is applied for SBP estimation, which is also compared with many PTT-SBP models to demonstrate the necessity to introduce HR information in model establishment. Fourthly, the fitted SBP models are further evaluated on the unseen data to illustrate the generalization ability. A customized hardware prototype was established and a dataset collected from ten volunteers was acquired to evaluate the proof-of-concept system. RESULTS: The semi-customized prototype successfully acquired from the left upper arm the PPG signal, and the weak ECG signal, the amplitude of which is only around 10% of that of the chest-ECG. The HR estimation has a mean absolute error (MAE) and a root mean square error (RMSE) of only 0.21 and 1.20 beats per min, respectively. Through the comparative analysis, the PTT&HR-SBP models significantly outperform the PTT-SBP models. The testing performance is 1.63 ± 4.44, 3.68, 4.71 mmHg in terms of mean error ± standard deviation, MAE and RMSE, respectively, indicating a good generalization ability on the unseen fresh data. CONCLUSIONS: The proposed proof-of-concept system is highly wearable, and its robustness is thoroughly evaluated on different modeling strategies and also the unseen data, which are expected to contribute to long-term pervasive hypertension, heart health and fitness management.

Ferric Perchlorate Promoted Reaction of [60]Fullerene with N-Sulfonyl Aldimines: Synthesis and Functionalization of Fulleroxazolidines.

The rare fulleroxazolidines 2 were successfully synthesized by the facile ferric perchlorate promoted reaction of [60]fullerene with various N-sulfonyl aldimines 1. Further functionalization of fulleroxazolidines by arenes in the presence of boron trifluoride afforded 1,4-bisarylation products 4. A possible reaction mechanism for the formation of the fulleroxazolidines is proposed.

Isothermal nucleic acid amplification strategy by cyclic enzymatic repairing for highly sensitive microRNA detection.

Technologies enabling highly sensitive and selective detection of microRNAs (miRNAs) are critical for miRNA discovery and clinical theranostics. Here we develop a novel isothermal nucleic acid amplification technology based on cyclic enzymatic repairing and strand-displacement polymerase extension for highly sensitive miRNA detection. The enzymatic repairing amplification (ERA) reaction is performed via replicating DNA template using lesion bases by DNA polymerase and cleaving the DNA replicate at the lesions by repairing enzymes, uracil-DNA glycosylase, and endonuclease IV, to prime a next-round replication. By utilizing the miRNA target as the primer, the ERA reaction is capable of producing a large number of reporter sequences from the DNA template, which can then be coupled to a cyclic signal output reaction mediated by endonuclease IV. The ERA reaction can be configured as a single-step, close-tube, and real-time format, which enables highly sensitive and selective detection of miRNA with excellent resistance to contaminants. The developed technology is demonstrated to give a detection limit of 0.1 fM and show superb specificity in discriminating single-base mismatch. The results reveal that the ERA reaction may provide a new paradigm for efficient nucleic acid amplification and may hold the potential for miRNA expression profiling and related theranostic applications.

Highly sensitive and selective strategy for microRNA detection based on WS2 nanosheet mediated fluorescence quenching and duplex-specific nuclease signal amplification.

MicroRNAs (miRNAs) play vital roles in physiologic and pathologic processes and are significant biomarkers for disease diagnostics and therapeutics. However, rapid, low-cost, sensitive, and selective detection of miRNAs remains a challenge because of their short length, sequence homology, and low abundance. Herein, we report for the first time that WS2 nanosheet can exhibit differential affinity toward short oligonucleotide fragment versus ssDNA probe and act as an efficient quencher for adsorbed fluorescent probes. This finding is utilized to develop a new strategy for simple, sensitive, and selective detection of miRNA by combining WS2 nanosheet based fluorescence quenching with duplex-specific nuclease signal amplification (DSNSA). This assay exhibits highly sensitive and selective with a detection limit of 300 fM and even discriminate single-base difference between the miRNA family members. The result indicates that this simple and cost-effective strategy holds great potential application in biomedical research and clinical diagnostics.

