Chimeric antigen receptor (CAR)-T cell therapy has achieved remarkable success in the treatment of hematological malignancies. Based on the immunomodulatory capability of CAR-T cells, efforts have turned toward exploring their potential in treating autoimmune diseases. Bibliometric analysis of 210 records from 128 academic journals published by 372 institutions in 40 countries/regions indicates a growing number of publications on CAR-T therapy for autoimmune diseases, covering a range of subtypes such as systemic lupus erythematosus, multiple sclerosis, among others. CAR-T therapy holds promise in mitigating several shortcomings, including the indiscriminate suppression of the immune system by traditional immunosuppressants, and non-sustaining therapeutic levels of monoclonal antibodies due to inherent pharmacokinetic constraints. By persisting and proliferating in vivo, CAR-T cells can offer a tailored and precise therapeutics. This paper reviewed preclinical experiments and clinical trials involving CAR-T and CAR-related therapies in various autoimmune diseases, incorporating innovations well-studied in the field of hematological tumors, aiming to explore a safe and effective therapeutic option for relapsed/refractory autoimmune diseases.

4017 Background: Claudin18.2 (CLDN18.2) has emerged as a promising therapeutic target, which is normally confined to gastric mucosa tight junctions but is often expressed in gastric/gastroesophageal junction (G/GEJ) cancer. CT041, an CLDN18.2-redirected CAR T-cell therapy, showed promising anti-tumor activity in preclinical studies (Hua J. J Natl Cancer Inst. 2019). Recently reported results of a phase I study (Qi C. Ann. Oncol 2021) showed that CT041 was well tolerated and had encouraging efficacy in previously treated patients with CLDN18.2-positive advanced G/GEJ cancer. Here we report the preliminary safety and efficacy data on patients with G/GEJ cancer in an ongoing phase Ib/II study (CT041-ST-01, NCT04581473). Methods: This open-label, 2-part, multicenter, phase Ib/II study was conducted to assess the safety, tolerability and efficacy of CT041 in patients with previously treated, CLDN18.2-positive advanced G/GEJ cancer. The study consisted of a dose escalation/dose-expansion phase (phase Ib) and a safety/efficacy confirmatory phase (phase II). In the dose escalation/de-escalation phase, CT041 dose levels of 2.5 × 108 and 3.75 × 108 were investigated using 3 + 3 design. The primary objective of the phase Ib part was to determine the safety, tolerability and recommended phase 2 dose (RP2D) of CT041. Data are reported as of December 22, 2021. Results: From November 2020 to May 2021,14 eligible patients with G/GEJ cancer were enrolled in phase Ib. The median (range) age was 44.5 (23-71); 85.7% had received 2 prior lines of treatment and 14.3% had at least 3 lines; 57.1% had ≥ 3 metastatic organs, with 92.9% had peritoneal dissemination; 64.3% had signet ring cell carcinoma. Among them, 3 received 3.75 × 108 and 11 received 2.5 × 108 dose level with up to 3 doses, respectively. Most commonly reported AEs of grade 3 or higher were hematologic toxicity related with lymphodepletion. There were no dose-limiting toxicities, treatment-related death, neurologic toxicity (ICANS) or gastrointestinal toxicities observed. Most CRS were grade 1 or 2, and only one patient experienced grade 4 CRS and fully recovered. As of the data cut-off, 8 of 14 (57.1%) patients achieved partial response (PR); 2 of 14 (14.3%) patients showed stable disease (SD) . With a median follow-up time of 8.9 months (95%CI 5.91, NE), the median progression-free survival (PFS) was 5.6 months (95%CI 1.9, 7.4), and median overall survival (OS) was 10.8 months (95%CI 5.1, NE) with 7 patients still alive at last follow-up. Conclusions: These preliminary results suggest that CT041 had manageable safety/tolerability profile and promising efficacy in patients with previously treated advanced G/GEJ cancer. This study is ongoing with further investigation of CT041 in phase II underway. Clinical trial information: NCT04581473.

