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Background: Airway remodeling, which contributes to the clinical course of childhood asthma, occurs due to airway inflammation and is featured by anomalous biological behaviors of airway smooth muscle cells (ASMCs). microRNA (miRNA) plays an essential role in the etiopathogenesis of asthma. Objective: This research was aimed to characterize miR-506 in asthma and uncover potential regulatory machinery. Material and methods: The asthmatic cell model was established by treating ASMCs with transforming growth factor-beta1 (TGF-β1) and assessed by the levels of interleukin (IL)-1β and interferon gamma (IFN-γ). Using real-time quantitative polymerase chain reaction, mRNA expression of miR-506 and polypyrimidine tract-binding protein 1 (PTBP1) was measured. Cell counting kit-8 and Transwell migration tests were used for estimating the capacity of ASMCs to proliferate and migrate. Luciferase reporter assay was used to corroborate whether miR-506 was directly bound to PTBP1. Expression of PTBP1, collagen I and III, and essential proteins of the wingless-related integration (Wnt)/β-catenin pathway (β-catenin, c-MYC and cyclin D1) was accomplished by Western blot analysis. The involvement of Wnt/β-catenin signaling in asthma was confirmed by Wnt signaling pathway inhibitor (IWR-1). Results: miR-506 was poorly expressed in asthmatic tissues and cell model. Functionally, overexpression of miR-506 reduced aberrant proliferation, migration, inflammation and collagen deposition of ASMCs triggered by TGF-β1. Mechanically, miR-506 directly targeted the 3’ untranslated region (3-UTR) of PTBP1 and had a negative regulation on PTBP1 expression. Moreover, overexpression of miR-506 suppressed the induction of Wnt/β-catenin pathway. The administration of IWR-1 further validated negative correlation between miR-506 and the Wnt/β-catenin pathway in asthma. Conclusion: Our data indicated that targeting miR-506/PTBP1/Wnt/β-catenin axis might point in a helpful direction for treating asthma in children.

Few prospective studies have examined posttransplant chimeric antigen receptor (CAR) T cell infusion as candidates for front-line consolidation therapy for high-risk multiple myeloma (MM) patients. This single-arm exploratory clinical trial is the first to evaluate the safety and efficacy of sequential anti-CD19 and anti-BCMA CAR-T cell infusion, followed by lenalidomide maintenance after autologous stem cell transplantation (ASCT), in 10 high-risk newly diagnosed multiple myeloma (NDMM) patients. The treatment was generally well tolerated, with hematologic toxicities being the most common grade 3 or higher adverse events. All patients had cytokine release syndrome (CRS), which was grade 1 in 5 patients (50%) and grade 2 in 5 patients (50%). No neurotoxicity was observed after CAR-T cell infusion. The overall response rate was 100%, with the best response being 90% for a stringent complete response (sCR), and 10% for a complete response (CR). At a median follow-up of 42 (36-49) months, seven (70%) of 10 patients showed sustained minimal residual disease (MRD) negativity for more than 2 years. The median progression-free survival (PFS) and overall survival (OS) were not reached. Although the sample size was small and there was a lack of control in this single-arm study, the clinical benefits observed warrant ongoing randomized controlled trials.

To determine Calculation method of sprinklerand micro-sprinklers, computational models for sprinkler range model is constructed, based on hydraulic parameters of nozzle diameter, working pressure, Installation Heights, spray elevation angle, discharge coefficient, wind direction and speed, water flow regime, and water droplet motion in air, etc., as well by Newton's second law of motion, aerodynamics, and fluid mechanics principles, and by experimental verification for common sprinkler range, nozzle diameter, working pressure, spray elevation angle, Installation Heights, discharge coefficient, and wind direction and speed. The results indicate that sprinkler range with nozzle diameter, working pressure, Installation Heights, spray elevation angle, discharge coefficient, wind direction and speed, water flow regime, and droplet motion in air was in highly significant correlation, the sprinkler range Progressive decreases around the sprinkler along the sprinkler range direction, as well increases by 5.2342%~10.6278% in the downwind direction and decreases by 4.6897%~9.8623% in the headwind direction compared with no wind. The wind speed increases, then the range decreases, and the wind direction shifts, then the range shifts, so the wind direction wind speed changes then the range changes. The coefficients of determination, the consistency Index, the root mean square error, absolute error, relative error between calculated Values and Measured Values of computational models are 0.9146, 0.9205, 8.7748%, 10.4980%, 8.2524% and 8.1421%, respectively. The smaller coefficients of determination and the consistency Index of calculated Values and Measured Values of computational model under windy conditions comparing with no wind, as well the larger root error, deviation, absolute error and relative error. The calculation model in this paper has a clear principle, comprehensive influence factors, complete physical meaning, high calculation accuracy, small error, and wide applicability. This calculation model can effectively reflect the nozzle range change law. This study provides theoretical basis for determining the sprinkler hydraulic performance and provides technology support for Planning and Design of sprinkler irrigation system.

Introduction Lumbar muscle strain is a chronic injury to soft tissues such as the lumbar muscles, ligaments, and fascia. Functional exercise has specific applications in treating lumbar muscle injuries caused by sports. However, analyses on the treatment results in the psoas muscle are inconclusive. Objective Analyze the clinical efficacy of functional exercise in treating psoas muscle dysfunction. Methods 10 athletes diagnosed with lumbar muscle strain received continuous training with a functional exercise protocol for two weeks, five times a week. Clinical efficacy was assessed by visual analog scale for pain score and Prokin254 for proprioception ability indices before and after treatment. The article adopts a mathematical statistics analysis method to analyze the therapeutic effect of motor function exercise with SPSS 13.0. Results Patients reported a reduction of pain in the muscles under exertion after functional exercise. The results were significantly different (P

NOVA1 (neuro-oncological ventral antigen 1) is a neuron specific RNA binding protein, belonging to the Nova family, which plays an important role in various diseases. However, the role of NOVA1 in childhood asthma remains unclear. This study was aimed to investigate the role of NOVA1 in TGF-β1-induced ASMCs proliferation and migration as well as the potential mechanisms. In our study, the NOVA1 expression was significantly increased in asthmatic tissues and TGF-β1-induced ASMCs. Inhibition of NOVA1 significantly inhibited TGF-β1-induced ASMCs cell proliferation and migration, and alleviates TGF-β1-induced inflammation. NOVA1 positively regulated the PTBP1 expression and si-NOVA1 inhibited the activation of PTEN/AKT signal pathway. Importantly, the overexpression of PTBP1 partially reversed the effect of NOVA1 on cell viability, migration, inflammation and the activation of PTEN/AKT signal pathway. Generally, our study demonstrated that si-NOVA1 inhibited TGF-β1-induced inflammation and migration in ASMCs through PTBP1/PTEN/AKT pathway. Therefore, inhibition of NOVA1 may be useful for the prevention or treatment of asthma airway remodeling.

