Sepsis is a systemic inflammatory response syndrome caused by infection, resulting in organ dysfunction. Sepsis‐induced acute kidney injury (AKI) is one of the most common potential complications. ...Increasing reports have shown that M1 and M2 macrophages both take part in the progress of AKI by influencing the level of inflammatory factors and the cell death, including pyroptosis. However, whether M1 and M2 macrophages regulate AKI by secreting exosome remains unknown. In the present study, we isolated the exosomes from M1 and M2 macrophages and used Western blot and enzyme‐linked immunosorbent assay (ELISA) to investigate the effect of M1 and M2 exosomes on cell pyroptosis. miRNA sequencing was used to identify the different miRNA in M1 and M2 exosomes. Luciferase reporter assay was used to verify the target gene of miRNA. We confirmed that exosomes excreted by macrophages regulated cell pyroptosis in vitro by using Western blot and ELISA. miRNA sequencing revealed the differentially expressed level of miRNAs in M1 and M2 exosomes, among which miR‐93‐5p was involved in the regulation of pyroptosis. By using bioinformatics predictions and luciferase reporter assay, we found that thioredoxin–interacting protein (TXNIP) was a direct target of miR‐93‐5p. Further in vitro and in vivo experiments indicated that exosomal miR‐93‐5p regulated the TXNIP directly to influence the pyroptosis in renal epithelial cells, which explained the functional difference between different phenotypes of macrophages. This study might provide new targets for the treatment of sepsis‐induced AKI.
This study re-examines the healthy migrant phenomenon in China’s internal migration process and investigates the different trajectories of place of origin on migrants’ self-rated physical health and ...psychological distress. Data came from a household survey (N = 1474) conducted in Beijing between May and October in 2009. Multiple regression techniques were used to model the associations between self-rated physical health, psychological distress, and migration experience, controlling for sociodemographic characteristics. The healthy migrant phenomenon was observed among migrants on self-rated physical health but not on psychological distress. Different health status trajectories existed between physical health versus mental health and between rural-to-urban migrants versus urban-to-urban migrants. The study draws particular attention to the diminishing physical health advantage and the initial high level of psychological distress among urban-to-urban migrants. The initial physical health advantage indicates that it is necessary to reach out to the migrant population and provide equal access to health services in the urban area. The high level of psychological distress suggests that efforts targeting mental health promotion and mental disorder prevention among the migrant population are an urgent need. The findings of the study underline the necessity to make fundamental changes to the restrictive hukou system and the unequal distribution of resources and opportunities in urban and rural areas. These changes will lessen the pressure on big cities and improve the living conditions and opportunities of residents in townships/small cities and the countryside.
Background LCAR-B38M is a chimeric antigen receptor T cell product with two binding domains targeting B cell maturation antigen. Our previous reports showed a remarkable efficacy of LCAR-B38M in ...patients with relapsed/refractory multiple myeloma (RRMM) at a median follow-up of 2 years. Here, we report long-term safety and efficacy data from a median follow-up of 4 years. Methods LEGEND-2 was a phase 1, single-arm, open-label study conducted in four registered sites in China. Seventy-four participants with RRMM received LCAR-B38M treatment. Lymphodepletion was performed using cyclophosphamide or cyclophosphamide plus fludarabine. LCAR-B38M, at a median dose of 0.513 x 10.sup.6 cells/kg, was intravenously administered either in three split infusions or in a single infusion. The primary objective was the safety of LCAR-B38M, and the secondary objective was efficacy. Results As of May 25, 2021, the median follow-up was 47.8 months. All patients experienced greater than or equal to 1 adverse events (AEs). Grade greater than or equal to 3 AEs were observed in 45/74 (60.8%) patients. Cytokine release syndrome (CRS) occurred in 68/74 (91.9%) cases; 7 (9.5%) had grade greater than or equal to 3 CRS. One patient experienced grade 1 central nervous system toxicity. The overall response rate was 87.8%. Fifty-four out of 74 (73.0%) patients achieved complete response. The median progression-free survival was 18.0 months, and the median overall survival for all patients was not reached. The median duration of response was 23.3 months. Four patients experienced viral infection more than 6 months post-infusion, and four patients developed second primary non-hematological malignancies at a median time of 11.5 months post-CAR-T cell transfer. Conclusions The 4-year follow-up data of LCAR-B38M therapy demonstrated a favorable long-term safety profile and a durable response in patients with RRMM. Trial registration Clinicaltrials.gov NCT03090659 (retrospectively registered on March 27, 2017); ChiCTR-ONH-17012285. Keywords: Multiple myeloma, Chimeric antigen receptor therapy, B cell maturation antigen, Safety, Efficacy
The autologous anti-B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T-cell therapy LCAR-B38M has been approved for the treatment of relapsed and refractory multiple myeloma in many ...countries across the world under the name ciltacabtagene autoleucel. LEGEND-2 was the first-in-human trial of LCAR-B38M and yielded deep and durable therapeutic responses. Here, we reported the outcomes in LEGEND-2 after a minimal 5-year follow-up.
