Outcomes of Second Anti-CD19 CAR T-Cell Therapy (CART2) in Acute B Lymphoblastic Leukemia and the Impact of Allo-HSCT on Efficacy.

For patients exhibiting a suboptimal response to the first chimeric antigen receptor (CAR) T-cell therapy (CART1) or relapse after remission, secondary CAR T-cell therapy (CART2) for the same target may be an option. We retrospectively analyzed patients with acute B-cell lymphoblastic leukemia (B-ALL) receiving CD19 CART1 at our center (n = 84) to report the clinical outcomes of CART2 and to identify the factors that may influence the outcomes. Twenty-six patients received CART2 for suboptimal response or relapse post-CART1. The incidence of cytokine release syndrome (CRS) after CART2 was 65.4% (17/26), with 11 cases classified as grade 1 (42.3%), four cases as grade 2 (15.4%), and two cases as grade 3 (7.7%). Neurotoxicity was observed in one patient (3.8%) after CART2 infusion. Fourteen patients (53.8%) achieved complete remission (CR) after CART2. CART2 exhibited an inferior response rate (CART2: 53.8%, 14/26; CART1: 81.0%, 64/79; P = 0.006) and a lower incidence of severe CRS (CART2: 7.7%, 2/26; CART1: 30.4%, 24/79; P = 0.020) compared with CART1, with a median progression-free survival (PFS) and a median overall survival (OS) of 6.2 months and 11.2 months, respectively. In particular, patients who progressed after consolidative allogeneic hematopoietic stem cell transplantation (allo-HSCT) following CART1 and then received CART2 demonstrated promising outcomes with a response rate of 80.0% (8/10), a median PFS of 7.9 months, and a median OS of 25.1 months. After adjusting for the confounding factors, the response rate (85.7%, 6/7) of CART2 administered to this cohort was better than those who did not bridge to allo-HSCT receiving CART2 (28.6%, 2/7) or non-CART2 treatments (13.3%, 2/15). The median OS after CART2, which was not reached, was significantly better than the median OS after CART2 (3.9 months, P = 0.014) and non-CART2 treatments (6.0 months, P = 0.012) administered in patients who did not undergo consolidative allo-HSCT post-CART1. Our results indicated that, although less effective than CART1, a subset of patients can still benefit from CART2 with mild adverse effects. For patients who relapsed after consolidative allo-HSCT post-CART1, treatment with CART2 is a viable option.

Longitudinal Serum Proteomics Characterization of CD19-CAR-T Cell Therapy for B-Cell Malignancies.

Chimeric antigen receptor (CAR)-modified T cells have demonstrated remarkable efficacy in treating B-cell leukemia. However, treated patients may potentially develop side effects, such as cytokine release syndrome (CRS), the mechanisms of which remain unclear. Here, we collected 43 serum samples from eight patients with B-cell acute lymphoblastic leukemia (B-ALL) before and five time points after CD19-specific CAR-T cell treatment. Using TMTpro 16-plex-based quantitative proteomics, we quantified 1151 proteins and profiled the longitudinal proteomes analysis of each patient. Seven days after therapy, we found the most dysregulated inflammatory proteins. Lipid metabolism proteins, including APOA1, decreased after therapy, reached their minimum after 7 days, and then gradually recovered. Hence, APOA1 has been selected as a potential biomarker of the CRS disease progression. Furthermore, we identified CD163 as a potential biomarker of CRS severity. These two biomarkers were successfully validated using targeted proteomics in an independent cohort. Our study provides new insights into CAR-T cell therapy-induced CRS. The biomarkers we identified may help develop targeted drugs and monitoring strategies.

An Exploration into Human-Computer Interaction: Hand Gesture Recognition Management in a Challenging Environment.