Background: Although nonalcoholic fatty liver disease (NAFLD) is related to obesity, it may also affect lean individuals. Recent data suggest that lean NAFLD patients can develop the whole spectrum of NASH. However, the NAFLD predictive model for lean populations remains lacking. Methods: A total of 5037 lean individuals were included in this study, and the data were separated for training and validation. The logistic regression method was used, and a nomogram, a type of prediction model, was constructed according to the logistic regression analysis and the significant clinical factors. The performance of this model was evaluated based on its discrimination, calibration, and clinical utility. Results: The individuals were divided into the training (n = 4068) or validation (n = 969) cohorts at a ratio of 8 to 2. The overall prevalence of NAFLD in the lean cohort was 6.43%. The nomogram was constructed based on seven predictors: alanine aminotransferase, total cholesterol, triglycerides, low-density lipoprotein cholesterol, creatinine, uric acid, and hemoglobin A1C. The model based on these factors showed good predictive accuracy in the training set and in the internal validation set, with areas under the curve (AUCs) of 0.870 and 0.887, respectively. The calibration curves and decision curve analysis (DCA) displayed good clinical utility. Conclusion: the nomogram model provides a simple and reliable ability to predict the risk of NAFLD in lean subjects. The model can predict lean NAFLD and can help physicians screen and identify lean subjects at a high risk of NAFLD.

Ecosystem vulnerability in the Yellow River Basin (YRB) is a prominent concern. An in-depth exploration of net primary productivity (NPP) serves as an important aspect of assessing and protecting ecosystem health. We explored spatiotemporal changes and influencing factors of NPP in the YRB from 2000–2015, using a range of spatial analysis techniques, and cutting-edge computing-intensive variable importance decomposition methods. We found that NPP showed a fluctuating growth trend over time, ranging from 181.0–259.1 gC∙m ∙a , as well as a clear negative south-north spatial gradient. Significant spatial clustering patterns were observed, with Low-Low and High-High clusters being the dominant area classifications at grid cell, county, and city scales in the study area. We also found that NPP was statistically significantly affected by both natural factors (including climate and topography), and human activities, whilst meteorological factors were the most important factor and explained, on average, roughly 66% of the variability in NPP. Although the impact of human activities on NPP was relatively low when compared to natural factors, the former tended to increase with time and accounted for roughly 30% of the total variability explained by the model in 2015. Overall, this study provides an improved technical framework for undertaking a comprehensive analysis of the spatiotemporal pattern of NPP and its influencing factors at multiple-spatial scales.

The low rate of durable response against relapsed and/or refractory multiple myeloma (RRMM) in recent studies indicates that chimeric antigen receptor T‐cell (CART) treatment is yet to be optimized. This study aims to investigate the safety and efficacy of sequential infusion of CD19‐CART and B‐cell maturation antigen (BCMA)‐CARTs for RRMM with a similar 3 + 3 dose escalation combined with a toxicity sentinel design. We enrolled 10 patients, among whom 7 received autologous infusion and 3 received allogeneic infusion. The median follow‐up time was 20 months. The most common grade 3/4 treatment‐emergent toxicities were hematological toxicities. Cytokine‐release syndrome (CRS) adverse reactions were grade 1/2 in 9 out of 10 subjects. No dose‐limited toxicity (DLT) was observed for BCMA‐CAR‐positive T cells ≤5 × 107/kg), while two patients with dose‐levels of 5–6.5 × 107/kg experienced DLTs. The overall response rate was 90% (five partial responses and four stringent complete responses). Three out of four patients with stringent complete responses to autologous CART had progression‐free survival for over 2 years. The three patients with allogeneic CART experienced disease progression within 2 months. These results evidence the sequential infusion's preliminarily tolerability and efficacy in RRMM, and present a simple and safe design applicable for the establishment of multiple CART therapy., We conducted a pilot study to assess the feasibility of the sequential infusion of CD19 and B‐cell maturation antigen (BCMA)‐specific chimeric antigen receptor T‐cell (CART) for relapsed and/or refractory multiple myeloma treatment with a similar 3 + 3 dose escalation design. Translational Significance: The favorable and persistent responses against RRMM were observed in those patients with a combined infusion of autologous CD19‐CART and BCMA‐CART. The emergence of intolerant adverse event (neurotoxicity and sever CRS) was associated with increased dose level of BCMA‐CARTs infusion.

The preparation of cobalt–chromium alloy materials by different processes was studied and used to repair the full crown of experimental dogs. First, the casting method combined with 3D printing to obtain a cobalt–chromium alloy test piece, and the mechanical and microscopic properties of the test piece were analyzed during the preparation process; And then, selective laser melting (SLM) was used to perform single-channel, single-layer, and multi-layer scanning on the specimens obtained based on this technology during the preparation process. Two kinds of samples were selected from the cobalt–chromium test pieces obtained by the casting method, which were CS01 and CS02. And then selected one kind of sample from the cobalt–chromium test piece obtained by the SLM method, which was SLM01. Firstly, the roughness and contact angle of the planting material were compared, and the saliva-streptococcus mutant cell culture solution was configured to compare the amount of cell adhesion on the surface of different planting materials. Finally, the planting materials were used to repair the dog's full crown and establish animal models. The expressions of Bcl-2, Bax, Ki67 and p53 genes in gingival cells before and after canine crown wearing were compared in gingival tissues. The test results show that the mechanical properties and microstructure of the cobalt–chromium alloy material obtained based on the casting method meet the requirements. Based on the cobalt–chromium test piece obtained by the SLM method, the process parameters were optimized so that the corresponding density of the test piece reached 98.3%; Comparing roughness and surface contact angle, there was no statistical difference between different planting materials (P > 0.05 ). At the same time, the number of Streptococcus mutant adhered to the surface of different specimens was not statistically significant (P > 0.05 ); In the expression of gingival tissue, the implant material was obtained based on the SLM01 test piece, which promoted the decrease of Ki67 gene expression (P < 0.05 ), and also promoted the proliferation of other gingival cell genes (P < 0.05 ).