Participants received an average dose of 0.5 × 10
cells/kg LCAR-B38M in split or single unfractionated infusions after cyclophosphamide-based lymphodepletion therapy. Investigator-assessed response, survival, safety and pharmacokinetics were evaluated.
Seventy-four participants enrolled and had a median follow-up of 65.4 months. The 5-year progression-free survival (PFS) and overall survival (OS) rates were 21.0% and 49.1%, with progressive flattening of the survival curves over time. Patients with complete response (CR) had longer PFS and OS, with 5-year rates of 28.4% and 65.7%, respectively. Twelve patients (16.2%) remained relapse-free irrespective of baseline high-risk cytogenetic abnormality and all had normal humoral immunity reconstituted. An ongoing CR closely correlated with several prognostic baseline indices including favorable performance status, immunoglobulin G subtype, and absence of extramedullary disease, as well as a combination cyclophosphamide and fludarabine preconditioning strategy. Sixty-two (83.8%) suffered progressive disease (PD) and/or death; however, 61.1% of PD patients could well respond to subsequent therapies, among which, the proteasome inhibitor-based regimens benefited the most. Concerning the safety, hematologic and hepatic function recovery were not significantly different between non-PD and PD/Death groups. A low rate of second primary malignancy (5.4%) and no severe virus infection were observed. The patients who tested positive for COVID-19 merely presented self-limiting symptoms. In addition, a sustainable CAR T population of one case with persistent remission was delineated, which was enriched with indolently proliferative and lowly cytotoxic CD4/CD8 double-negative functional T lymphocytes.
These data, representing the longest follow-up of BCMA-redirected CAR T-cell therapy to date, demonstrate long-term remission and survival with LCAR-B38M for advanced myeloma.
LEGEND-2 was registered under the trial numbers NCT03090659, ChiCTRONH-17012285.
The exploration of high nuclearity molecular metal oxide clusters and their reactivity is a challenge for chemistry and materials science. Herein, we report an unprecedented giant molecular ...cerium–bismuth tungstate superstructure formed by self‐assembly from simple metal oxide precursors in aqueous solution. The compound, {W14CeIV6O61(W3Bi6CeIII3(H2O)3O14B‐α‐BiW9O333)2}34− was identified by single‐crystal X‐ray diffraction and features 104 metal centers, a relative molar mass of ca. 24 000 and is ca. 3.0×2.0×1.7 nm3 in size. The cluster anion is assembled around a central {Ce6} octahedron which is stabilized by several molecular metal oxide shells. Six trilacunary Keggin anions (B‐α‐BiW9O339−) cap the superstructure and limit its growth. In the crystal lattice, water‐filled channels with diameters of ca. 0.5 nm are observed, and electrochemical impedance spectroscopy shows pronounced proton conductivity even at low temperature.
A giant cerium–bismuth tungstate cluster featuring more than 100 metal ions and a relative molar mass of approximately 24 000 is structurally characterized. The cluster anions form a highly 3D‐porous crystalline lattice featuring water‐filled channels. Proton conductivity measurements show high proton mobility within the framework.
Chemoresistance, whether intrinsic or acquired, is a major obstacle in the treatment of cancer. The resistance of cancer cells to chemotherapeutic drugs can result from various mechanisms. Over the ...last decade, it has been reported that 1ong noncoding RNAs (lncRNAs) can mediate carcinogenesis and drug resistance/sensitivity in cancer cells. This article reviews, in detail, recent studies regarding the roles of lncRNAs in mediating drug resistance.