Scientists are developing hand gesture recognition systems to improve authentic, efficient, and effortless human-computer interactions without additional gadgets, particularly for the speech-impaired community, which relies on hand gestures as their only mode of communication. Unfortunately, the speech-impaired community has been underrepresented in the majority of human-computer interaction research, such as natural language processing and other automation fields, which makes it more difficult for them to interact with systems and people through these advanced systems. This system's algorithm is in two phases. The first step is the Region of Interest Segmentation, based on the color space segmentation technique, with a pre-set color range that will remove pixels (hand) of the region of interest from the background (pixels not in the desired area of interest). The system's second phase is inputting the segmented images into a Convolutional Neural Network (CNN) model for image categorization. For image training, we utilized the Python Keras package. The system proved the need for image segmentation in hand gesture recognition. The performance of the optimal model is 58 percent which is about 10 percent higher than the accuracy obtained without image segmentation.

Do patients with metastatic renal cell carcinoma obtain survival benefits from cytoreductive nephrectomy? A population-based study.

PURPOSE: This study aimed to explore the value of cytoreductive nephrectomy (CN) and develop nomograms to predict the prognosis of metastatic renal cell carcinoma (mRCC) patients with receiving radiology therapy or/and chemotherapy (RT/&CT). METHODS: Clinical data of patients with mRCC between 2010 and 2015 were collected from the Surveillance, Epidemiology, and End Results (SEER) database. Prognostic nomograms were constructed to predict the overall survival (OS) and cancer-specific survival (CSS) probability for 1-, 3-, and 5- years in patients with mRCC. A series of validation methods were used to validate the accuracy and reliability of the model, including area under the receiver operating curve (AUC), consistency index (C-index), calibration curve, and decision curve analysis (DCA). RESULTS: 1394 patients were enrolled in this study. All patients were randomly divided into the training cohort (n = 976) and the validation cohort (n = 418). In the training cohort, multivariate Cox regression analysis suggested that pathology grade, histology type, T stage, N stage, surgery, and distant metastasis were independent risk factors for OS and CSS. The AUC and C-index were both over 0.65 in both cohorts, indicating that the nomograms for OS and CSS had satisfactory discriminative power. The calibration curves revealed that the predictive nomograms had a good consistency between the observed and the predicted survival. CONCLUSION: This study provided evidence that mRCC patients underwent RT/&CT could gain survival benefits from CN. The prognostic nomogram constructed in our study is reliable and practical, may help guide clinical strategies in the treatment of mRCC.

Self-Supervised Video Representation Learning by Video Incoherence Detection.

This article introduces a novel self-supervised method that leverages incoherence detection for video representation learning. It stems from the observation that the visual system of human beings can easily identify video incoherence based on their comprehensive understanding of videos. Specifically, we construct the incoherent clip by multiple subclips hierarchically sampled from the same raw video with various lengths of incoherence. The network is trained to learn the high-level representation by predicting the location and length of incoherence given the incoherent clip as input. Additionally, we introduce intravideo contrastive learning to maximize the mutual information between incoherent clips from the same raw video. We evaluate our proposed method through extensive experiments on action recognition and video retrieval using various backbone networks. Experiments show that our proposed method achieves remarkable performance across different backbone networks and different datasets compared to previous coherence-based methods.

Mechanism of miR-338-3p in sepsis-induced acute lung injury via indirectly modulating ATF4.

Sepsis is recognized as an inflammation-related syndrome in response to invading pathogens. Many patients suffer from sepsis including transplant recipients. Lipopolysaccharide (LPS) is known to trigger sepsis-related organ dysfunction. This study expounded on the possible effect of microRNA (miR)-338-3p in sepsis-induced acute lung injury (ALI). Firstly, human bronchial epithelial cell line 16HBE received LPS treatment to establish the cell models of sepsis-induced ALI. The expression patterns of miR-338-3p, long non-coding RNA OPA-interacting protein 5 antisense transcript 1 (lncRNA OIP5-AS1), and activating transcription factor 4 (ATF4) in 16HBE cells were examined. Afterwards, 16HBE cell viability, the apoptosis rate, and the levels of inflammation and lactate dehydrogenase (LDH) were determined to assess the degree of cell injury. We disclosed that LPS treatment triggered 16HBE cell injury, downregulated miR-338-3p, and upregulated OIP5-AS1 and ATF4. miR-338-3p overexpression repressed LPS-induced 16HBE cell injury. miR-338-3p diminished OIP5-AS1 stability via binding to OIP5-AS1 and downregulated OIP5-AS1 expression and OIP5-AS1 can enhance ATF4 mRNA stability and upregulate ATF4 mRNA level. The rescue experiments showed that ATF4 overexpression aggravated LPS-induced 16HBE cell injury. Overall, miR-338-3p overexpression decreased OIP5-AS1 expression and stability and further downregulated ATF4 mRNA level, thereby mitigating LPS-induced 16HBE cell injury.