YAP1 was previously reported to regulate the development of multiple tumors, angiogenesis included. Angiogenesis was a specific process of remodeling in asthma. In a recent study, YAP1 was correlated with the progression of asthma. However, the role of YAP1 in airway smooth muscle cell and the asthmatic airway angiogenesis was unclear. In the present study, we used cytokine-stimulated airway smooth muscle cells as asthma cell model in vitro. The results showed a significant up-regulation of YAP1 in asthmatic airway smooth muscle tissue and cytokine-stimulated asthmatic cell model by Western blot. The experimental results of YAP1 loss-of-function combined with STAT3 inhibitor (WP1066) showed that YAP1 knockdown inhibited the expression of VEGF by deactivating STAT3 in cytokine-stimulated ASM cells, which hindered the pro-angiogenesis ability of ASM cells. Besides, by combining prediction and binding site mutation along with luciferase reporter gene experiments, we confirmed direct binding between miR-375 and YAP1. Based on that, the decreased expression level of miR-375 was found to be correlated with the pathogenesis of asthma. Finally, miR-375 was verified to participate in the YAP1-regulated pro-angiogenesis ability of ASM cells. To sum up, we provided the evidence that YAP1 directly binds to miR-375 and takes part in the regulation of the pro-angiogenic ability of ASM cells by activating STAT3 and VEGF signaling.

Stable nitrogen isotope (δ

Although the testis is not uncommonly involved during the course of disease in both nasal and non-nasal extranodal NK/T-cell lymphoma (ENKTCL), only a few cases presenting initially with a testicular mass have been previously reported. These have been documented as case reports, rather than as study series. Because of its rarity, the clinicopathologic features and the prognosis of de novo testicular ENKTCL have not been well characterized. Clinicopathologic features of 21 cases of de novo testicular ENKTCL from 3 institutions in China were retrospectively analyzed with review of an additional 18 cases from the literature. De novo testicular ENKTCL accounted for 0.72% (21/2906) of all ENKTCL during the study period. The median age of patients with de novo testicular ENKTCL was 45 years (range, 21 to 79 y). Most (90.9%) cases occurred in Asians. All patients initially presented with testicular swelling and most (91.9%) had unilateral testicular masses. The majority (73.0%) of patients presented at Ann Arbor stage I/II. Expression of CD56 was found in 92.1% (35/38) of the available cases. Interestingly, aberrant expression of CD20 was found in the tumor cells in 10.3% (4/39) of cases. The majority of patients with follow-up data (24/30, 80%) had extratesticular involvement during the follow-up period (median follow-up, 6 months; range, 0.5 to 87 mo). Preferential sites of extratesticular involvement included lymph nodes, skin, contralateral testis, bone marrow, spleen, adrenal gland, and central nervous system. Of the 30 patients with survival data, 70% (22/30) of patients died of the disease. The 2-year overall survival of patients with de novo testicular ENKTCL was 23%, and the median survival was 9.5 months. Patients that presented with B symptoms showed a trend toward inferior overall survival (P=0.095). No statistical significance was found between patients with stage I/II and stage III/IV (P=0.783). De novo testicular ENKTCL tends to disseminate early, shows extremely poor outcome, and should be recognized as a highly aggressive form of ENKTCL. A portion of cases show aberrant expression of CD20, and accurate diagnosis as well as timely and optimal treatment are very important.

The past decade saw an increasing development and improvement of green supply chain, but the environmental performances cannot be achieved by single enterprises. Therefore, it is necessary to find out the influencing factors that hinder the cooperation of green supply chain, so as to make full use of these influencing factors to improve environmental performance. In consultation with supply chain management practitioners and academics, this paper establishes a set of 19 influencing factors for green supply chain cooperation among Chinese manufacturers The corporate social responsibility as internal effect and external stakeholder concern as external effect is considered in this study and the interpreted structural model (ISM) method is used to analyze the interaction among these influencing factors and its impact on green supply chain cooperation. This study aims to identify the most significant impacts on environmental issues with supply chain partners and to understand how these impacts can help improve the environmental performance throughout the supply chain.

China’s waste plastic ban has sparked a discussion about how the global plastic waste trade (GPWT) will develop in the future. To answer this question, this article uses the link forecasting and QAP method to predict and analyze the possible development trend of the GPWT in the future. The research results show that GPWT has certain stability and sustainability; although plastic waste trade has narrowed under the ban, it still has the potential trend of reconnecting the same type of links. Specifically, from a regional perspective, the future trade of new plastic waste trade will be dominated by cross-regional trade. Plastic waste may continue to flow to countries in the Asian–Pacific, Middle East, and African regions, while European countries will strengthen the internal recycling and processing of plastic waste. From the perspective of the national income level, the establishment of the new relationship will show an evolutionary trend in which high-income countries are dominated and the scale of trade between non-high-income countries expands. In addition, the differences in the level of economic development, liner transport connectivity, and the proportion of mismanagement of plastic waste among countries has a positive effect on the establishment of a new relationship in the GPWT, while tariff rates have an inhibitory effect. In general, the GPWT will still exist in the future, which requires the international community to guide the GPWT to promote the recycling and reuse of plastic waste in a real sense and adjust the unreasonable trade model.

