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A hierarchically cleaved amphiphile, mPEG-pep-etcSS-CPT, was synthesized to pursue actively targeted cancer therapy through self-assembly. This micelle can respond to MMP-2 achieving dePEGylation and releasing RGD peptides to be internalized into targetable tumor cells. Inside the cell, free CPT could be released by reduction-response leading to cytotoxicity.

Along with cytokine release syndrome (CRS) and neurotoxicity, coagulation disorder is a common early complication of chimeric antigen receptor (CAR)-T cell therapy. However, the mechanisms and prognostic significance of CAR-T-related coagulation disorders are not fully known. This study explored the possible correlation factors and prognostic significance of coagulation disorders after CAR-T cell infusion in patients with relapsed/refractory hematological malignancies.This cohort study included 56 patients with relapsed/refractory hematological malignancies who were treated with CAR-T cells between April 2017 and February 2022. The median follow-up was 26.8 months. Coagulation disorders were defined as the abnormality in at least one coagulation parameters, including prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT), fibrinogen, and D-dimer. The correlation factors of coagulation disorders were analyzed using Wilcoxon rank-sum test, Fisher's exact test, pairedThe incidence of coagulation disorders was 59% within 1 month of CAR-T cell infusion. PT prolongation, APTT prolongation, TT prolongation, and D-dimer increase peaked at a median of 6-9 days, and fibrinogen decreased to its lowest value at a median of 12 days. Coagulation disorders in patients with severe CRS were more significant (P0.001). Abnormality of coagulation parameters was closely related to cytokines, CAR-T cells, liver function parameters, and von Willebrand Factor (VWF) in both peak level and peak time (P0.05). Statistical analysis showed that coagulation disorders were associated with higher initial response rates (TT, P=0.006; D-dimer, P=0.010) and also longer progression-free survival (PFS) (PT, P=0.017; APTT, P=0.018; TT, P=0.001; Fibrinogen, P=0.003; D-dimer, P0.001) in CAR-T therapy, with TT prolongation (HR =0.279, 95% CI: 0.099-0.782, P=0.015) and D-dimer increase (HR =0.218, 95% CI: 0.087-0.548, P=0.001) independent predictors for PFS.The protection of liver and endothelial cells may reduce CAR-T-related coagulation disorders. Further, coagulation disorders occurring within 1 month of CAR-T cell infusion can serve as a new predictor for prognosis in patients with hematological malignancies.

In this paper, we study the problem of comparing the similarity and dissimilarity between two distinct vehicular trajectories by proposing an adjacency-based metric. This approach has a broad application in building truthfulness by comparing the similarity between two vehicles and evaluating the dissimilarity between two distinct paths in hazardous materials transportation. Given two sequences $A$ and $B$ of Point of Interests (POIs) visited by two vehicles in a road/transportation network, the problem is to delete some nodes from $A$ and $B$ to obtain $A'$ and $B'$ such that the number of adjacencies in $A'$ and $B'$ is maximized. In the sequences $A'$ and $B'$ duplicated nodes are allowed, e.g., to represent road edges. We prove that this problem is NP-hard when noisy POIs are deleted and all the remaining POIs must be involved in some adjacency. On the other hand, when the adjacency involvement constraint is dropped, a variation of the problem is as hard as Exact Set Cover hence cannot be approximated within a constant factor unless P=NP. At last, we design a practical approach based on local search and show that the algorithm is very effective on simulation data.

This work, two turn-on fluorescent probes (3-acetyl-2H-chromen-2-one (ACO) & (1E)-1-(1-(2-oxo-2H-chromen-3-yl)ethylidene)thiosemicarbazide (CETC)) based on coumarin have been designed and synthesized, which could selectively and sensitively recognize ClO− with fast response time. ACO & CETC were almost non fluorescent possibly due to both the lacton form of coumarin and unbridged C N bonds which can undergo a nonradiative decay process in the excited state. Upon the addition of ClO−, ACO & CETC were oxidized to ring - opened by cleavage the C O and C N and the fluorescence intensity were increased considerably. Fluorescence titration experiments showed that the detection limit ACO & CETC is as low as 22 nm and 51 nm respectively. In particular, some relevant reactive species, including OH, 1O2, H2O2, KO2, some anions and cations cannot be interference with the test. In live cell experiments, ACO & CETC were successfully applied to image exogenous ClO− in HepG2 cells. Therefore, ACO & CETC not only could image ClO− in living cells but also proved that C O and C N can be cleavage by ClO−.

A simple fluorescence switch based on Congo red (Probe 1) was developed and used to sense Cu2+. UV–vis absorption and fluorescence emission spectra showed that Probe 1 was high selectivity/sensitivity and reversible for Cu2+. Based on the chelation enhanced fluorescence (CHEF) mechanisms, Probe 1 exhibited a fluorescence “turn-on” switch signal for Cu2+. A 1: 1 binding model of Probe 1 and Cu2+ could be obtained by the Job-plot and ESI-MS. Noticeably, the color changes (from brown to colorless under visible light and from colorless to red under 365 nm UV lamp) of Probe 1 solutions for Cu2+ sensing could be observed by naked eyes. The detection limit of Probe 1 towards Cu2+may reach 10−8 M with a good linear relation in the low concentrations of Cu2+. To develop the practical application, the Cu2+ in water samples were observed. Results showed that Probe 1 was acted as a fluorescent probe could be utilized to detect the trace level of Cu2+ in the environmental samples. The reversible ‘‘off-on’’ Cu2+ response, fine cell permeability and cell imaging ability displays that Probe 1 potential application in both environmental and Cu2+ polluted biological samples.