The clinical efficacy of current therapies for Hepatocellular carcinoma (HCC) are unsatisfactory. In recent years, chimeric antigen receptor (CAR) T-cell therapies have been developed for solid tumors including advanced HCC (aHCC), but limited progress has been made. Glypican-3 is a promising immunotherapeutic target for HCC since it is specifically highly expressed in HCC. A previous study indicated that GPC3-targeted CAR T-(CAR-GPC3) cells were well-tolerated and had prolonged survival for HCC patients and that Sorafenib could increase the antitumor activities of CAR-GPC3 T-cells against HCC in mouse models. Here, we report a patient with aHCC who achieved a complete response (CR) and a long survival period after the combination therapy of CAR-GPC3 T-cell plus sorafenib. A 60-year-old Asian male diagnosed with hepatitis B virus (HBV) related HCC developed liver recurrence and lung metastasis after liver tumor resection and trans-arterial chemoembolization therapy. The patient also previously received microwave ablation therapy for lung metastasis. After the enrollment, the patient underwent leukapheresis for CAR-GPC3 T-cells manufacturing. Seven days after leukapheresis, the patient started to receive 400 mg of Sorafenib twice daily. The patient received 4 cycles of CAR-GPC3 T cells (CT011) treatment and each cycle was divided into two infusions. Prior to each cycle of CT011 treatment, lymphodepletion was performed. The lymphodepletion regimen was cyclophosphamide 500 mg/m2/day for 2 to 3 days, and fludarabine 20-25 mg/m2/day for 3 to 4 days. A total of 4×109 CAR-GPC3 T cells were infused. The CT011 plus Sorafenib combination therapy was well tolerated. All the ≥ grade 3 AEs were hematological toxicities which were deemed an expected event caused by the preconditioning regimen. This patient obtained partial responses from the 3rd month and achieved CR in the 12th month after the first cycle of CT011 infusion according to the RECIST1.1 assessment. The tumor had no progression for more than 36 months and maintained the CR status for more than 24 months after the first infusion.

4088 Background: GPC3 is highly expressed in hepatocellular carcinoma (HCC) and is a promising target for HCC immunotherapy. Earlier phase I trial results demonstrated that second-generation GPC3-specific chimeric antigen receptor (CAR-GPC3) T cells were well tolerated in advanced HCC patients and showed clinical benefits (Shi D, Clin Can Res, 2020). Further preclinical studies showed that CAR-GPC3 T cells combined with multi-tyrosine kinase inhibitors (TKIs) were more effective in killing GPC3 + HCC xenografts (Wu X, Mol Ther, 2019), and fourth-generation (4G) CAR-GPC3 T cells co-expressing a transcription factor more effectively killed GPC3 + HCC xenografts. Methods: In this single-arm, open-label, first-in-human phase I trial (NCT03980288), we investigated the safety and antitumor activity of autologous 4G-CAR-GPC3 T cells for GPC3 + heavily pretreated advanced HCC patients. Patients received 4G-CAR-GPC3 T cell infusion(s) after lymphodepletion pretreatment and 67% patients combined with TKIs. Adverse events (AEs) were graded by CTCAE 5.0. Cytokine release syndrome (CRS) was graded by American Society for Transplantation and Cellular Therapy criteria (2019). Tumor response was assessed by RECISTv1.1. Results: As of January 30th, 2021, 6 subjects with HBV-related metastatic HCC were enrolled. All had progressed on ≥ 2 lines of systemic therapy, with at least one TKI combined with anti-PD-1/PD-L1 immunotherapy or FOLFOX4 chemotherapy. After lymphodepletion, patients were treated with 1-2 cycles (totaling 2.5–5×10 8 CAR + cells) of 4G-CAR-GPC3 T cell therapy. Among them, 1 patient received half dose of sorafenib and 3 patients received half dose of regorafenib along with cell infusion. No dose limiting toxicity (DLT) occurred. The maximum tolerated dose (MTD) was not observed. No patient withdrew from the trial due to AE. No treatment-related death or neurotoxicity occurred. The most common ≥ grade 3 AEs were hematological toxicity, mainly due to lymphodepletion, and patients recovered within 2 weeks after therapy. All patients developed CRS including 3 at grade 2 and 3 at grade 3. Patients recovered from CRS after tocilizumab therapy with corticosteroid (4 patients) or without. One patient achieved partial response and continued after 18 weeks. The objective response rate (ORR) and disease control rate (DCR) were 16.7% and 50%, respectively. The median progression free survival (mPFS) was 4.2 months. The median peak CAR-GPC3 copies were 5067 copies/ug gDNA, and CAR-GPC3 copies were detectable on day 28 ranging 113–2071 copies/ug gDNA. Conclusions: Our study is the first to report that 4G-CAR-GPC3 T cell therapy in combination with TKIs has a manageable safety profile while demonstrating potential antitumor activity for heavily pretreated advanced HCC patients; however, CRS should be diligently managed. Clinical trial information: NCT03980288.