Motivational Influences Affecting Middle-Aged and Elderly Users' Participation Intention in Health-Related Social Media.

Social media provide users with multi-directional dialogue for creating and sharing health information that can effectively promote the self-management of health. In regard to the 'greying' trend in social media, most researchers have studied the health-related social media (HRSM) acceptance status and use behavior of middle-aged and elderly people, and have explored the role of HRSM in this group. However, the continuous participation of users is the key to the successful operation of HRSM, and is an essential prerequisite for the subsequent HRSM behavior habits of middle-aged and elderly people. Therefore, we aimed to explore what motivations drive the first use of HRSM among middle-aged and older adults, and the impact of their perception of HRSM, after personal use, on their intention to use it continually. In the study, we used the partial least squares structural equation model (PLS-SEM) to analyze data collected from online questionnaires. The results showed that a self-protection motivation and a social motivation promoted the initial participation of middle-aged and elderly individuals. In addition, these people experienced deeper levels of perceived usefulness and perceived entertainment after their initial participation. The results also revealed that these two perceptions could positively influence middle-aged and elderly individuals' intention to continue with their participation. Our findings should help service platforms to better understand the needs of middle-aged and elderly users. This would help researchers and practitioners to gain a more complete understanding of the motivation of middle-aged and elderly people for participating in HRSM, and the related impacts this may have.

Disruption of sncRNA Improves the Protective Efficacy of Outer Membrane Vesicles against Helicobacter pylori Infection in a Mouse Model.

The outer membrane vesicles (OMVs) secreted by Helicobacter pylori contain various bacterial components, such as proteins, phospholipids, toxins, and nucleic acids, including small noncoding RNA (sncRNA), which have regulatory functions in cell envelope structure, metabolism, bacterial communication, biofilm formation, and virulence. We previously showed that knocking out sncRNAs sR-989262 and sR-2509025 at the cellular level increased interleukin 8 (IL-8) levels in mice exposed to OMVs. In this study, we show that immunization with ΔsR-989262 and ΔsR-2509025 OMVs intragastrically significantly increased immunoglobulin G (IgG) and secreted IgA levels in mice compared to wild-type OMVs and without weight changes, which indicated that sncRNA-deficient OMVs are relatively safe to immunize mice. The detection of IgG subtypes IgG1 and IgG2c showed that the sncRNA-deficient OMVs primarily stimulate the T helper 2 (Th2)-mediated immune response. Moreover, levels of the cytokines IL-4, IL-13, gamma interferon (IFN-γ), IL-12 (p40), IL-8, and IL-17 indicate that ΔsR-989262 and ΔsR-2509025 OMVs trigger the Th2-type immune response but primarily trigger a Th1-mediated and Th17-mediated immune response. These findings show that OMV-encapsulated sncRNA plays an important role in regulating the immune response in hosts infected by H. pylori at the animal level. Moreover, they show that knocking out of sR-989262 and sR-2509025 improves the immunogenicity and protective efficacy of OMVs, and this may be beneficial to the design of OMV-based H. pylori vaccines.

Cytokine release syndrome and relevant factors of CD19 targeted chimeric antigen receptor T cell therapy in relapsed/refractory B cell hematological malignancies.

