A versatile double‐network (DN) hydrogel with two noncovalent crosslinked networks is synthesized by multiple hydrogen bonding (H‐bonding) interactions. The DN hydrogels are synthesized via a ...heating–cooling photopolymerization process by adding all reactants of agar, N‐acryloyl glycinamide (NAGA) and N‐benzylacrylamide (NBAA) monomers, UV initiators to a single water pot. Poly(N‐acryloyl glycinamide‐co‐N‐benzyl acrylamide) (P(NAGA‐co‐NBAA)) with a triple amide in one side group is synthesized via UV‐light polymerization between NAGA and NBAA, forming a strong intermolecular H‐bonding network. Meanwhile, the intramolecular H‐bonding network is formed between P(NAGA‐co‐NBAA) and agars. The sol–gel phase transition of agars at 86 °C generates the molecular entanglement network. Such a double network enables the hydrogel high self‐healing efficiency (about 95%), good shape memory ability, and high mechanical strength (1.1 MPa). Additionally, the DN hydrogel is completely crosslinked by multiple hydrogen bonds (H‐bonds) and the physical crosslinking of agar without extra potential toxic chemical crosslinker. The DN hydrogels find extensive applications in the biomedical materials due to their excellent biocompatibility.
Poly(N‐acryloyl glycinamide‐co‐N‐benzyl acrylamide)/agar double‐network hydrogels crosslinked by multiple hydrogen bonds are synthesized. The double network gives the hydrogel high self‐healing efficiency (about 95%), high mechanical strength (1.1 MPa), and good shape memory ability.
Elderly patients with relapsed and refractory acute lymphoblastic leukemia (ALL) have poor prognosis. Autologous CD19 chimeric antigen receptor-modified T (CAR-T) cells have potentials to cure ...patients with B cell ALL; however, safety and efficacy of allogeneic CD19 CAR-T cells are still undetermined.
We treated a 71-year-old female with relapsed and refractory ALL who received co-infusion of haplo-identical donor-derived CD19-directed CAR-T cells and mobilized peripheral blood stem cells (PBSC) following induction chemotherapy. Undetectable minimal residual disease by flow cytometry was achieved, and full donor cell engraftment was established. The transient release of cytokines and mild fever were detected. Significantly elevated serum lactate dehydrogenase, alanine transaminase, bilirubin and glutamic-oxalacetic transaminase were observed from days 14 to 18, all of which were reversible after immunosuppressive therapy.
Our preliminary results suggest that co-infusion of haplo-identical donor-derived CAR-T cells and mobilized PBSCs may induce full donor engraftment in relapsed and refractory ALL including elderly patients, but complications related to donor cell infusions should still be cautioned.
Allogeneic CART-19 for Elderly Relapsed/Refractory CD19+ ALL. NCT02799550.
Autologous CD19-targeted chimeric antigen receptor-modified T cells (CD19-CART) remarkably improved the outcome of patients with advanced B-cell acute lymphoblastic leukemia (B-ALL). However, the ...application and outcomes of allogeneic CART cells is still uncertain. Two patients with advanced B-ALL were enrolled to receive a co-infusion of high-dose human leukocyte antigen-haploidentical donor granulocyte colony-stimulating factor mobilized peripheral blood mononuclear cells (GPBMCs; 21.01–25.34 × 108/kg) and the same donor-derived CD19-targeted CART cells (8.44–22.19 × 106/kg) without additional in vitro gene-editing following a reinduction chemotherapy as precondition. They achieved complete remission and full donor chimerism (FDC) with ongoing 20- and 4-month leukemia-free survival. A significant amplification of donor CART cells was detected in peripheral blood and/or cerebrospinal fluid and was associated with the formation of FDC. The highest amount of copies of the donor CART cells reached 4962 per µg of genomic DNA (gDNA) and 2449 per µg of gDNA, and the longest persistence was 20 months associated with B cell aplasia. Two patients experienced Grade II or III cytokine release syndromes and developed controllable Grade II intestinal acute graft-versus-host disease (GVHD) or limited chronic oral GVHD. High-dose donor GPBMC infusion may enhance amplification and persistence of haploidentical CD19-targeted CART cells, suggesting an alternative therapy for advanced B-ALL patients.