Background: B cell maturation antigen (BCMA) is a potential therapeutic target in multiple myeloma. CT053 comprises autologous T cells transduced with a second-generation chimeric antigen receptor (CAR) utilizing a fully human BCMA-specific single-chain fragment variant (25C2) with high binding affinity. CT053 was firstly studied in a single-arm, open-label Phase I, investigator-initiated program (NCT03716856, NCT03302403, and NCT03380039) in eastern China. Here we present the 24-month follow-up results of the study. Methods: The multicenter exploratory Phase 1 studies included adult subjects with relapsed/ refractory multiple myeloma (RRMM) who had received at least 2 prior lines of myeloma treatment. After preconditioning treatment with fludarabine and cyclophosphamide for 2-4 days, 21 subjects received one cycle of 1.5 × 108 T cells CT053 CAR-BCMA T cells. Three subjects respectively received 0.5 × 108, 1 × 108, or 1.8 × 108 cells. The primary objective was subject safety. The secondary objectives were pharmacokinetics and efficacy. Efficacy was assessed according to IMWG 2016 criteria. Results: A total of 24 subjects with a median age of 60.1 years (range, 38.5-69.9) were enrolled from Sept. 10, 2017 to Sept. 22, 2018. The subjects had a median of 4.5 (range, 2-11) prior lines of therapy, and 41.7% (10/24) underwent autologous stem cell transplantation. At baseline, 10 subjects (41.7%) had concomitant extramedullary involvement, 8 subjects (33.3%) had ECOG scores 2-3, and 9 subjects (37.5%) reported ISS Grade III. As of June 30, 2020, 9 subjects completed 24 months of follow-up with responses including 8 stringent complete response (sCR) and 1 complete response (CR). Also, 15 subjects discontinued prior to completing the 24-month follow-up, of whom 13 discontinued due to disease progression (PD), and 2 discontinued for other anticancer therapy. The overall response rate was 87.5% (21/24) including 79.2% (19/24) with complete responses or stringent complete responses (3 CR, 16 sCR). The median duration of response (DOR) was 21.8 months (95%CI: 9.2, not evaluable [NE]). The median progression-free survival (PFS) was 18.8 months (95%CI: 10.1, NE), with 6-month and 12-month PFS rates of 87% and 60.9%, respectively. Thirteen subjects progressed with median PFS of 10.2 months (range, 0.9-23 months): 3 progressed within 6 months, 6 progressed within 6-12 months, and 4 within 12-24 months. Compared to 9 subjects with persistent CR/sCR, the 13 progressed subjects had a higher percentage of ECOG scores 2-3 (46.2% vs 22.2%), ISS Grade III (53.9% vs 11.1%) and high-risk cytogenetics profiles (53.8% vs 33.3%). Rates of concomitant extramedullary diseases were similar, 46.2% and 44.4%, respectively. Hematological toxicities were the most common treatment-related adverse events of grade (G) 3 or higher, including leukopenia (83.3%), neutropenia (85%), lymphocytopenia (79.2%) and thrombocytopenia (20.8%). In general, cytokine release syndrome (CRS) occurred at 1-4 days and resolved in a median 6 days (range, 3-9 days). Low-grade CRS was reported in 15 of 24 (62.5%) subjects. All CRS events (4 G1, 11 G2) resolved within 2-8 days; among them, 9 patients received a low dose of tocilizumab 4-6 mg/kg. One patient experienced G3 neurotoxicity, presenting as epilepsy and accompanied by simultaneous G2 CRS. This patient fully recovered within 3 days after treatment with methylprednisolone, diazepam and sodium valproate. Six patients (25%) experienced 10 cases of treatment-related serious adverse events (SAEs), including lung infection (3), gastroenteritis (1), neutropenic infection (1), fever (1) and hematological toxicities (4). By the cutoff date, one subject died of SAE a (bone morrow failure and neutropenic infection) and PD, and seven subjects died of PD. CAR-BCMA T cell expansion was detectable as early as day 1-7 after infusion and reached peak values on day 7-21 with the highest concentration at 4.5×105 copies/µg genomic DNA. Median T cell persistence was 172 days. The longest persistence of CAR-BCMA copies was measured at 341 days and continues. No immunogenicity was detected. Conclusion: These studies demonstrated that CT053 had excellent efficacy in RRMM, showing early, deep and durable response with 21.8 months DOR. CT053 was well tolerated among the subjects. Figure 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. Yuan:CARsgen Therapeutics Corp.: Current Employment. Ma:CARsgen Therapeutics Corp.: Current Employment.