OBJECTIVES AND METHODS: We reviewed the outcomes of 77 episodes of CD19 CAR-T therapy in 67 patients with B cell hematological malignancies from October 2016 to January 2020. Factors related to the grade of cytokine release syndrome (CRS) were explored by multivariate analysis, nonparametric test was conducted to explore the correlation between CRS and response. Kaplan-Meier curves were used to indicate survival profiles, and the correlation between CRS and survival was determined by the log-rank test. RESULTS: The rate of complete remission (CR) was 74.0% (57/77). CRS of any grade occurred in 68 of 77 episodes (grade 1: 32.5%, grade 2: 24.7%, grade 3: 22.1%, grade 4: 6.5%, grade 5: 2.6%). Patients with a history of transplantation had less severe CRS, and dose escalation-based infusion reduced the severity of CRS. Severe CRS was related to a higher CR rate but had no significant impact on event-free survival (EFS), relapse-free survival (RFS), or overall survival (OS). CONCLUSION: As a common adverse reaction of CAR-T therapy, the severity of CRS can be alleviated by dose escalation infusion, a history of transplantation was correlated with less severe CRS. Severe CRS was related to better response but was unrelated to long-term survival.

Heterostructured ZnCo2O4-CoOOH nanosheets on Ni foam for a high performance bifunctional alkaline water splitting catalyst.

It is of utmost importance to explore bifunctional electrocatalysts for water splitting. Herein, unique ZnCo2O4-CoOOH heterostructured ultrathin nanosheets on Ni foam are reported that combines a two-step hydrothermal method. This catalyst exhibits excellent catalytic performances to achieve a current density of 10 mA cm-2 with an ultralow overpotential of 115 mV for HER, attaining an overpotential of 238 mV at 20 mA cm-2 for OER. Remarkably, ZnCo2O4-CoOOH/Ni shows a voltage of 1.494 V to drive a current density of 10 mA cm-2. Such performances are due to the inter-penetrative pores present in the ultrathin nanosheets that provide large surface areas and expose massive active sites to enhance activities. In addition, the unique nanosheet structure and the 3D Ni foam substrate possess large specific surface areas, which can facilitate mass diffusion. This excellent performance is ascribed to the ZnCo2O4-CoOOH heterostructure that manipulates strong synergy to improve the electrochemical activity. This study offers new insight on an innovative approach for the exploitation of effective bifunctional electrocatalysts with a heterostructure.

Impact of Consolidative Unrelated Cord Blood Transplantation on Clinical Outcomes of Patients With Relapsed/Refractory Acute B Lymphoblastic Leukemia Entering Remission Following CD19 Chimeric Antigen Receptor T Cells.

Background: While chimeric antigen receptor (CAR)-T cell therapy is becoming widely used in hematological malignancies with remarkable remission rate, their high recurrence remains an obstacle to overcome. The role of consolidative transplantation following CAR-T cell-mediated remission remains controversial. We conducted a retrospective study to explore whether bridging to unrelated cord blood transplantation (UCBT) could improve the prognosis of patients entering remission after CAR-T therapy with different characteristics through subgroup analyses. Methods: We reviewed 53 patients with relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL) successfully infused with CD19 CAR-T cells and achieved complete remission (CR). In this study, 25 patients received consolidative UCBT (UCBT group) and 28 patients did not accept any intervention until relapse (non-UCBT group). Subgroup analysis on prognosis was then performed according to gender, age, number of previous relapses, tumor burden, presence of poor prognostic markers, and structure of CAR. Results: Compared with the non-UCBT group, patients who underwent consolidative UCBT had better median event-free survival (EFS; 12.3 months vs. 6.2 months; P = 0.035) and relapse-free survival (RFS; 22.3 months vs. 7.2 months; P = 0.046), while no significant difference was found in overall survival (OS; 30.8 months vs. 15.3 months; P = 0.118). Subsequent multivariate analysis revealed that bridging to UCBT was a protective factor for RFS (P = 0.048) but had no significant effect on EFS (P = 0.205) or OS (P = 0.541). In the subgroup analysis, UCBT has an added benefit in patients with specific characteristics. Patients who experienced ≥2 relapses or with sustained non-remission (NR) showed better RFS (P = 0.025) after UCBT. Better EFS was seen in patients with poor prognostic markers (P = 0.027). In the subgroup with pre-infusion minimal residual disease (MRD) ≥5% or with extramedullary disease (EMD), UCBT significantly prolonged EFS (P = 0.009), RFS (P = 0.017), and OS (P = 0.026). Patients with occurrence of acute graft-versus-host disease (aGVHD) appeared to have a longer duration of remission (P = 0.007). Conclusion: Consolidative UCBT can, to some extent, improve clinical outcomes of patients with R/R B-ALL entering remission following CD19 CAR-T therapy, especially in patients with more recurrences before treatment, patients with poor prognostic markers, and patients with a higher tumor burden. The occurrence of aGVHD after UCBT was associated with better RFS.