Synthesis of [60]Fullerene-Fused Lactones via Carboxylic Acid Group-Directed C-H Bond Activation and Further Retro Baeyer-Villiger Reaction.

An efficient palladium-catalyzed reaction of [60]fullerene with benzoic acids via carboxylic acid group-directed C-H bond activation is achieved. The obtained [60]fullerene-fused lactones can undergo a retro Baeyer-Villiger reaction to provide [60]fullerene-fused ketones via apparent reduction in the presence of triflic acid. A representative ketone product obtained by the reduction reaction can be employed as an overcoating layer for the electron-transporting layer in an n-type perovskite solar cell.

Anti-BCMA/GPRC5D bispecific CAR T cells in patients with relapsed or refractory multiple myeloma: a single-arm, single-centre, phase 1 trial.

BACKGROUND: Some challenges still exist with single-target B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T-cell therapies due to variable or negative BCMA expression, although they have yielded remarkable efficacy in relapsed or refractory multiple myeloma. We developed anti-BCMA/GPRC5D bispecific CARs to mitigate the limitations and potentiate the functions of CAR T cells. METHODS: This single-arm, phase 1 trial was conducted at the Affiliated Hospital of Xuzhou Medical University (Xuzhou, China). The trial enrolled patients aged 18-75 years with relapsed or refractory multiple myeloma and an Eastern Cooperative Oncology Group performance status of 0-3. Anti-BCMA/GPRC5D bispecific CAR T cells were administered at 0·5 × 106, 1·0 × 106, 2·0 × 106, and 4·0 × 106 CAR T cells per kg in the dose-escalation phase, with additional patients included at the dose selected for the dose-expansion phase. The primary endpoint was safety, which included dose-limiting toxicity and maximum tolerated dose. Activity was also evaluated as a secondary endpoint. The maximum tolerated dose was chosen for the dose-expansion phase. Safety and activity analyses were done in all patients who received anti-BCMA/GPRC5D bispecific CAR T cells as defined in the protocol. This trial is registered with ClinicalTrials.gov (NCT05509530) and is complete. FINDINGS: Between Sept 1, 2022, and Nov 3, 2023, 24 patients were enrolled and underwent apheresis. Three patients were excluded after apheresis (two patients discontinued due to rapid disease progression and one patient was withdrawn because of failed manufacture of CAR T cells), so 21 patients were infused with anti-BCMA/GPRC5D bispecific CAR T cells. Median follow-up was 5·8 months (IQR 5·2-6·7). Median age was 62 years (IQR 56-67). Eight (38%) patients were male, and 13 (62%) female. All patients were Chinese. At the 4·0 × 106 CAR T cells per kg dose, two patients had dose-limiting toxicities, of whom one died of subarachnoid haemorrhage (which was not considered to be related to the study treatment). The maximum tolerated dose was identified as 2·0 × 106 CAR T cells per kg. The most common grade 3 or worse adverse events were haematological toxicities in 19 (90%) patients (except lymphopenia). 15 (71%) patients had cytokine release syndrome, of which all cases were grade 1 or 2. One case of grade 1 immune effector cell-associated neurotoxicity syndrome (ICANS) was observed in a patient who received 4·0 × 106 CAR T cells per kg. No ICANS or grade 3 or worse organ toxicities were observed in patients who received 0·5-2·0 × 106 CAR T cells per kg. The overall response rate was 86% (18 of 21 patients), with 13 (62%) patients having a complete response or better, and 17 (81%) patients having measurable residual disease negativity. Of the 12 patients who received 2·0 × 106 CAR T cells per kg (three in the dose-escalation phase and an addition nine in the dose-expansion phase), the overall response rate was 92% (11 of 12 patients) with nine (75%) patients having a complete response or better. INTERPRETATION: Anti-BCMA/GPRC5D bispecific CAR T cells show a good safety profile and encouraging activity in patients with relapsed or refractory multiple myeloma. FUNDING: National Natural Science Foundation of China. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

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.

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.

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.