Background: B cell maturation antigen (BCMA) is a potential therapeutic target in multiple myeloma. CT053 CAR-BCMA, which is a BCMA-specific chimeric antigen receptor (CAR) T cell, consists of autologous T cells genetically modified with a second-generation CAR incorporating a fully human anti-BCMA single chain fragment variant, a 4-1BB co-stimulatory domain and a CD3-zeta signaling domain. CT053 was studied in a single-arm, open-label phase I program (NCT03716856, NCT03302403, and NCT03380039) in eastern China. Methods: This investigation is a 3-site study in adult subjects with relapsed/refractory multiple myeloma (rrMM) who had received at least 2 prior myeloma regimens. Subjects received one cycle of CT053 CAR-BCMA after fludarabine/cyclophosphamide infusion. The primary objective was the assessment of subject safety. The secondary objectives were pharmacokinetics and efficacy. Efficacy was assessed according to IMWG 2016 criteria. The data cutoff date was June 30, 2019. Results: A total of 24 subjects with median age of 60.1 years (range, 38.5-69.9) were enrolled from Sep 10, 2017 to Sep 22, 2018 (Table 1). The subjects had a median of 4.5 (range, 2-11) prior regimens of therapy, and 41.7% (10/24) underwent autologous stem cell transplantation. At baseline, eleven out of 24 subjects (45.8%) had concomitant extramedullary involvement. Eight subjects (33.3%) had ECOG score 2-3, and 9 subjects (37.5%) reported ISS grade III. All subjects received lymphodepletion preconditioning of fludarabine/cyclophosphamide for 2-4 days, followed by one cycle of CT053 at a dose of 1.5 x 108 T cells except 3 subjects who received 0.5 x 108, 1 x 108, and 1.8 x 108 cells, respectively. The overall response rate was 87.5% (21/24) including 79.2% (19/24) with complete responses or stringent complete response (5 CR, 14 sCR). As shown in Figure 1, P1 who received the lowest dose of 0.5 x 108 experienced partial response (PR) at M1 and very good partial response (VGPR) at M2. P1 then converted to CR at M14 and sCR at M16. Among 20 subjects who underwent the evaluation of minimal residual disease (MRD) status, 17 achieved MRD-negative (≤10−4 nucleated cells) and reported a tumor response (17 CR/sCR). In 13 subjects with ongoing CR/sCR, the median follow-up after CT053 infusion was 383 days (range, 301-467). Nine subjects progressed with median progression-free period of 281 days (range, 57-573); among them, 5 progressed within 6-12 months, 1 at 13 months and 1 at 19 months. Compared to 13 subjects with persistent CR/sCR, the 9 progressed subjects were observed to have a higher percentage of ECOG score 2-3 (66.7% vs 15.4%), ISS Grade III (55.6% vs 15.4%), and concomitant extramedullary diseases (66.7% vs 38.5%) and a decreased hemoglobin (70g/L vs 92g/L) at baseline. Three subjects died of disease progression at the time of analysis. Hematologic toxic effects were the most common treatment-related adverse events of grade (G) 3 or higher, including white blood cell count decreased (87.5%), neutrophil count decreased (66.7%), lymphocyte count decreased (79.2%) and thrombocytopenia (25%). No dose limiting toxicities were observed. Low-grade cytokine release syndrome (CRS) was reported in 15 of 24 (62.5%) subjects. All CRS events (3 G1, 12 G2) recovered within 2-8 days; among them 8 received tocilizumab. Three subjects (12.5%) had neurotoxicity (2 G1, 1 reversible G3). One subject died of bone marrow failure and neutropenic infection. CAR-BCMA T cell expansion was detected as early as Day 1-7 after infusion and reached peak values on Day 7-21 with the highest at 4.5×105 copies/µg genomic DNA. Median T cell persistence was 172 days. The longest persistence of CAR-BCMA copies was measured at 341 days and continues. Conclusion: This study demonstrated that CT053 had an excellent efficacy and a good safety profile in subjects with rrMM. Disclosures Li: CARsgen Therapeutics Co. Ltd: Employment, Equity Ownership. Xiao:CARsgen Therapeutics Co. Ltd: Employment. WANG:CARsgen Therapeutics Co. Ltd: Employment. Yuan:CARsgen Therapeutics Co. Ltd: Employment. Ma:CARsgen Therapeutics Co. Ltd: Employment.

