High-Throughput Multitarget Molecular Detection in an Automatic Light-Addressable Photoelectrochemical Sensing Platform.

Successively emerged high-throughput multitarget molecular detection methods bring significant development tides in chemical, biological, and environmental fields. However, several persistent challenges of intricate sample preparation, expensive instruments, and tedious and skilled operations still need to be further addressed. Here, we propose an automatic light-addressable photoelectrochemical (ALA-PEC) sensing platform for sensitive and selective detection of multitarget molecules. With Au nanoparticle-decorated TiO2 nanotube photonic crystals (Au-TiO2 NTPCs) as a photoelectrode and 8 kinds of antibiotics as target molecules, the ALA-PEC sensing system implements automatic detection of multimolecules in a short time with high sensitivity and good selectivity. Random samples with different amounts of antibiotics have been well-distinguished in the ALA-PEC system, and both the chemical components and concentrations have been well-illustrated in a pattern recognition model. It is worth noting that 8 samples are not the limit of the ALA-PEC sensing platform, which can be easily expanded to more complex detection arrays based on practical needs. The emerging ALA-PEC sensing platform provides a new solution for rapid screening and detection of multitarget and high-throughput substances and potentially brings the automatic, portable, sensitive, high-throughput, and cost-effective detection technique to an entire new realm.

Self-Assembled PD-L1 Downregulator to Boost Photodynamic Activated Tumor Immunotherapy Through CDK5 Inhibition.

The immunosuppressive characteristics and acquired immune resistance can restrain the therapy-initiated anti-tumor immunity. In this work, an antibody free programmed death receptor ligand 1 (PD-L1) downregulator (designated as CeSe) is fabricated to boost photodynamic activated immunotherapy through cyclin-dependent kinase 5 (CDK5) inhibition. Among which, FDA approved photosensitizer of chlorin e6 (Ce6) and preclinical available CDK5 inhibitor of seliciclib (Se) are utilized to prepare the nanomedicine of CeSe through self-assembly technique without drug excipient. Nanoscale CeSe exhibits an increased stability and drug delivery efficiency, contributing to intracellular production of reactive oxygen species (ROS) for robust photodynamic therapy (PDT). The PDT of CeSe can not only suppress the primary tumor growth, but also induce the immunogenic cell death (ICD) to release tumor associated antigens. More importantly, the CDK5 inhibition by CeSe can downregulate PD-L1 to re-activate the systemic anti-tumor immunity by decreasing the tumor immune escape and therapy-induced acquired immune resistance. This work provides an antibody free strategy to activate systemic immune response for metastatic tumor treatment, which may accelerate the development of translational nanomedicine with sophisticated mechanism.

Tumor Homing Chimeric Peptide Rhomboids to Improve Photodynamic Performance by Inhibiting Therapy-Upregulated Cyclooxygenase-2.

Negative therapeutic feedback of inflammation would extensively attenuate the antitumor effect of photodynamic therapy (PDT). In this work, tumor homing chimeric peptide rhomboids (designated as NP-Mel) are fabricated to improve photodynamic performance by inhibiting PDT-upregulated cyclooxygenase-2 (COX-2). The hydrophobic photosensitizer of protoporphyrin IX (PpIX) and palmitic acid are conjugated onto the neuropilin receptors (NRPs) targeting peptide motif (CGNKRTR) to obtain tumor homing chimeric peptide (Palmitic-K(PpIX)CGNKRTR), which can encapsulate the COX-2 inhibitor of meloxicam. The well dispersed NP-Mel not only improves the drug stability and reactive oxygen species (ROS) production ability, but also increase the breast cancer targeted drug delivery to intensify the PDT effect. In vitro and in vivo studies verify that NP-Mel will decrease the secretion of prostaglandin E2 (PGE2) after PDT treatment, inducing the downregulation of IL-6 and TNF-α expressions to suppress PDT induced inflammation. Ultimately, an improved PDT performance of NP-Mel is achieved without inducing obvious systemic toxicity, which might inspire the development of sophisticated nanomedicine in consideration of the feedback induced therapeutic resistance.

Spinal cord injury: Olfactory ensheathing cell-based therapeutic strategies.

Spinal cord injury (SCI) is a highly disabling neurological disorder that is difficult to treat due to its complex pathophysiology and nerve regeneration difficulties. Hence, effective SCI treatments are necessary. Olfactory ensheathing cells (OECs), glial cells derived from the olfactory bulb or mucosa, are ideal candidates for SCI treatment because of their neuroprotective and regenerative properties, ample supply, and convenience. In vitro, animal model, and human trial studies have reported discoveries on OEC transplantation; however, shortcomings have also been demonstrated. Recent studies have optimized various OEC transplantation strategies, including drug integration, biomaterials, and gene editing. This review aims to introduce OECs mechanisms in repairing SCI, summarize the research progress of OEC transplantation-optimized strategies, and provide novel research ideas for SCI treatment.