In the present study, the role of Tremella polysaccharides in cellular apoptosis and autophagy induced by Pseudomonas aeruginosa lipopolysaccharide (LPS) in human epithelial A549 lung-cancer cells was investigated. Initially, it was demonstrated that LPS attenuated A549 cell viability in a time- and dose-dependent manner. Furthermore, LPS induced apoptotic cell death and autophagy in A549 cells and increased reactive oxygen species (ROS) production in a time-dependent manner. In addition, LPS treatment was demonstrated to markedly suppress sirtuin 1 (SIRT1) protein expression in A549 cells. Notably, it was demonstrated that Tremella polysaccharides activate SIRT1, leading to increased p62 expression, decreased p53 acetylation and B-cell lymphoma 2-associated X protein expression, and subsequently attenuate LPS-induced apoptotic cell death and autophagy. The results of the present study demonstrated that Tremella polysaccharides activate SIRT1 and inhibit LPS-induced ROS production, apoptosis and autophagy. This may have critical implications for the treatment of Pseudomonas aeruginosa infection.

Background: CT053 is a fully human autologous chimeric antigen receptor (CAR) T-cell therapy comprising a B-cell maturation antigen (BCMA)-specific single-chain variable fragment (25C2). A clinical trial of CT053 is ongoing in LUMMICAR STUDY 1 (NCT03975907) for patients with relapsed and refractory multiple myeloma (RRMM) in China. The pivotal Phase 2 of LUMMICAR STUDY 1 is actively enrolling patients. Here, we report clinical data from Phase 1 with 12 months of follow-up. Methods: Subjects with RRMM who had received ≥3 prior therapies, including at least one proteasome inhibitor and one immunomodulatory drug were enrolled in Phase 1 study. Adverse events (AEs) were graded according to CTCAE, v5.0; Cytokine release syndrome (CRS) and neurotoxicity were graded according to ASTCT CRS consensus grading system (Lee DW et al, 2019). Response was assessed per IMWG 2016 criteria. Minimal residual disease (MRD) was tested by next-generation flow cytometry on bone marrow aspirates by the EuroFlow assay with a minimum sensitivity of 1 in 10⁵ nucleated cells or higher, and CAR copies in the subject peripheral blood were monitored by quantitative real-time polymerase chain reaction (qPCR). Results: Fourteen subjects with a median age of 54 years (range 34-62) received CT053 infusion. Three subjects received 1.0×10 8 CAR+ T cells and eleven subjects received 1.5×10 8 CAR+ T cells. As of July 8, 2021, 14 subjects with a median follow-up of 13.6 months since infusion. Of the 14 subjects, 11 (78.6%) had received autologous stem cell transplantation, 2 (14.2%) had extramedullary disease at baseline, 2 (14.3%) had ISS stage III, and 5 (35.7%) had high-risk cytogenetics. The median prior therapies was 6 (range 3-7) and no subject received bridging therapy. The most common AEs were expected hematological toxicities. All subjects (100%) experienced ≥ grade 3 neutropenia, 91.7% experienced ≥ grade 3 thrombocytopenia, and most recovered to ≤ grade 2 within 2 weeks. No dose limiting toxicity or treatment-related death was reported. Additionally, no ≥ grade 3 CRS or neurotoxicity was observed, 92.9% subjects (13/14) experienced grade 1 or 2 CRS (9 grade 1, 4 grade 2). CRS occurred at a median of 6 days (range 2-12) post-infusion with a median duration of 7 days. No severe infections were reported except one case of grade 3 lung infection. A 100% overall response rate was achieved in 14 subjects, with 11 stringent complete responses (sCR, 78.6%), 2 very good partial responses (VGPR), and 1 partial response, with a ≥VGPR rate of 92.9%. Four subjects achieved sCR at week 52. As of July 8, 2021, 12 subjects with at least 12 months of efficacy assessment were still in the study, and the 12-month progression-free survival (PFS) rate was 85.7%. With a median follow-up of 13.6 months, the median duration of response and the median PFS had not been reached. All 11 subjects with sCR were MRD-negative, and 9 subjects reached sustained CR/sCR for more than 12 months (Figure 1). Three subjects had disease progressed including two subjects with extramedullary disease progressed at week 16. Interestingly, the CR/sCR rate for the subjects without extramedullary disease is 91.7% (11/12). The 1-year PFS rate for subjects without extramedullary disease reached 100%。 CT053 cells expanded and persisted well. No immunogenicity was detected. Conclusion: These results demonstrate that CT053 CAR T cells at a dose of 1.0-1.5×10 8 cells achieve a deep and durable response, including a high MRD-negative sCR rate, with an acceptable safety profile in subjects with heavily pretreated RRMM. Figure 1 Figure 1. Disclosures Li: CARsgen: Current Employment, Current equity holder in publicly-traded company. Wang: CARsgen Therapeutics Corp: Current Employment. Xiao: CARsgen Therapeutics Corp: Current Employment. Wang: CARsgen Therapeutics Co. LtD: Current Employment, Current equity holder in publicly-traded company. Tang: CARsgen Therapeutics Corp: Current Employment.