Introduction: B Cell Mature Antigen (BCMA)-targeted chimeric antigen receptor T (CAR-T) cell therapy emerges as promising treatment for patients with relapse/refractory multiple myeloma (RRMM). Previous studies indicate patients who receive high-dose CAR-T cells may achieve better remission but have worse adverse events, like cytokine release syndrome (CRS). To solve this dilemma, we have developed novel autologous CAR-T therapeutics CT053 that are genetically modified T cells comprising an extracellular anti-BCMA human scFv and an intracellular 4-1BB costimulatory motif connected to a CD3-zeta T cell activation domain. Methods: A multi-center investigator-initiated clinical study is designed to evaluate CT053 in patients with RRMM who have failed in the prior treatment with ≥2 regimens, including a proteasome inhibitor, an immunomodulatory agent, and anti-CD38 monoclonal antibody. All patients have ≥50% BCMA expression on malignant cells. Patients are subjected to the lymphodepletion with 20-25 mg/m2 fludarabine and 300-500 mg/m2 cyclophosphamide daily for 2-4 days prior to receiving single-dose infusion of CT053 CAR-T cells. In case of progressive disease, patient may be dosed again on basis of investigators' evaluation of the disease status, BCMA expression and CAR-T persistence. Most enrolled patients received a single dose of 1.5 x 108 cells, except for 1 patient who received 0.5 x 108 cells and 1 patient who was infused with 1.8 x 108 cells. The primary outcome measure is incidence of adverse events (AEs), including dose-limiting toxicities (DLTs) and CAR T related AEs. Additional outcome measures include clinical response assessed according to the IMWG Uniform Response Criteria for Multiple Myeloma, overall and progression-free survival, pharmacokinetics and pharmacodynamic of CT053. Results: The study was performed in compliance with the declaration of Helsinki. As of the data cut-off date (July 10th, 2018), 16 patients (median 55 [39 to 67] years old) with a median of 3.9 (0.4 to 16.7) years since MM diagnosis, were infused with CT053. Patients had a median of 4 prior different regimens (range 2 to 10), and 56% (9/16) patients received prior autologous or allogeneic stem cell transplant. Among 16 patients, no neurotoxicity and no dose-limiting toxicities (DLT) were observed. The most common grade≥3 CAR-T related AEs were 3 thrombocytopenia (19%), 3 leukopenia (19%), 2 anemia (13%), 2 neutropenia (13%), 2 fever (13%) (Figure 1A). CRS was reported in 3 patients, including 1 Grade 3, 1 Grade 2 and 1 Grade 1, who had rapid recovery after Tocilizumab administration. 13/16 patients were eligible for initial evaluation of early clinical response with a median observation period of 8 (4 to 36) weeks. Overall response rate (ORR) in 13/13 patients was 100% post treatment. 12/13 patients (92%) quickly achieved partial response (4 PR), very good PR (6 VGPR), and complete response (2 CR) within 4 weeks post single-dose infusion (Figure 1B). 5/12 patients (42%) who were dosed at ≥1.5 x 108 CT053 CAR-T cells obtained CR at a median of 8 weeks post treatment. Durable responses from 4 weeks towards the data cut-off date were found in 12/13 patients (92%). One relapse from VGPR by the Week 12 was reported in a patient who had aggressive RRMM at enrollment and received the reduced dose of lymphodepletion regimen at 19 mg/m2 fludarabine and 192 mg/m2 cyclophosphamide for 2 days prior to CT053 infusion. Because positive BCMA expression on malignant cells was verified at relapse, the patient was re-dosed with CT053 at the Week 16 and subjected to the further evaluation. All patients had detectable CAR-T expansion from Day 3 post CT053 infusion. Expansion peaks were found on Day 7 (5/13), Day 14 (6/13) and Day 21 (2/13). 11/13 patients had notable persistence of CT053 CAR-T cells up to 4-6 months. The only relapsed patient had the lowest CAR-T expansion peak among 13 patients, indicating the potential correlation between CAR-T expansion and response outcome. Conclusions: Data from this early-stage clinical study showed the unparalleled safety and efficacy of CT053 CAR-T cells. Major AEs were transient, manageable, and reversible. 100% ORR in 13/13 evaluable patients were reported post single-dose infusion of 0.5~1.8 x 108 cells. 5/12 patients who were dosed at ≥1.5 x 108 CAR-T cells rapidly achieved durable CR at median of 8 weeks, suggesting CT053 could be developed as competitive therapeutics to treat patients with RRMM. Ruan: CARsgen Therapeutics: Employment. Xiao:CARsgen Therapeutics: Employment, Equity Ownership. Wang:CARsgen Therapeutics: Employment, Equity Ownership. Li:CARsgen Therapeutics: Employment, Equity Ownership.

