Despite worldwide promising clinical outcome of CD19 CART therapy, relapse after this therapy is associated with poor prognosis and has become an urgent problem to be solved. We conducted a CD22 CAR T-cell therapy in 34 relapsed or refractory (r/r) BALL pediatric and adult patients who failed from previous CD19 CAR T-cell therapy. Complete remission (CR) or CR with incomplete count recovery (CRi) was achieved in 24 of 30 patients (80%) that could be evaluated on day 30 after infusion, which accounted for 70.5% of all 34 enrolled patients. Most patients only experienced mild cytokine-release syndrome and neurotoxicity. Seven CR patients received no further treatment, and 3 of them remained in remission at 6, 6.6, and 14 months after infusion. Eleven CR patients were promptly bridged to transplantation, and 8 of them remained in remission at 4.6 to 13.3 months after transplantation, resulted in 1-year leukemia-free survival rate of 71.6% (95% CI, 44.2-99.0). CD22 antigen loss or mutation was not observed to be associated with relapsed patients. Our study demonstrated that our CD22 CAR T-cells was highly effective in inducing remission in r/r BALL patients, and also provided a precious window for subsequent transplantation to achieve durable remission.

Lys63-linked polyubiquitination of TAK1 plays an important role in TNFα-induced NF-κB activation. Using a functional genomic approach, we have identified Ubiquitin Specific Peptidase 4 (USP4) as a deubiquitinase for TAK1. USP4 deubiquitinates TAK1 in vitro and in vivo. TNFα induces association of USP4 with TAK1 to deubiquitinate TAK1 and downregulate TAK1-mediated NF-κB activation. Overexpression of USP4 wild-type, but not deuibiquitinase-deficient C311A mutant, inhibits both TNFα- and TAK1/TAB1 co-overexpression-induced TAK1 polyubiquitination and NF-κB activation. Notably, knockdown of USP4 in HeLa cells enhances TNFα-induced TAK1 polyubiquitination, IKK phosphorylation, IκBα phosphorylation and ubiquitination as well as NF-κB-dependent gene expression. Moreover, USP4 negatively regulates IL-1β-, LPS-and TGFβ-induced NF-κB activation. Together, our results demonstrate that USP4 serves as a critical control to downregulate TNFα-induced NF-κB activation through deubiquitinating TAK1.

Perforated single-layered graphene has demonstrated selectivity and flux that is orders of magnitude greater than state-of-the-art polymer membranes. However, only individual graphene sheets with sizes up to tens of micrometers have been successfully fabricated for pressurized permeation studies. Scaling-up and reinforcement of these atomic membranes with minimum cracks and pinholes remains a major hurdle for practical applications. We develop a large-area in situ, phase-inversion casting technique to create 63 cm high-quality single-layered perforated graphene membranes for ultrafast nanofiltration that can operate at pressures up to 50 bar. This result demonstrates the feasibility of our technique for creating robust large-area, high quality, single-layered graphene and its potential use as a pressurized nanofiltration membrane.

The removal and inactivation of waterborne pathogens from drinking water are important for human health. Here, a polyacrylonitrile/polyaniline/silver nanowires-carbon fiber cloth (PAN/PANI/AgNWs-CC) composite nanofiber membrane was fabricated using a simple and rapid coelectrospinning process, and an electrical device was applied with the PAN/PANI/AgNWs-CC filter for water electrochemical disinfection. The effects of voltage, flow rate, and microbial concentration on the filtration and electrochemical disinfection performance of the nanocomposite membrane were investigated. The characterization results show that PAN/PANI/AgNWs with uniform diameters and without beads were successfully fabricated on CC. AgNWs were uniformly distributed in the PAN/PANI/AgNWs. The PAN/PANI/AgNWs-CC filter was an effective sieve for completely removing both Escherichia coli and Staphylococcus aureus in the absence of applied voltage, and the sieved bacteria were completely inactivated by the released silver within 8 h. Over 99.999% inactivation of the sieved bacteria was achieved within a few seconds by concurrent filtration and electrochemical disinfection under a voltage of 3 V. This high performance is enabled by means of an electrical mechanism, and an extremely high electric field induces sharp AgNWs tips to generate electroporated pores in the bacteria. The electrochemical PAN/PANI/AgNWs-CC membrane is an excellent material with potential application value in point-of-use drinking water treatment.

Summary Although chimeric antigen receptor T cells (CAR‐T) targeted at CD19 or CD22 have achieved high complete remission (CR) in refractory/relapsed B‐cell acute lymphoblastic leukaemia (B‐ALL), it is uncertain if allogeneic haematopoietic stem cell transplantation (allo‐HSCT) should be performed after CAR‐T therapy to accomplish a sustainable remission. Fifty‐two cases with relapsed/refractory B‐ALL who underwent allo‐HSCT after CR by CD19 or CD22 CAR‐T were enrolled. The median time from CAR‐T infusion to allo‐HSCT was 50 (34–98) days. Myeloablative reduced‐intensity conditioning (RIC) with total body irradiation/fludarabine‐based or busulfan/fludarabine‐based regimens was used. Incidences of grade II–IV acute graft‐versus‐host disease (aGVHD) and severe aGVHD were 23·1% and 5·8% respectively. Of 48 evaluable cases, 16 developed chronic GVHD (cGVHD) and in three of them the pattern was extensive. With a median follow‐up of 334 (41–479) days, one‐year overall survival and event‐free survival (EFS) were 87·7% and 73·0%. One‐year relapse rate and transplant‐related mortality (TRM) were 24·7% and 2·2% respectively. With quick bridge to allo‐HSCT after CAR‐T therapy, high EFS for refractory/relapsed B‐ALL has been achieved in this relatively large cohort. Our myeloablative RIC regimens have resulted in low incidences of aGVHD, cGVHD, viral reactivation and very low TRM even majority of transplants from haploidentical donors. Long‐term follow‐up is warranted.