Background Bortezomib with lenalidomide and dexamethasone (VRd) is a standard regimen for the induction treatment of multiple myeloma (MM) transplant eligible and ineligible patients. Deregulation of histone acetylation has been recognized to serve a critical role in the pathogenesis of MM, which histone deacetylase (HDACs) are overexpressed in plasma cells derived from patients with MM. Therefore, HDACs may promise targets for MM therapy, and panobinostat was approved by FDA for the treatment of relapsed/refractory MM in 2015. Chidamide, a novel oral benzamide type HDAC inhibitor independently developed and approved as anticancer drugs in China, selectively suppresses the activity of class I HDACs. Our studies have shown that chidamide can enhance cytotoxic effect of bortezomib or lenalidomide on MM cells in vitro, which suggested a synergistic combination of chidamide with bortezomib or lenalidomide at low dose. In ASH 2019 we reported Phase 1 Suzhou MM02 study in which chidamide at 4 dose levels (15mg/20mg/25mg/30mg d 0,3,7,10) were administered to 12 patients with VRd for 4-cycle induction therapy. No DLT in Chi-VRd group were observed. This phase 2 trial was designed to further assess the safety and efficacy of Chi-VRd versus VRd for induction treatment in patients with newly diagnosed high risk MM before autologous transplantation (NCT 04025450). Methods In this study, we enrolled patients from the First Affiliated Hospital of Soochow University and Soochow Hopes Hematology Hospital with newly diagnosed high-risk multiple myeloma who were aged 18 years or older and eligible for autologous stem-cell transplant (ASCT) according to International Myeloma Working Group diagnostic criteria. All the patients were randomly assigned to Chi-VRd and VRd group. Chi-VRd group patients received Chidamide 20mg orally on days -1,2,6 and 9 in combination with VRd (bortezomib 1.3mg/m2 subcutaneously on days 1,4,8,11; lenalidomide 25mg orally on days 1-14; dexamethasone 20mg iv or orally on days 1,2,4,5,8,9,11,12) for 4 cycles. VRd group patients received VRd (bortezomib 1.3mg/m2 subcutaneously on days 1,4,8,11; lenalidomide 25mg orally on days 1-14; dexamethasone 20mg iv or orally on days 1,2,4,5,8,9,11,12) for 4 cycles. All the patients proceed with ASCT after four cycles or continue VRd therapy for up to eight cycles, followed by maintenance therapy for up to 2 years. Primary efficacy endpoints were overall response rate (ORR), rate of very good partial response (VGPR) or better and rate of complete response (CR) for Chi-VRd and VRd. Safety data described rates of adverse events. Results Between Mar 16, 2020, and Jul 22, 2021, 40 patients were enrolled and randomly assigned to either the VRd regimen (n=20) or the Chi-VRd regimen (n=20). In the Chi-VRd group, 1 patient was discharged due to severe tumor lysis syndrome, and another 1 patient was discharged from sick sinus syndrome (considering lenalidomide related). By the deadline for submission, 18 patients in the VRd group and 11 patients in the Chi-VRd group had completed induction chemotherapy. The total adverse events were listed in the table below. The main treatment-related adverse events were hematological toxicity, hepatotoxicity, constipation, and peripheral neuropathy. ORR was 90.9% (10/11) for Chi-VRd and was 100% for VRd. Response of VGPR or better was 81.8% (9/11) for Chi-VRd and was 83.3% (15/18) for VRd. And rate of CR was 63.6%(7/11) for Chi-VRd and was 44.4%(8/18) for VRd. Conclusion The Chi-VRd group had more adverse events of thrombocytopenia, peripheral neuropathy and pulmonary. No treatment-related death was observed in two groups. Patients received Chi-VRd get more CR rate. Updated PFS and OS with comparison between VRd and Chi-VRd will be presented at the following study. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Background: CT053 are autologous T cells genetically modified with a second-generation chimeric antigen receptor (CAR) incorporating a fully human B-cell maturation antigen (BCMA)-specific single-chain fragment variant (25C2) with high binding affinity. Twenty-four subjects were previously treated in investigator-initiated (IIT) studies with 87.5% overall response rate (ORR), 79.2% complete response (CR) and a median duration of response of 21.8 months without inducing immunogenicity [Blood (2019) 134 (Supplement_1): 4435]. We report herein the first disclosed results from the ongoing phase 1 study (LUMMICAR-1) in China (NCT03975907). Methods: The phase 1 study included subjects with relapsed/refractory multiple myeloma (RRMM) who had received ≥3 prior therapy regimens including a proteasome inhibitor and an immunomodulatory drug, and had measurable disease per 2016 International Myeloma Working Group (IMWG) criteria. All subjects received conditioning treatment of cyclophosphamide (300 mg/m2/day ×3 days) and fludarabine (25 mg/m2/ day × 3 days). After conditioning, subjects received a single infusion of CT053 at the 1.0-1.5×108 CAR+ T-cell dose. Primary objectives for phase 1 were to evaluate the safety and tolerability of CT053 and to identify the recommended phase 2 dose. Adverse events (AEs) were graded using CTCAE, v5.0; cytokine release syndrome (CRS) and neurotoxicity were graded according to ASTCT CRS consensus grading system (Lee DW et al, 2019). Response was assessed per 2016 IMWG criteria. Results: As of July 20, 2020, a total of 14 subjects have been enrolled in the study. All 14 subjects have been apheresed and received CT053 infusion, including 3 subjects who received 1.0×108 CAR+ T cells and 3 subjects who received 1.5×108 CAR+ T cells at dose escalation, followed by 8 subjects who received 1.5×108 CAR+ T cells at dose expansion. The 14 batches of CT053 were manufactured in a median of 8 days (range 7-10). Treated subjects had a median age of 54 years (range 34-62) and had received a median of 6 (range 3-7) prior lines of therapy. Of the 14 subjects, 10 (71.4%) received autologous stem cell transplantation, 2 (14.2%) had extramedullary disease at baseline, and 5 (35.7%) had high-risk cytogenetics. No subject received bridging therapy. At data cutoff, 12 subjects had at least 4 weeks of safety and efficacy assessment with median follow-up of 5 months (range, 1-11). No dose-limiting toxicities were detected. The most common ≥ grade 3 AE was hematological toxicity. Of the 12 subjects with at least 4 weeks follow-up, all experienced ≥ grade 3 neutropenia (100%), 91.7% of subjects had ≥ grade 3 thrombocytopenia, and most recovered to ≤ grade 2 within 2 weeks. No grade 3 or higher CRS or neurotoxicity was observed. Eleven of 12 subjects (91.7%) experienced grade 1 or 2 CRS, including 3 subjects who experienced grade 2 CRS and 8 subjects who experienced grade 1 CRS. CRS events occurred at a median of 6 days (range 2-12) post-infusion with a median duration of 7 days, following a generally predicable onset pattern. Eight subjects received tocilizumab treatment, of whom one subject with grade 2 CRS received both tocilizumab and steroid. At the data cutoff, among 12 subjects with at least 4 weeks of efficacy assessment, a 100% ORR was observed, with 4 stringent complete responses (sCR), 1 CR, 3 very good partial responses and 4 partial responses. All 5 subjects with CR/sCR were minimal residual disease (MRD)-negative at the 10 5 sensitivity level. Responses were independent of baseline BCMA expression in bone marrow. CT053 transgene levels showed expansion and persistence in peripheral blood, with peak expansion at 7-14 days after dosing in all subjects, with peak copies 45,469 (range 11,825-258,574). Serum C-reactive protein and cytokine levels (i.e., IL-6, IFNγ, IL-8, IL-10) increased post-infusion within 7 days and correlated with the onset of CRS symptoms. No immunogenicity was detected. Conclusion: These results demonstrate that CT053 at a target dose of 1.0-1.5×108 CAR+ T cells delivers early and deep responses, including MRD negativity in all complete responders, with an acceptable safety profile in subjects with heavily pretreated RRMM. The results from this LUMMICAR-1 study are consistent with the previous IIT phase 1 studies and the ongoing North American LUMMICAR-2 study and support the launch of pivotal LUMMICAR-1 study in China. Updated results will be presented at this conference. Disclosures Li: CARsgen Therapeutics Co. LtD: Current Employment, Current equity holder in private company. Wang:CARsgen Therapeutics Corp.: Current Employment. Xiao:CARsgen Therapeutics Corp.: Current Employment. Wang:CARsgen Therapeutics Co. LtD: Current Employment, Current equity holder in private company. Ma:CARsgen Therapeutics Corp.: Current Employment.