Objective The incidence of childhood onset myasthenia gravis (CMG) in China is higher than that in other countries; however, the reasons for this are unclear. Methods We investigated the clinical and immunological profiles of CMG, and assessed the potential precipitating factors. For the mouse studies, the possible implication of vaccination in the pathogenesis was explored. Results In our retrospective study, 51.22% of the 4,219 cases of myasthenia gravis (MG) were of the childhood onset type. The cohort study uncovered that the pathophysiology of CMG was mediated by immune deviation, rather than through gene mutations or virus infections. The administration of the live‐attenuated Japanese encephalitis vaccine (LA‐JEV), but not the inactivated vaccine or other vaccines, in mice induced serum acetylcholine receptor (AChR) antibody production, reduced the AChR density at the endplates, and decreased both muscle strength and response to repetitive nerve stimulation. We found a peptide (containing 7 amino acids) of LA‐JEV similar to the AChR‐α subunit, and immunization with a synthesized protein containing this peptide reproduced the MG‐like phenotype in mice. Interpretation Our results describe the immunological profile of CMG. Immunization with LA‐JEV induced an autoimmune reaction against the AChR through molecular mimicry. These findings might explain the higher occurrence rate of CMG in China, where children are routinely vaccinated with LA‐JEV, compared with that in countries, where this vaccination is not as common. Efforts should be made to optimize immunization strategies and reduce the risk for developing autoimmune disorders among children. Ann Neurol 2018;84:386–400

The harmless treatment and energy conversion of the sewage sludge can be implemented by pyrolysis,and the understanding of speciation distribution of the heavy metals in pyrolysis residue is particularly important.The pyrolysis experiments were conducted at different temperatures (500,600,700,800 and 900 ℃),and the contents of heavy metals in raw sludge(RS)and dewatered sludge cake(FS) were studied.The concentrations of Cu,Zn,Cr,Pb and Cd in the pyrolysis residue were determined and the speciation of heavy metals was analyzed following Tessier sequential extraction procedure.An enrichment effect of heavy metals was found during the pyrolysis process.An enrichment of Cu and Zn in the pyrolysis residue was found for the raw sludge and an enrichment of Cr,Pb and Cd was found for the FS.From the chemical state analysis of the pyrolysis residue,most of the heavy metals (Cu,Zn,Cr,Pb,Cd) were presented in a more chemical stable form than those from raw sludge.

Electro-dewatering (EDW) is an innovative method for volume reduction of sewage sludge before re utilization and disposal. In this study, dewaterability limit and energy consumption in sludge electrodewatering process were directly explored using in-situ linear sweep voltammetry (LSV) analysis by a high-voltage electrochemical workstation instead of a traditional DC power source. Dewaterability limits of biosolids EDW were identified under a constant-voltage dewatering mode with different applied voltages at 10, 20, 30, 40, and 50 V, independently. The LSV tests reveal that the dewaterability limit of sludge is attributed to the higher electrical resistance of the sludge layer near the anode. The mass of the filtrate flow was linearly proportional to the total amount of electric charge corresponding to the energy consumption in EDW, which elucidated the principal mechanism of EDW. Under a constant-voltage dewatering mode, the applied voltage is a key factor in controlling the energy consumption. Reducing the applied voltage while extending the dewatering time is proposed to reduce the energy consumption and obtain a good dewatering result. As the applied voltage decreased from 50 to 10 V, the energy consumption could be reduced from 403.6 to 80.3 kWh/m(3) removed water, the dewatering times was increased from 6.4 to 85.4 min, and the dry solids content of dewatered cake increased from 16.1 to 34.4 wt%. Those results indicate that LSV is an effective method to reveal the mechanism of EDW and optimize the operation parameters to reduce energy consumption. (C) 2017 Elsevier B.V. All rights reserved.