Relapsed and refractory (R/R) multiple myeloma (MM) patients have very poor prognosis. Chimeric antigen receptor modified T (CAR T) cells is an emerging approach in treating hematopoietic ...malignancies. Here we conducted the clinical trial of a biepitope-targeting CAR T against B cell maturation antigen (BCMA) (LCAR-B38M) in 17 R/R MM cases. CAR T cells were i.v. infused after lymphodepleting chemotherapy. Two delivery methods, three infusions versus one infusion of the total CAR T dose, were tested in, respectively, 8 and 9 cases. No response differences were noted among the two delivery subgroups. Together, after CAR T cell infusion, 10 cases experienced a mild cytokine release syndrome (CRS), 6 had severe but manageable CRS, and 1 died of a very severe toxic reaction. The abundance of BCMA and cytogenetic marker del(17p) and the elevation of IL-6 were the key indicators for severe CRS. Among 17 cases, the overall response rate was 88.2%, with 13 achieving stringent complete response (sCR) and 2 reaching very good partial response (VGPR), while 1 was a nonresponder. With a median follow-up of 417 days, 8 patients remained in sCR or VGPR, whereas 6 relapsed after sCR and 1 had progressive disease (PD) after VGPR. CAR T cells were high in most cases with stable response but low in 6 out of 7 relapse/PD cases. Notably, positive anti-CAR antibody constituted a high-risk factor for relapse/PD, and patients who received prior autologous hematopoietic stem cell transplantation had more durable response. Thus, biepitopic CAR T against BCMA represents a promising therapy for R/R MM, while most adverse effects are clinically manageable.
The hierarchical aggregation of molecular nanostructures from multiple components is a grand synthetic challenge, which requires highly selective linkage control. We demonstrate how two orthogonal ...linkage groups, that is, organotin and lanthanide cations, can be used to drive the aggregation of a giant molecular metal oxide superstructure. The title compound {(Sn(CH3)2)2O4{CeW5O18 TeW4O16CeSn(CH3)24TeW8O314}2}46− (1 a) features dimensions of ca. 2.2×2.3×3.4 nm3 and a molecular weight of ca. 25 kDa. Structural analysis shows the hierarchical aggregation from several independent subunits. Initial biomedical tests show that 1 features an inhibitory effect on the proliferation of HeLa cells based on an apoptosis pathway. In vivo experiments in mice reveal the antiproliferative activity of 1 and open new paths for further development of this new compound class.
Hierarchical assembly of a giant heterometallic polyoxotungstate supercluster with a molecular weight of ca. 25 kDa is reported. Geometrically unrestricted cerium(III) and geometrically restricted dimethyl tin cation linkers are used to gain access to a giant molecular species featuring three different polyoxometalate building units. The compound demonstrates in vitro and in vivo antiproliferative activity against HeLa cervical cancer cell lines.
Polymeric carbon nitride (PCN) as a class of two‐electron oxygen reduction reaction (2 e− ORR) photocatalyst has attracted much attention for H2O2 production. However, the low activity and inferior ...selectivity of 2 e− ORR greatly restrict the H2O2 production efficiency. Herein, we develop a new strategy to synthesize hydrophilic, fragmented PCN photocatalyst by the terminating polymerization (TP‐PCN) effect of iodide ions. The obtained TP‐PCN with abundant edge active sites (AEASs), which can form quasi‐homogeneous photocatalytic system, exhibits superior H2O2 generation rate (3265.4 μM h−1), far surpassing PCN and other PCN‐based photocatalysts. DFT calculations further indicate that TP‐PCN is more favorable for electron transiting from β spin‐orbital to the π* orbitals of O2, which optimizes O2 activation and reduces the energy barrier of H2O2 formation. This work provides a new concept for designing functional photocatalysts and understanding the mechanism of O2 activation in ORR for H2O2 production.
Iodide ions are utilized as an inhibitor for terminating the polymerization of PCN (TP‐PCN). The resulting ultrathin and small‐sized TP‐PCN have abundant edge active sites (AEASs). They greatly enhance the O2 adsorption/activation capacity and the 2 e− oxygen reduction reaction (ORR) selectivity. As expected, the TP‐PCN affords a remarkably increased photocatalytic H2O2 production activity.
To improve the aqueous solubility and cancer targeting of the photosensitizers in photodynamic therapy (PDT), we encapsulated the photosensitizer in a biocompatibility and pH-sensitive drug delivery ...system, zeolitic imidazolate frameworks-8 (ZIF-8) nanospheres. Powder X-ray diffraction and electron microscopy show that our nanospheres are uniform and single-crystalline particles. Owing to the cleavage of zinc–ligand coordination bonds, more ZnPc–COOH were released much faster in the mild acidic conditions (pH 5.0 and 6.0) in comparison with physiological environment (pH 7.4). By incorporating ZnPc–COOH in ZIF-8, our nanospheres exhibited high singlet oxygen quantum yield and intracellular ROS generation. Cell viability experiments toward HepG2 cells demonstrated the low toxicity of ZIF-8 and the good anticancer efficacy of the nanospheres with low IC
50
values (4.2–4.9 μg/mL) under light illumination (670 nm, 1.5 J/cm
2
). Collectively, these results suggested that our nanospheres are the promising pH-responsive drug delivery systems for PDT.
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