CT053 comprises autologous T cells genetically modified with a second-generation chimeric antigen receptor (CAR) incorporating a fully human B-cell maturation antigen (BCMA)-specific single-chain fragment variant (25C2) with high binding affinity. Twenty-four subjects have been treated in phase 1 studies with an 87.5% overall response rate (ORR), 79.2% complete response (CR), and a median duration of response of 21.8 months without inducing immunogenicity [Blood (2019) 134 (Supplement_1): 4435]. Here we present the ongoing phase 1b/2 study (LUMMICAR-2) conducted in North America (NCT03915184) to evaluate safety and clinical efficacy. Eligible subjects with relapsed/refractory multiple myeloma (RRMM) had received ≥3 prior lines of therapy including a proteasome inhibitor (PI), an immunomodulatory drug (IMiD), and an anti-CD38 antibody, and had measurable disease per International Myeloma Working Group (IMWG) criteria. All subjects received a lymphodepletion regimen of cyclophosphamide (500 mg/m2/day ×2 days) and fludarabine (25 mg/m2/ day × 3 days). A single infusion of CT053 at the targeted 1.5-3.0×108 CAR+ T-cell dose was administered after lymphodepletion. Primary objectives for phase 1b were to evaluate the safety and tolerability of CT053 and to identify the recommended phase 2 dose. Adverse events (AEs) were graded using CTCAE, v5.0; cytokine release syndrome (CRS) and neurotoxicity were graded according to ASTCT CRS consensus grading system (Lee DW et al, 2019). The response was assessed per 2016 IMWG criteria, and minimal residual disease (MRD) was assessed by next generation flow cytometry or sequencing. As of July 28, 2020, 20 subjects have enrolled, and 14 subjects have received CT053 infusion in the phase 1b portion of the study, including 8 subjects who received 1.5-1.8×108 CAR+ T cells while 6 subjects received 2.5-3.0×108 CAR+ T cells. The treated subjects had a median age of 59 years (range 42-73), had received a median of 6 (range 3-11) prior lines of treatment, 93% were triple refractory to a PI, IMiD, and anti-CD38 antibody, and 64% were penta-refractory. In addition, 36% of the subjects had extramedullary disease at baseline, and 64% had high-risk cytogenetics. All subjects received bridging therapy. The most common ≥ grade 3 AE was hematological toxicity. All subjects experienced ≥ grade 3 neutropenia (100%) and leukopenia (100%), and 36% of subjects had ≥ grade 3 thrombocytopenia within 30 days of treatment. No grade 3 or higher CRS or neurotoxicity was observed. Twelve of 14 subjects (86%) experienced grade 1 or 2 CRS, including 2 subjects who experienced grade 2 CRS and 1 subject who had grade 2 neurotoxicity. CRS events had a generally predictable time to onset, occurring at a median of 2 days post infusion with a median duration of 4 days (range 1-6). Two subjects received tocilizumab, and one subject with grade 2 CRS received both tocilizumab and steroids. One subject experienced grade 2 neurotoxicity with complete resolution within 24 hours upon administration of dexamethasone. At the data cutoff, 10 subjects were evaluable for at least two months of efficacy assessment with a median follow-up of 4.5 months (range 2-8). A 100% ORR was observed, with 2 stringent complete responses, 2 CRs, 1 very good partial response, and 5 partial responses. Of the 12 subjects with evaluable bone marrow samples, 11 were MRD-negative at the 10-5 sensitivity level. Responses were independent of baseline bone marrow BCMA expression. CT053 transgene levels showed expansion and persistence in peripheral blood, with peak expansion at 7-14 days after infusion. All subjects showed similar kinetics of rapid declines in serum free light chains and soluble BCMA (sBCMA) levels within 1 month, and continued depletion in sBCMA suggests CT053-mediated pharmacodynamic activity. Serum C-reactive protein and cytokine levels (i.e., IL-6, IFNγ, IL-8, IL-10) increased post-infusion within 7 days and correlated with the onset of CRS symptoms. Collectively, these results demonstrate that CT053 at a target dose of 1.5-3.0×108 CAR+ T cells delivers early and deep responses, including MRD negativity, with an acceptable safety profile in subjects with heavily pretreated relapsed or refractory MM. The promising results from the ongoing LUMMICAR-2 study are consistent with the previous phase 1 studies and support the launch of a pivotal Phase 2 LUMMICAR-2 study. Updated results will be presented at the conference. Disclosures Kumar: Carsgen: Other, Research Funding; Kite Pharma: Consultancy, Research Funding; Oncopeptides: Consultancy, Other: Independent Review Committee; IRC member; Celgene/BMS: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Genentech/Roche: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Adaptive Biotechnologies: Consultancy; Janssen Oncology: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Dr. Reddy's Laboratories: Honoraria; Tenebio: Other, Research Funding; Genecentrix: Consultancy; BMS: Consultancy, Research Funding; AbbVie: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Amgen: Consultancy, Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments, Research Funding; MedImmune: Research Funding; Cellectar: Other; Merck: Consultancy, Research Funding; Takeda: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Sanofi: Research Funding; Novartis: Research Funding; Karyopharm: Consultancy. Baz:Sanofi, Karypharm, Janssen, Celgene: Other: Advisory board; Karyopharm, janssen, Bristol Myers Squibb, Celgene, Merck, Sanofi, Abbvie Inc.: Research Funding. Orlowski:Amgen, Inc., AstraZeneca, BMS, Celgene, EcoR1 Capital LLC, Forma Therapeutics, Genzyme, GSK Biologicals, Ionis Pharmaceuticals, Inc., Janssen Biotech, Juno Therapeutics, Kite Pharma, Legend Biotech USA, Molecular Partners, Regeneron Pharmaceuticals, Inc.,: Honoraria, Membership on an entity's Board of Directors or advisory committees; Founder of Asylia Therapeutics, Inc., with associated patents and an equity interest, though this technology does not bear on the current submission.: Current equity holder in private company, Patents & Royalties; STATinMED Research: Consultancy; Sanofi-Aventis, Servier, Takeda Pharmaceuticals North America, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees; Laboratory research funding from BioTheryX, and clinical research funding from CARsgen Therapeutics, Celgene, Exelixis, Janssen Biotech, Sanofi-Aventis, Takeda Pharmaceuticals North America, Inc.: Research Funding. Anderson:Amgen: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; GSK: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding. Ma:CARsgen Therapeutics Corp.: Current Employment. Bilgi:CARsgen Therapeutics Corp.: Other: Current shareholder in the company. Kansagra:Alnylam Pharmaceuticals, Bristol Myers Squibb /Celgene, GlaxoSmithKline, Janssen, Pharmacyclics, Takeda Pharmaceuticals, Pfizer, Karyopharm Therpeutics: Other: Advisory Board. Kapoor:Janssen: Research Funding; Cellectar: Consultancy; Takeda: Honoraria, Research Funding; GlaxoSmithKline: Research Funding; Celgene: Honoraria; Amgen: Research Funding; Sanofi: Consultancy, Research Funding. Li:CARsgen Therapeutics Co. LtD: Current Employment, Current equity holder in private company. Brayer:Bristol-Myers Squibb, WindMIL Therapeutics: Research Funding; Janssen: Consultancy; Bristol-Myers Squibb, Janssen, Amgen: Speakers Bureau.