Neural Effects of Cognitive Behavioral Therapy in Psychiatric Disorders: A Systematic Review and Activation Likelihood Estimation Meta-Analysis.

Background: Cognitive behavioral therapy (CBT) is a first-line psychotherapeutic treatment that has been recommended for psychiatric disorders. Prior neuroimaging studies have provided preliminary evidence suggesting that CBT can have an impact on the activity of brain regions and functional integration between regions. However, the results are far from conclusive. The present article aimed to detect characteristic changes in brain activation following CBT across psychiatric disorders. Method: Web of Science, Cochrane Library, Scopus, and PubMed databases were searched to identify whole-brain functional neuroimaging studies of CBT through 4 August 2021. To be included in the meta-analysis, studies were required to examine functional activation changes between pre-and post-CBT. The included studies were then divided into subgroups according to different task paradigms. Then, an activation likelihood estimation algorithm (ALE) was performed in the different meta-analyses to identify whether brain regions showed consistent effects. Finally, brain regions identified from the meta-analysis were categorized into eight functional networks according to the spatial correlation values between independent components and the template. Results: In total, 13 studies met inclusion criteria. Three different meta-analyses were performed separately for total tasks, emotion tasks, and cognition tasks. In the total task ALE meta-analysis, the left precuneus was found to have decreased activation. For the cognition task ALE meta-analysis, left anterior cingulate (ACC) and left middle frontal gyrus (MFG) were found to have decreased activation following CBT. However, the emotion task ALE meta-analysis did not find any specific brain regions showing consistent effects. A review of included studies revealed default mode network (DMN), executive control network (ECN), and salience network (SN) were the most relevant among the eight functional networks. Conclusion: The results revealed that the altered activation in the prefrontal cortex and precuneus were key regions related to the effects of CBT. Therefore, CBT may modulate the neural circuitry of emotion regulation. This finding provides recommendations for the rapidly developing literature.

Pima Indians diabetes mellitus classification based on machine learning (ML) algorithms.

This paper proposes an e-diagnosis system based on machine learning (ML) algorithms to be implemented on the Internet of Medical Things (IoMT) environment, particularly for diagnosing diabetes mellitus (type 2 diabetes). However, the ML applications tend to be mistrusted because of their inability to show the internal decision-making process, resulting in slow uptake by end-users within certain healthcare sectors. This research delineates the use of three interpretable supervised ML models: Naïve Bayes classifier, random forest classifier, and J48 decision tree models to be trained and tested using the Pima Indians diabetes dataset in R programming language. The performance of each algorithm is analyzed to determine the one with the best accuracy, precision, sensitivity, and specificity. An assessment of the decision process is also made to improve the model. It can be concluded that a Naïve Bayes model works well with a more fine-tuned selection of features for binary classification, while random forest works better with more features.

Metal-organic framework derived carbon-encapsulated hollow CuO/Cu2O heterostructure heterohedron as an efficient electrocatalyst for hydrogen evolution reaction.

It is of pivotal significance to probe highly efficient, cost-effective and low-cost catalysts for the hydrogen evolution reaction. Herein, a closely packed carbon-encapsulated CuO/Cu2O heterohedron with a heterojunction structure is reported that combines chemical etching and thermal oxidation processes. CuO/Cu2O@C-10 has remarkable catalytic activity for HER with an overpotential of 121 mV at a current density of 10 mA cm-2 and a Tafel slope of 81.58 mV dec-1, along with excellent stability in alkaline media under optimal conditions. Benefiting from CuO/Cu2O nanoparticles embedded in a carbon matrix, it forms a porous heterohedron structure by a close packing mode, owing to the unique CuO/Cu2O heterostructure with an ultrathin coated carbon layer and an interconnected conductive carbon network structure. These characteristics make a great contribution to the massive number of active interfacial sites, alleviating the aggregation of active substances, enhancing ion diffusion and the conductivity of the materials. This facile strategy sheds new light on a rational synthesis for a highly efficient hydrogen evolution catalyst with a heterostructure.