In this study, the influence of Na2SO4 on electro-dewatering (EDW) of waste activated sludge (WAS) was investigated. The highest water removal efficiency of 42.5% was achieved at the optimum Na2SO4 dosage of 12.5 g kg(-1) DS during EDW process at a constant voltage of 20 V. The migration and distribution of water, organic matters and Na+ at different Na2SO4 dosages were investigated through layered experiments. The results indicated the entire EDW process followed the S curve model, and it can be divided into three stages: (1) initial desalination stage: at the initial few min of EDW process, the rate of electroosmosis was extremely slow while electromigration of ions like Na+ was intense, and the electromigration was more obvious with increased Na2SO4 dosage; (2) dewatering stage: the dewatering efficiency increased dramatically via electroosmosis; (3) the dewaterability limit stage: the maximum value of dewatering efficiency has been achieved, while the water removal efficiency and dry solids content remained constant. During the EDW process, the possible electrolysis resulted in a pH gradient in the sludge cake. With the addition of Na2SO4 in the EDW, the pH gradient was intensified, and the migration rate of organic matters moving from cathode to anode increased while compared with the raw WAS. This study provided insights into the mechanism of EDW process at different dosages of Na2SO4. (C) 2017 Elsevier Ltd. All rights reserved.

The skeleton builders improve the geotechnical properties and heavy metal leaching characteristics of the dewatered sludge cakes which make them appropriate for re-use as landfill cover materials after a certain curing time.

该文在前期研究的市政污泥经Fenton试剂与赤泥复合调理,机械压滤脱水,得到深度脱水污泥泥饼的基础上,重点探讨脱水泥饼热解气化实验,首次研究了复合调理剂中不同种类赤泥对热解产气效果的影响.结果表明,经过高铁含量的澳洲矿赤泥复合调理的深度脱水泥饼热解产气量在700、800、900℃时与Fenton试剂单独调理泥饼相比均有明显提高.经过低铁含量的河南矿赤泥和印尼矿赤泥复合调理的深度脱水泥饼热解产气量仅在900℃时明显提高.经过赤泥复合调理的深度脱水泥饼在700、800、900℃时的热解产氢量都比Fenton试剂单独调理泥饼高,其中经过澳洲矿赤泥复合调理的深度脱水泥饼产氢量最高.这表明:赤泥中F2O3能够有效促进泥饼中有机物的裂解产H2、产CH4等气体,并具有裂解催化效果.

This study investigated the pyrolytic performances of deep-dewatered sludge cakes which were previously conditioned with Fenton's reagent and red mud. The pyrolytic products, including fuel gas, tar and solid char, were characterized by GC, GC-MS and FTIR. The results showed that pyrolysis of sludge cakes conditioned with Fenton's reagent and red mud produced more gas, especially higher H2 yield, compared with pyrolysis of raw sludge. In addition, red mud promoted PAHs formation and tar re-formation through side-chain-cleaving, dehydrogenation, polycondensation and aromatization of hydrocarbon during the pyrolysis, resulting in enhancement of the H2 yield. The sharp decrease in the absorbance of CHaromatic group of chars from the conditioned cakes implied that red mud could intensify the cracking and re-formation of aromatics. The higher the iron oxide content in red mud was, the better catalytic efficiency in the decomposition of organics and tar re-formation was, which led to more H2 production.

Astrocytes play important roles in homeostatic regulation in the central nervous system and are reported to influence the outcome of ischemic injury. Regulating Ca2+ signaling of astrocytes is a promising strategy for stroke therapy. Herein, we report for the first time that transient receptor potential vanilloid 2 (TRPV2), a Ca2+-permeable channel that is important in osmotic balance regulation, expresses in rat cortical astrocytes by immunofluorescence. Moreover, oxygen-glucose deprivation and reoxygenation (OGD/R) treatment enhanced the expression. The TRPV2 is functional because Ca2+ imaging showed that activating the TRPV2 channel in cultured astrocytes increased intracellular Ca2+ level and the increment of intracellular Ca2+ level expanded when astrocytes were treated with OGD/R. Staining with 5-ethynyl-2-deoxyuridine (EdU) revealed that while blocking the TRPV2, it promoted the proliferation of astrocytes. Additionally, blocking the TRPV2 in astrocytes increased the synthesis of nerve growth factor (NGF) mRNA and the secretion of NGF by real-time PCR and enzyme-linked immunosorbent assay respectively. We further found that the increased secretion of NGF could be reversed by c-JunN-terminalkinase (JNK) inhibitor and blocking the TRPV2 caused the phosphorylation of JNK. These indicated that blocking the TRPV2 induced NGF secretion via the mitogen-activated protein kinase (MAPK)-JNK signaling pathway. As the promoted proliferation of astrocytes and secretion of NGF were reported to have neuroprotective effects in the early stage of stroke, we concluded that targeting the TRPV2 channel in astrocytes might be a potential new therapeutic strategy in ischemic stroke.