Background Multiple myeloma (MM) is a heterogenous plasma cell malignancy. About 30-40% of newly diagnosed and 20-60% of relapsed/refractory MM patients carry 1q21 amplification worldwide, a high-risk indicator for poor prognosis in RRMM. Different BCL-2 family anti-death proteins play important roles in MM survival and drug resistance. High expression of BCL-2 due to t (11;14) renders cell vulnerability to BCL-2 antagonist, however, patients carrying other genetic abnormality including 1q21 amplification have limited response to the newly emerged treatment choice. With MCL-1 upregulation accompanied with 1q21 amplification, we tested whether BCL-2 antagonist combined with IMiDs (immunomodulatory imide drugs), improves cell killing in high-risk MM patient models, including those resistant to bortezomib and lenalidomide. For that aim, we studied APG-2575, a novel and potent BCL-2 inhibitor developed by Ascentage Pharma Group and it is currently in clinical trials for hematologic malignances, including MM. Methods 1. Cells were treated with APG-2575 single agent or in combination with lenalidomide; 2. Cell line viability was assessed by CellTiter-Glo (CTG) assay; 3. Flow cytometry analysis was used to detect CD138+ cell surface marker in primary cells derived from MM patients; 4. Western blot analysis for BCL-2 family and IMiD signaling proteins. Results We first determined the cell sensitivity of APG-2575 as a single agent in a panel of MM cell lines, and as expected, those carrying t (11;14) were very sensitive to APG-2575, with low IC50 values ranging 7-23 nM. The IC50 values for cells carrying other genetic markers were greater than 5-10 μM. We then evaluated cell-death inducing activity of APG-2575 in MM patient-derived primary cells ex vivo, which were freshly prepared from patients' bone marrow aspirates. Primary cells were treated with APG-2575 or ABT-199 (venetoclax) for 18-24 hours, and the loss of CD138 surface marker was used to quantify cell death. As shown in Figure 1a, APG-2575 induced cell death (CD138+ loss) in a dose-dependent manner, and significant cell death was observed at 0.37-3.3 μM of APG-2575, indicating primary cells more sensitive than MM cell lines. Interestingly, the sensitivity to APG-2575 is similar in primary MM cells with or without 1q21 amplification. Since moderate cell death inducing activity was observed in MM cells when APG-2575 used as a single agent, we combined APG-2575 with lenalidomide. Cell death was increased in the combination groups compared with single agent, and it was dose-dependent (Figure 1b).Similar enhanced antiproliferative activity was confirmed in RPMI 8226 cell line, which carries 1q21 amplification (Figure 1c). We furthered to understand the mechanism of action (MoA) of this combination. In Figure 1d, Western blot analysis of RPMI 8226 cell line revealed that IKZF1 and IKZF3 proteins from the NF-KB pathway were downregulated by lenalidomide. And the decrease of MCL-1 protein and the strong induction of pro-death protein BAK were evident in the combination group of APG-2575 and lenalidomide, which helps to illustrate MoA underlying the synergistic effect of APG-2575 and lenalidomide in MM models. Conclusions In both cell lines and primary samples derived from MM patients, APG-2575 demonstrates cell death inducing activity as a single agent, and enhanced/synergistic effects when it combines with lenalidomide in RRMM resistant to lenalidomide and bortezomib. The combination decreases IKZF1, IKZF3 and MCL-1 proteins, and upregulates pro-death protein BAK, thus providing a strong rationale to combine BCL-2 inhibitor and lenalidomide to treat high-risk patient populations carrying 1q21 amplification. Disclosures FU: Ascentage Pharma (SuZhou) Co., Ltd: Other: research agreement contract . Yin:Ascentage Pharma (SuZhou) Co., Ltd: Current Employment. Mao:Ascentage Pharma (SuZhou) Co., Ltd: Current Employment. Deng:Ascentage Pharma (SuZhou) Co., Ltd: Current Employment. Fang:Ascentage Pharma (SuZhou) Co., Ltd: Current Employment. Yang:Ascentage Pharma (SuZhou) Co., Ltd: Current Employment, Current equity holder in publicly-traded company, Other: Leadership and other ownership interests. Zhai:Ascentage Pharma (SuZhou) Co., Ltd: Current Employment, Current equity holder in publicly-traded company, Other: Leadership and other ownership interests.