Adaptive Resilient Secondary Control for Microgrids With Communication Faults.

In this article, we consider the resilience problem in the presence of communication faults encountered in distributed secondary voltage and frequency control of an islanded alternating current microgrid. Such faults include the partial failure of communication links and some classes of data manipulation attacks. This practical and important yet challenging issue has been taken into limited consideration by existing approaches, which commonly assume that the measurement or communication between the distributed generations (DGs) is ideal or satisfies some restrictive assumptions. To achieve communication resilience, a novel adaptive observer is first proposed for each individual DG to estimate the desired reference voltage and frequency under unknown communication faults. Then, to guarantee the stability of the closed-loop system, voltage and frequency restoration, and accurate power sharing regardless of unknown communication faults, sufficient conditions are derived. Some simulation results are presented to verify the effectiveness of the proposed secondary control approach.

Big Data Applications in Guangzhou Restaurants Analysis.

With the development of modern information and communication technologies, such as the internet of things and big data analytics, businesses and users have become more adaptable to rapid changes. Both consumers and merchants have obtained great convenience. Meanwhile, a huge amount of data is generated. However, many businesses lack the ability to process these data, which contain critical business values. Therefore, this article uses data from the Dianping website to show how to use big data analytics techniques to exploit the valuable information from these raw data. First, descriptive analysis is conducted by using kernel density estimation. Then, multilinear regression analysis, Naive Bayes, and J48 are used to predict the level of restaurants. We found that flavor, environment, and service score are essential factors to the restaurant level. Moreover, J48 performs best among the three models with an accuracy of 88.89%.

Chimeric antigen receptor T cells self-neutralizing IL6 storm in patients with hematologic malignancy.

IL6 is one of the most elevated cytokines during chimeric antigen receptor (CAR) T cell cytokine release syndrome (CRS), and IL6R blockade by Tocilizumab has successfully relieved the most life-threatening aspects of CRS in patients. In addition, latest studies demonstrated the essential role of IL1 in driving CART induced neurotoxicity in mouse models. Here we present a clinical investigation (ChiCTR2000032124; ChiCTR2000031868) of anti-CD19 and anti-BCMA CART (41BBζ) secreting an anti-IL6 scFv and IL1 receptor antagonist (IL1RA) in treating patients with hematologic malignancy. Our results revealed that IL6 and IL1B were maintained at low levels without significant elevation during CRS, rendering Tocilizumab dispensable. Moreover, treated patients did not show neurotoxicity during CRS and exhibited mild to moderate CRS. Notably, we observed high rate of complete response (CR) and significant CART expansion during treatment. In sum, we conclude that CART-secreting anti-IL6 scFv and IL1RA could self-neutralize IL6 storm and maintain low levels of IL1B during CART therapy to minimize IL6- and IL1-associated cytokine toxicity and neurotoxicity without impairing therapeutic efficacy.

Characterization and Evaluation of 3D-Printed Connectors for Microfluidics.

3D printing is regarded as a useful tool for the fabrication of microfluidic connectors to overcome the challenges of time consumption, clogging, poor alignment and bulky fixtures existing for current interconnections. 3D-printed connectors without any additional components can be directly printed to substrate with an orifice by UV-assisted coaxial printing. This paper further characterized and evaluated 3D-printed connectors fabricated by the proposed method. A process window with an operable combination of flow rates was identified. The outer flow rate could control the inner channel dimensions of 3D-printed connectors, which were expected to achieve less geometric mismatch of flow paths in microfluidic interfaces. The achieved smallest inner channel diameter was around 120 µm. Furthermore, the withstood pressure of 3D-printed connectors was evaluated to exceed 450 kPa, which could enable microfluidic chips to work at normal pressure.