Background The JAK2-STAT signaling pathway plays a critical role in myeloproliferative neoplasms (MPN). An activating mutation in JAK2 (V617F) is present in ~ 95% of polycythemia vera, essential ...thrombocythemia, and primary myelofibrosis cases. This study aims to explore the selective JAK2.sup.V617F inhibitor, evaluate the efficacy and possible mechanism of ZT55 on MPN. Methods HTRF assays were conducted to evaluate the selective inhibition of ZT55 for JAKs. Cell apoptosis, proliferation, and cycle arrest assays were performed to examine the effect of ZT55 on HEL cell line with JAK2.sup.V617F mutation in vitro. Western analysis was used to monitor the expression and activity of proteins on JAK2/STAT pathway. A mice xenograft model was established to evaluate the antitumor efficacy of ZT55 in vivo. Peripheral blood samples from patients with the JAK2.sup.V617F mutation were collected to estimate the effect of ZT55 on erythroid colony formation by colony-forming assay. Results We found that ZT55 showed a selective inhibition of a 0.031 muM IC.sub.50 value against JAK2. It exhibited potent effects on the cellular JAK-STAT pathway, inhibiting tyrosine phosphorylation in JAK2.sup.V617F and downstream STAT3/5 transcription factors. ZT55 inhibited the proliferation of the JAK2.sup.V617F-expressing HEL cell line, leading to cell cycle arrest at the G.sub.2/M phase and induction of caspase-dependent apoptosis. Notably, ZT55 also significantly suppressed the growth of HEL xenograft tumors in vivo. Further evaluation indicated that ZT55 blocked erythroid colony formation of peripheral blood hematopoietic progenitors from patients carrying the JAK2.sup.V617F mutation. Conclusion These results suggest that ZT55 is a highly-selective JAK2 inhibitor that can induce apoptosis of human erythroleukemia cells by inhibiting the JAK2-STAT signaling. Keywords: JAK2.sup.V617F, JAK2 inhibitor, Myeloproliferative neoplasms, Apoptosis, ZT55
Photothermal-induced self-healable and shape memory materials have drawn much attention due to the rapidly growing technical applications and environmental requirements. As epoxy natural rubber (ENR) ...is a kind of bio-based elastomer with good mechanical properties, weather resistance, and air impermeability, it is of great significance to incorporate ENR with recyclable, photothermal-induced self-healable and shape memory properties. In this study, we report a simple method to cross-link ENR with dodecanedioic acids (DAs) through esterification reaction, and during the cross-linking process, a little aniline trimer (ACAT, a kind of oligoaniline) was added at the same time. Then, the ENR-DA-ACAT vitrimers that were covalently cross-linked with recyclable, self-healable, and multiple responsive properties were obtained, which also possessed various functions. As a result of the transesterification reactions at elevated temperatures, the ENR-based vitrimers possess the ability to be reprocessed and self-healed, and the mechanical properties could be maintained even after three consecutive breaking/mold pressing cycles. Besides, the vitrimer is also responsive to near-infrared (NIR) light and pH with the introduction of ACAT, and we also find that ACAT can be used as a catalyst to accelerate the transesterification reaction. Moreover, it is demonstrated that the ENR-DA-ACAT vitrimer could also be used to construct the reconfigurable shape memory polymer; the shape fixing ratio and shape recovery ratio are both above 95% in the reconfiguration process, and the multistage shape memory performance can also be achieved by NIR irradiation, which will potentially lead to a wide application for ENR in the field of actuators.
Vitrimer is a new class of polymeric materials which can be reprocessed to any shape while being permanently cross-linked. We designed and synthesized a catalyst-free network with ...poly(dimethylsiloxane)etherimide (PDMS-NH2), terephthalaldehyde (TA), and tri(2-aminoethyl)amine (TREA) through the condensation reaction between amino groups and aldehyde groups. As a result of the exchange reaction of the dynamic imine bond obtained, this PDMS network exhibits the nature of vitrimer-like material, which is examined by solubility and stress-relaxation experiments, and the relaxation time is as short as 64 s at 130 °C. In addition, the vitrimer-like PDMS is malleable and capable of self-healing, and the mechanical properties can be maintained even after three consecutive breaking/mold pressing cycles. Especially, besides heating, this vitrimer-like PDMS can also be recycled and reshaped at ambient temperature due to the exchange reaction of dynamic imine bond when immersed in water, which will potentially lead to green processing of the elastomers.
