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Claudin18.2 (CLDN18.2) is highly expressed with the development of various malignant tumors, especially gastrointestinal cancers, and is emerging as a new target for cancer treatment. Satricabtagene autoleucel (satri-cel)/CT041 is an autologous chimeric antigen receptor (CAR) T cell targeting CLDN18.2, and the interim results of the CT041-CG4006 trial were reported in June 2022. Here we present the final results of this single-arm, open-label, phase 1 trial, which evaluated the safety and efficacy of satri-cel in patients with CLDN18.2-positive advanced gastrointestinal cancers. This trial included a dose-escalation stage (n= 15) and a dose-expansion stage in four different cohorts (total n= 83): cohort 1, satri-cel monotherapy in 61 patients with standard chemotherapy-refractory gastrointestinal cancers; cohort 2, satri-cel plus anti-PD-1 therapy in 15 patients with standard chemotherapy-refractory gastrointestinal cancers; cohort 3, satri-cel as sequential treatment after first-line therapy in five patients with gastrointestinal cancers; and cohort 4, satri-cel monotherapy in two patients with anti-CLDN18.2 monoclonal antibody-refractory gastric cancer. The primary endpoint was safety; secondary endpoints included efficacy, pharmacokinetics and immunogenicity. A total of 98 patients received satri-cel infusion, among whom 89 were dosed with 2.5 × 108, six with 3.75 × 108and three with 5.0 × 108CAR T cells. Median follow-up was 32.4 months (95% confidence interval (CI): 27.3, 36.5) since apheresis. No dose-limiting toxicities, treatment-related deaths or immune effector cell-associated neurotoxicity syndrome were reported. Cytokine release syndrome occurred in 96.9% of patients, all classified as grade 1–2. Gastric mucosal injuries were identified in eight (8.2%) patients. The overall response rate and disease control rate in all 98 patients were 38.8% and 91.8%, respectively, and the median progression-free survival and overall survival were 4.4 months (95% CI: 3.7, 6.6) and 8.8 months (95% CI: 7.1, 10.2), respectively. Satri-cel demonstrates therapeutic potential with a manageable safety profile in patients with CLDN18.2-positive advanced gastrointestinal cancer. ClinicalTrials.gov identifier: NCT03874897.

Despite success in hematologic malignancies, the treatment landscape of chimeric antigen receptor (CAR) T cell therapy for solid tumors remains limited. Claudin18.2 (CLDN18.2)-redirected CAR T cells showed promising efficacy against gastric cancer (GC) in a preclinical study. Here we report the interim analysis results of an ongoing, open-label, single-arm, phase 1 clinical trial of CLDN18.2-targeted CAR T cells (CT041) in patients with previously treated, CLDN18.2-positive digestive system cancers (NCT03874897). The primary objective was safety after CT041 infusion; secondary objectives included CT041 efficacy, pharmacokinetics and immunogenicity. We treated 37 patients with one of three CT041 doses: 2.5 × 108, 3.75 × 108or 5.0 × 108cells. All patients experienced a grade 3 or higher hematologic toxicity. Grade 1 or 2 cytokine release syndrome (CRS) occurred in 94.6% of patients. No grade 3 or higher CRS or neurotoxicities, treatment-related deaths or dose-limiting toxicities were reported. The overall response rate (ORR) and disease control rate (DCR) reached 48.6% and 73.0%, respectively. The 6-month duration of response rate was 44.8%. In patients with GC, the ORR and DCR reached 57.1% and 75.0%, respectively, and the 6-month overall survival rate was 81.2%. These initial results suggest that CT041 has promising efficacy with an acceptable safety profile in patients with heavily pretreated, CLDN18.2-positive digestive system cancers, particularly in those with GC.

Size-control of species via wavelength to selectively synthesize Ag quantum clusters (QCs) was utilized and the synthesis conditions of this system (AgNO3, poly(methacrylic acid) (PMAA) with light) were optimized by changing a variety of parameters. Silver QCs, stabilized by PMAA with different compositions, have been synthesized in aqueous solution by tuning the irradiation monochromatic light wavelengths (300 or 365 nm) and AgNO3/MAA ratio (1 or 2). The novel preparation procedure has demonstrated a new approach to enlarge the population of the Ag QC family and proved the effectiveness of size control to prepare Ag QCs by tuning the light wavelength. Naked Ag QC species Agn(n= 2–9, 11, and 13) in polymer matrices are fully characterized by mass spectrometer, thus providing finger-printing evidence of their presence. Details regarding the photolysis reaction procedure, Ag QC optical properties, and the origins of fluorescence are discussed. Through a combination of results obtained from mass spectroscopy, fluorescence, and time-dependent density functional theory, we can assign the origin of fluorescence from a small silver cluster of Ag2in organic scaffolds. The kinetics of the photolysis reaction follows first-order kinetics (k= 0.1/h). After thiolphenol (C6H5SH) ligand functionalization of the generated silver clusters in aqueous solution, the low or high resolution mass spectra showed the constant species composites with a molecular formula AgnLn–1(n= 2–9 and L = C6H5S). More evidence indicated the formation of polymer-wrapped silver clusters. Their antibio property was explored, and we confirmed that they indeed show efficient activity.