Conditioning sewage sludge with Fenton's reagent could effectively improve its dewaterability. However, drawbacks of conditioning with Fenton's reagent are requirement of acidic conditions to prevent iron precipitation and subsequent neutralization with alkaline additive to obtain the pH of the filtrate close to neutrality. In this study, roles of pH were thoroughly investigated in the acidification pretreatment, Fenton reaction, and the final filtrate after conditioning. Through the response surface methodology (RSM), the optimal dosages of H2SO4, Fe2+, H2O2, and lime acted as a neutralizer were found to be 0 (no acidification), 47.9, 34.3 and 43.2 mg/g DS (dry solids). With those optimal doses, water content of the dewatered sludge cakes could be reduced to 55.8 +/- 0.6 wt, and pH of the final filtrate was 6.6 +/- 0.2. Fenton conditioning without initial acidification can simplify the conditioning process and reduce the usage of lime. The Fe3+ content in the sludge cakes showed a close correlation with the dewaterability of conditioned sludge, i.e., the water content of sludge cakes, SRF (specific resistance to filtration), CST (capillary suction time), bound water content, and specific surface area. It indicated that the coagulation by Fe3+ species in Fenton reaction could play an important role, compared to traditional Fenton oxidation effect on sludge conditioning. Thus, a two-step mechanism of Fenton oxidation and Fe(III) coagulation was proposed in sewage sludge conditioning. The mechanisms include the following: (1) extracellular polymeric substances (EPS) were firstly degraded into dissolved organics by Fenton oxidation; (2) bound water was converted to free water due to degradation of EPS; (3) the sludge particles were disintegrated into small ones by oxidation; (4) Fe3+ generated from Fenton reaction acted as a coagulant to agglomerate smaller sludge particles into larger dense particles with less bond water; (5) finally, the dewatered sludge cakes were obtained, with less small pores (1-10 nm) that contributed to water affinity, but with more large pores (>10 nm) that contributed to a permeable, rigid lattice structure. Morphology of the Fenton-conditioned sludge cake exhibited a porous structure. The estimated cost of the composite conditioner, Fenton's reagent and lime, is USD$ 43.8/t DS, which is less than that of ferric chloride and lime (USD$ 54/t DS). Furthermore, pH of the final filtrate using this composite conditioner is about 6.6. Comparatively, that using ferric chloride and lime is as high as 12.4. (C) 2016 Elsevier Ltd. All rights reserved.

Early postnatal GFAP-expressing cells are thought to be immature astrocytes. However, it is not clear if they possess multilineage capacity and if they can generate different lineages (astrocytes, neurons and oligodendrocytes) in the brain of adult mice. In order to identify the fate of astroglial cells in the postnatal brain, hGFAP-Cre-ER(T2) transgenic mice were crossed with the R26R Cre reporter mouse strains which exhibit constitutive expression of β-galactosidase (β-gal). Mice carrying the hGFAP-Cre-ER(T2)/R26R transgene were treated with Tamoxifen to induce Cre recombination in astroglial cells at postnatal (P) day 6 and Cre recombinase-expressing cells were identified by X-gal staining. Immunohistochemical staining was used to identify the type(s) of these reporter-tagged cells. Sixty days after recombination, X-gal-positive cells in different cerebral regions of the adult mice expressed the astroglial markers Blbp and GFAP, the neuronal marker NeuN, the oligodendrocyte precursor cell marker NG2 and the mature oligodendrocyte marker CC1. X-gal-positive cells in the cerebellum coexpressed the astroglial marker Blbp, but not the granule cell marker NeuN, Purkinje cell marker Calbindin or oligodendrocyte precursor cell marker NG2. Our genetic fate mapping data demonstrated that early postnatal GFAP-positive cells possessed multilineage potential and eventually differentiated into neurons, astrocytes, and oligodendrocyte precursor cells in the cerebrum and into astrocytes (including Bergmann glia) in the cerebellum of adult mice.