The Keriyan people live in an isolated village in the Taklimakan Desert in Xinjiang, Western China. The origin and migration of the Keriyans remains unclear. We studied paternal and maternal genetic ...variance through typing Y-STR loci and sequencing the complete control region of the mtDNA and compared them with other adjacent populations. Data show that the Keriyan have relatively low genetic diversity on both the paternal and maternal lineages and possess both European and Asian specific haplogroups, indicating Keriyan is an admixture population of West and East. There is a gender-bias in the extent of contribution from Europe vs. Asia to the Keriyan gene pool. Keriyans have more genetic affinity to Uyghurs than to Tibetans. The Keriyan are not the descendants of the Guge Tibetans.
Clinical studies have shown that NST has better therapeutic results with chronic myelogenous leukemia (CML) than acute leukemia (AL), but whether the generation of graft-versus-leukemia (GVL) effects ...is different between AL and CML patients early after NST has not yet been studied, so we used a pentamer-staining technique in combination with ICCS to detect WT1
+
CD8
+
CTL/WT1
+
Tc1 and WT1
+
Th1 cells in these two groups of patients. Results showed that the emergence time of WT1
+
CD
8
+
CTL/WT1
+
Tc1 cells after NST in AL patients was similar to that in CML patients (
P
= 0.58), while the emergence time of WT1
+
Th1 cells after NST in AL patients was shorter than in CML patients (
P
= 0.047). Furthermore, the peak proportions of WT1
+
CD
8
+
CTL/WT1
+
Tc1 (
P
> 0.05) and WT1
+
Th1 (
P
> 0.05) cells were similar between AL and CML patients, and the increased rates (
P
> 0.05) and elevated levels (
P
> 0.05) of WT1-specific T cells were not statistically different between the groups after G-CSF mobilized donor mononuclear cell infusion. In addition, the reconstruction of lymphocyte subsets (
P
> 0.05) and CD4/8 ratios (
P
> 0.05) in AL patients were not statistically different from those in CML patients within 180 days after NST. These results suggested that WT1 maybe induces similar GVL effects in both AL and CML patients early after NST.
Based on the adhesive mechanism of mussels, we present a facile strategy to prepare nanocomposite polydopamine–poly(N-acryloyl glycinamide)–graphene oxide (PDA–PNAGA–GO) hydrogels with lots of ...catechol groups in the matrix of hydrogel. The microfibril structure formed by PDA chains enables the hydrogels high stretchability (∼1500%) and toughness (6990 J/m2); the multiple hydrogen bonding interactions and π–π interactions among the PNAGA network and PDA chains also enable a hydrogel perfect self-healing performance. Moreover, GO in the hydrogel can absorb the near-infrared irradiation, resulting in the temperature difference between the surface and bottom area and then a bending deformation (with 40% of actuation degree) of the hydrogel. Besides, the GO can also make the hydrogels electrically conductive, and the self-healing efficiency (∼87% for the first healing) could also be calculated according to the retention rate of conductivity of hydrogel after being healed at 90 °C. The unique properties will enable the PDA–PNAGA–GO hydrogels to be widely used in the field of tissue engineering and soft actuators.
We developed a new technique to in situ exfoliate graphite into graphene nanosheets and simultaneously prepare graphene nanosheets/elastomer composites based on the Diels–Alder (DA) reaction under ...strong shearing force transferred by the hydrogenated nitrile butadiene rubber (HNBR) during melt mixing. To realize the DA reaction, expanded graphite (EG) was used as a diene and maleic anhydride (MA) was chosen as the dienophile. The results show the efficient functionalization and exfoliation of EG into MA-functionalized graphene nanosheets (MAG), the good dispersion of MAG, and the formation of the MAG network structure in MAG/HNBR composites at low content of MAG (∼1 wt %). These result in the significant increase in stress at certain strain and the electrical conductivity of MAG/HNBR composites over that of neat HNBR and EG/HNBR composites with 1 wt % MAG. Unlike the method used in solution, this method could be applied in industry for large-scale preparation of graphene nanosheets and their elastomer composites.
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