The bimetallic carbon-bridged bis(iminophosphorano)methanediide complexes [CpNd(Tl){C(Ph2P═NSiMe3)2}Cl2Li(THF)2]·Et2O (2) and [SmCl3Tl{C(Ph2P═NSiMe3)2}Li(THF)2]2(3) were prepared from reactions of the dilithiated bis(iminophosphorano)methanediide [Li2L] (1; L = C2–(Ph2P═NSiMe3)2) with Nd and Sm chlorides and with CpTl and TlCl, respectively, in THF. Both final products contain coordinated Li linked with Cl bridges. The complexes have been structurally characterized and show that the bridging methanediide backbone carbon of the ligand is substituted with one Tl(I) and one rare-earth atom and has a tetrahedral geometry. The 31P{1H} NMR spectrum (THF-d8) of 2shows a broad signal at 13.75 ppm with a two-bond spin–spin coupling (2JTl–P= 410 Hz), indicating that the C–Tl bond is maintained in solution. The 31P{1H} NMR spectrum of 3was less informative because the complex is more paramagnetic, and thus only a very broad single peak was observed. DFT calculations on the model compounds [CpNd(Tl){C(PhMeP═NSiH3)2}Cl2Li(THF)2] (2a) and [SmTl{C(PhMeP═NSiH3)2Cl2]2(3a), whose crystal structures are based on those for 2and 3, were performed; the results clearly demonstrate the bonding characteristics among the metal centers (Nd(III), Sm(III), Tl(I)) and bridged carbon. In contrast to most Tl(I) compounds, 2and 3are reasonably stable in air; this is attributed to protection of the Tl(I) by some of the phenyl substituents on the phosphorus through π-bonding interactions. X-ray and DFT data indicate that, for 2, Tl(I) is a five-coordinate center through one strong carbene carbon bond and four weak phenyl carbon bonds, while for 3, Tl(I) is six-coordinate through strong carbene carbon and chloride bonds and four weak phenyl carbon bonds. These complexes are the first examples of a single carbon or carbene forming a bridge between the main-group heavy metal Tl(I) and another rare-earth metal.

UHRF1 is best known for its positive role in the maintenance of DNMT1-mediated DNA methylation and is implicated in a variety of tumor processes. In this paper, we provided evidence to demonstrate a role of UHRF2 in cell motility and invasion through the regulation of the epithelial-mesenchymal transition (EMT) process by acting as a transcriptional co-regulator of the EMT-transcription factors (TFs). We ectopically expressed UHRF2 in gastric cancer cell lines and performed multidimensional proteomics analyses. Proteome profiling analysis suggested a role of UHRF2 in repression of cell-cell adhesion; analysis of proteome-wide TF DNA binding activities revealed the up-regulation of many EMT-TFs in UHRF2-overexpressing cells. These data suggest that UHRF2 is a regulator of cell motility and the EMT program. Indeed, cell invasion experiments demonstrated that silencing of UHRF2 in aggressive cells impaired their abilities of migration and invasion in vitro. Further ChIP-seq identified UHRF2 genomic binding motifs that coincide with several TF binding motifs including EMT-TFs, and the binding of UHRF2 to CDH1 promoter was validated by ChIP-qPCR. Moreover, the interactome analysis with IP-MS uncovered the interaction of UHRF2 with TFs including TCF7L2 and several protein complexes that regulate chromatin remodeling and histone modifications, suggesting that UHRF2 is a transcription co-regulator for TFs such as TCF7L2 to regulate the EMT process. Taken together, our study identified a role of UHRF2 in EMT and tumor metastasis and demonstrated an effective approach to obtain clues of UHRF2 function without prior knowledge through combining evidence from multidimensional proteomics analyses.

Leachate recirculation is a critical element in the evaluation of the availability of methane production enhancement in bioreactor landfills. Field experiments in leachate injection were conducted in horizontal wells at a landfill in Hubei Province in China. The experiments included the long-term test of methane concentration and production in three cells; the test was operated with nonrecirculation (NR), continued recirculation (CR), and descending recirculation (DR). The average methane concentration in CR is 54.8%, which is higher than that in the NR and DR sites. The average biogas flow rate in the CR site was 2.2 times that in the NR site. The recirculation loading should be determined with the specific conditions, to effectively improve the methane production in field site. The position of the gas collection well was also very important, coordinating with the distribution of the leachate injection well and influence area of the liquid injection. The long-term monitoring of injection volume and gas production is essential to determine the reliability of recirculation for methane reuse.