Aims The present study explored the function and regulatory mechanism of High mobility group box 1 (HMGB1) in asthma. Main methods OVA (ovalbumin)-induced asthmatic mice model and LPS-treated cellular model were established in this study. Airway inflammation was measured through detecting the expression of IL-4, IL-5, IL-13 and Interferon-γ (IFN-γ) in serum and BALF (bronchoalveolar lavage fluid) by ELISA kits. Bioinformatics predictive analysis, ChIP assays, Luciferase reporter assay and Western blotting were used to explore the relation between HMGB1 and HSF1 (Heat shock factor 1). Key findings HMGB1 expression was increased in OVA-induced asthmatic mice. Silencing HMGB1 attenuated the increasing of IgE, inflammatory factors (IL-4, IL-5 and IL-13), and airway hyperresponsiveness that induced by OVA. In addition, our study found that HSF1 directly bind with the HMGB1 promoter and negatively regulation of HMGB1. HSF-1 were upregulated in OVA-induced asthmatic mice, and knockdown of HSF1 aggravated the OVA-induced airway inflammation and airway hyperreactivity in mice may through promoting the expression of HMGB1 and the activation of the Toll-like receptor 4 (TLR4)/Myeloid differentiation primary response 88 (MyD88)/Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signal pathway. Significance The expression of HMGB1 could be negatively regulated by HSF1, and the TLR4/MyD88/NF-κB signal pathway was involved in HSF1/HMGB1-mediated regulation of asthma.

The processes of ammonia recovery from ammonia nitrogen containing wastewater by air stripping in the laboratory-scale and the pilot-scale rotating packed bed (RPB) were simulated by the Aspen with the module of RADFRAC. For a more accurate description of the model, a variety of correlations for the RPB were introduced into the Aspen by the FORTRAN, such as the gas-liquid mass transfer rate, the liquid holdup, the heat transfer rate and the effective gas-liquid interfacial area, etc. The predicted data of ammonia recovery rate were consistent with the experimental results. To further optimize the operating conditions of ammonia recovery, the research also covered the effects of high gravity factor, gas to liquid ratio, pH and temperature on ammonia recovery rate. The promising results had suggested the established model could serve as a powerful tool to simulate the processes of ammonia recovery from the ammonia nitrogen containing wastewater by air stripping in the laboratory-scale and the pilot-scale RPB.

Acute myeloid leukemia (AML) is a fatal hematopoietic malignancy with poor clinical outcomes. To determine whether the expression of the long non-coding (lnc)RNA zinc finger E-box binding homeobox 2 (ZEB2) antisense RNA 1 (ZEB2-AS1) is associated with clinical outcomes, its expression was analyzed in a retrospective cohort of 62 AML and 10 non-malignant cases. The results revealed that the expression of ZEB2-AS1 lncRNA was notably high and closely associated with adverse clinical outcomes in AML cases compared with the non-malignant cases, based on either modified Medical Research Council or European Leukemia Net risk stratification systems. Univariate analyses indicated that patients with a higher expression of ZEB2-AS1 lncRNA had significantly shorter overall survival (OS) (P=0.036) and disease-free survival (DFS) rates (P=0.039) compared with patients with a lower expression of ZEB2-AS1 lncRNA. In addition, patients with a higher expression of ZEB2-AS1 lncRNA had a significant lower complete remission rate in response to induction by chemotherapy compared with patients with a lower expression of ZEB2-AS1 lncRNA (P=0.031). In cases with low levels of ZEB2-AS1 lncRNA, patients treated with allogenic hematopoietic stem cell transplantation had significantly longer OS and DFS rates compared with that of chemotherapy-treated patients (P=0.037 and P=0.049 respectively). Furthermore, the knockdown of ZEB2-AS1 lncRNA effectively inhibited AML cell invasion and migration, which was closely associated with the downregulation of ZEB2 and upregulation of E-cadherin expression. Collectively, although its independent prognostic value for survival was not rigorously determined, ZEB2-AS1 lncRNA may function as a candidate marker to improve conventional risk stratification systems and the evaluation of therapeutic responses for AML.

The reversible resistive switching effect at oxide interface shows promising applications in information storage and artificial intelligence. However, the microscopic switching mechanism is still elusive due to the difficulty of direct observation of the electrical and chemical behavior at the buried interface, which becomes a major barrier to design reliable, scalable, and reproducible devices. Here we used a gold-coated AFM tip as a removable electrode to investigate the resistive switching effect in a microscopic Au/Nb:SrTiO3 Schottky junction. We found that unlike the inhomogeneous random resistive switching in the macroscopic Schottky junctions, the high and low resistance states can be reversibly switched in a controllable way on the Nb-doped SrTiO3 surface by the conductive tip. The switching between the high and low resistance states in vacuum is accompanied by the reversible shift of the surface Fermi level. We indicate that the transfer of the interface oxygen ion in a double-well potential is responsible for the resistive switching in both macroscopic and microscopic Schottky junctions. Our findings provide a guide to optimize the key performance parameters of a resistive switching device such as operation voltage, switching speed, on/off ratio, and state retention time by proper electrode selection and fabrication strategy.

The epitaxial c-axis orientated FeV2O4 films with different thicknesses on SrTiO3, LaAlO3 and MgAl2O4 (001) substrates were fabricated for the first time by pulsed laser deposition, and strain effects on the structure and magnetic anisotropy were investigated. The X-ray diffraction analysis shows that the lattice constants of the FeV2O4 films behave differently on different substrates. The compressive strain in the films on MgAl2O4 is dominantly controlled by the in-plane lattice mismatch. By contrast, the strain states in the films on LaAlO3 and SrTiO3 substrates can be explained by the difference in the thermal expansion coefficients between the films and substrates. In the temperature range investigated from 20 K to 300 K the fully relaxed FeV2O4 thick film is tetragonal with c>a, whereas its bulk is cubic. The magnetic easy axis of all the films is normal to the film plane, independent of substrates, film thickness, and strain states. The out-of-plane magnetic anisotropy is attributed to the high tetragonality with c>a due to the strong spin-lattice coupling.