Development of high performance fluorescent chemosensors for the detection of ClO− in vitro and in vivo is very desirable, because many human diseases are caused by ClO−. In this paper, a highly selectivity and sensitive fluorescent probe, EDPC, based on 3-acetylcoumarin, was synthesized, which could respond to ClO− and exhibit an “off–on” mode in Tris–HCl buffer (pH = 7.2, 10 mM, 50% C2H5OH) solutions. The detection limit of the EDPC probe for ClO− was as low as 1.2 × 10−8 M. Moreover, the high selectivity and high sensitivity of EDPC towards ClO− are attributed to the oxidation reaction between the C–O of the coumarin lactone and the CC formed by aldol condensation and the mechanism was further verified using ESI-MS and DFT. Additionally, the concentrations of ClO− in real water were also calculated using the EDPC probe and showed good recovery. Finally, the distribution of intracellular endogenous ClO− was gained by confocal fluorescence microscopy in living HEK293T cells.

The microenvironment of lysosomes plays an important role in various functions within cells. Abnormal pH changes in lysosomes account for multiple diseases including tumors. Acid-responsive nanomaterials with reconfigurable structures and properties have garnered significant interests. Owing to the potential in biosensing, controlled release and nanomachinery, DNA based pH-responsiveness has been widely pursued. Herein, we designed an AuNPs-i-motifs based SERS probe to monitor the pH dynamics of lysosomal maturation in different cells. Taking advantages of biocompatibility and structural flexibility of DNA, unique optical and plasmonic properties of gold nanoparticles, excellent stability and enhanced sensitivity of background-free Raman reporter, the designed SERS probe could indicate the pH variation dynamically in lysosomes. What is more valuable is that 4-mercaptobenzonitrile is not only used as a Raman reporter to provide sensitive Raman signal for pH sensing, but also used as a sealing agent allowing for controllable aggregation, to improve the stability and accuracy of the sensor. With this versatile design, the sensor was prepared simply and feasibly and a tedious trial was avoided. It provides a feasible tool for understanding the relationship of lysosomal pH with fundamental cellular functions and mechanism of diseases.

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.

A coumarin-based turn on probe, named 3-((E)-3-(1H-indol-3-yl)acryloyl)-2H-chromen-2-one(IAC) was designed and synthesized for the detection of H

It is necessary to develop simple and highly sensitive methods for the detection of hypochlorous acid (HOCl)/hypochlorite (ClO−) to ravel its relationship with disease. In this paper, a novel bio-compatible fluorescent (Z)-8-(hydrazonomethyl)-7-hydroxy-4-methyl-2H-chromen-2-one (probe 1b) based on coumarin was synthesized and used for detecting ClO− in PBS buffer (pH = 7.2, 10 mM, 60% C2H5OH). Probe 1b showed a remarkable fluorescence change from yellow to blue with the limit of detection as low as 2.4 × 10−9 M−1 when ClO− was added. The coexisted anions, metal ions and reactive oxygen species (•OH, 1O2, H2O2, KO2) showed any competitiveness towards ClO−. In response to ClO−, the fluorescence emission intensity of probe 1b was obviously enhanced within 20 s. The mechanism was confirmed by the ESI - MS and density functional theory calculations (DFT) to reveal that the coumarin lactone bonds C − O was cleavaged by oxidation of ClO−. What's more, probe 1b could be used in practical water samples and showed well recovery. Additionally, the cell imaging experiment was demonstrated that probe 1b could be effectively exploited to imaging exogenous ClO− in vitro.

This paper investigates the truthfulness establishment problem between two nodes (vehicles) in a vehicular network. We focus more on the case when no interaction has been conducted and we use the Point of Interests (POIs) visited by the two nodes (vehicles) to establish the initial truthfulness. It turns out that this is a general version of a well-studied problem in computational genomics called CMSR (Complementary Maximal Strip Recovery) in which the letters (similar to POIs) cannot be duplicated, while in our problem POIs could certainly be duplicated. We show that one version (when noisy POIs are deleted all the remaining POIs must be involved in some adjacency), is NP-hard; while the other version (with the adjacency involvement constraint is dropped), is as hard as Set Cover. We then design a practical solution based on local search for the first problem. Simulations with various synthetic data show that the algorithm is very effective.

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.

A coumarin-based turn on probe, named 3-((E)-3-(1H-indol-3-yl)acryloyl)-2H-chromen-2-one(IAC) was designed and synthesized for the detection of H2S in aqueous medium. IAC showed no obvious red fluorescence in Tris-HCl(pH = 7.2, 60% DMF), a 28.2-fold fluorescence enhancement was found when 40 equiv. H2S was added. Other analytes such as anions, metal ions and GSH, Cys, Gly did no significant fluorescence enhancement at 580 nm to IAC. The red fluorescence enhancement mechanism between IAC and H2S was considered by DFT and ESI-MS. Overall, IAC was successfully applied in cell imaging.

This paper addresses the problem of operating room (OR) scheduling by taking into account the factors such as surgeons and his(her) surgical patients with type and time, the admissibility of different surgical types to a certain operating room and the available time of operating rooms. In order to improve operating rooms efficiency and shorten the waiting time of surgical patients, we propose two 0–1 integer programming models, as well as the simulated data, and get the relatively ideal scheduling scheme.