Whole-genome long-read TAPS deciphers DNA methylation patterns at base resolution using PacBio SMRT sequencing technology.

Long-read sequencing provides valuable information on difficult-to-map genomic regions, which can complement short-read sequencing to improve genome assembly, yet limited methods are available to accurately detect DNA methylation over long distances at a whole-genome scale. By combining our recently developed TET-assisted pyridine borane sequencing (TAPS) method, which enables direct detection of 5-methylcytosine and 5-hydroxymethylcytosine, with PacBio single-molecule real-time sequencing, we present here whole-genome long-read TAPS (wglrTAPS). To evaluate the performance of wglrTAPS, we applied it to mouse embryonic stem cells as a proof of concept, and an N50 read length of 3.5 kb is achieved. By sequencing wglrTAPS to 8.2× depth, we discovered a significant proportion of CpG sites that were not covered in previous 27.5× short-read TAPS. Our results demonstrate that wglrTAPS facilitates methylation profiling on problematic genomic regions with repetitive elements or structural variations, and also in an allelic manner, all of which are extremely difficult for short-read sequencing methods to resolve. This method therefore enhances applications of third-generation sequencing technologies for DNA epigenetics.

The effect of negative pressure wound therapy on the outcome of diabetic foot ulcers: A meta-analysis.

Negative pressure injury is one of the auxiliary methods of treating diabetes foot ulcers. It has been shown to be superior to conventional techniques in randomized controlled trials (RCTs). Nevertheless, the results of observational research are still scarce. A systematic review of RCTs and observations was carried out to evaluate the effectiveness and security of negative pressure wound therapy (NPWT) treatment for diabetes foot ulcers. Three English e-databases have been found for NPWT research. The meta-analyses of the comparative studies provided point estimates of results. Intermediate results were given as median and binary values were given in the form of odds ratios (OR). Seventeen trials, 13 RCTs and four randomized, controlled trials were found in the survey. Of these, 831 were treated with NPWT, 834 were treated with standard therapy. A total of 14 studies have been conducted to investigate the influence of NPWT on the healing of diabetic foot ulcers(DFU). In the study, NPWT was shown to speed up the healing of the wound in DFU patients(OR, 2.57; 95% CI, 1.72, 3.85 p < 0.0001). A subgroup analysis showed that NPWT was associated with an acceleration of the wound healing rate in 10 RCT trials (OR, 2.48; 95% CI, 1.58, 3.89 p < 0.001). In the four nRCT trials, NPWT was also shown to speed up the healing of the wound(OR, 2.95; 95% CI, 1.03, 8.42 p = 0.04). In 11 studies, the influence of NPWT on amputations of diabetes mellitus (DM) foot ulcers was investigated. The results showed that NPWT was associated with a reduction in amputations (OR, 0.53; 95% CI, 0.37, 0.74 p = 0.0002).In a subgroup of RCT trials, nine RCT trials showed a reduction in amputations(OR, 0.61; 95% CI, 0.43, 0.87 p = 0.007). In both nRCT trials, NPWT also showed a reduction in amputations (OR, 0.03; 95% CI, 0.00, 0.24 p = 0.001). Generally speaking, NPWT can help to heal the wound and lower the risk of amputations in people with diabetes. The subgroup analysis showed similar results for the RCT and non-RCT trials. NPWT can be used to treat diabetes foot ulcers caused by diabetes.

Modular Oxidation of Cytosine Modifications and Their Application in Direct and Quantitative Sequencing of 5-Hydroxymethylcytosine.

Selective, efficient, and controllable oxidation of cytosine modifications is valuable for epigenetic analyses, yet only limited progress has been made. Here, we present two modular chemical oxidation reactions: conversion of 5-hydroxymethylcytosine (5hmC) into 5-formylcytosine (5fC) using 4-acetamido-2,2,6,6-tetramethylpiperidine-1-oxoammonium tetrafluoroborate (ACT+BF4-) and further transformation of 5fC into 5-carboxycytosine (5caC) through Pinnick oxidation. Both reactions are mild and efficient on double-stranded DNA. We integrated these two oxidations with borane reduction to develop chemical-assisted pyridine borane sequencing plus (CAPS+), for direct and quantitative mapping of 5hmC. Compared with CAPS, CAPS+ improved the conversion rate and false-positive rate. We applied CAPS+ to mouse embryonic stem cells, human normal brain, and glioblastoma DNA samples and demonstrated its superior sensitivity in analyzing the hydroxymethylome.

Chimeric Peptide-Engineered Self-Delivery Nanomedicine for Photodynamic-Triggered Breast Cancer Immunotherapy by Macrophage Polarization.

A systemic treatment strategy is urgently demanded to suppress the rapid growth and easy metastasis characteristics of breast cancer. In this work, a chimeric peptide-engineered self-delivery nanomedicine (designated as ChiP-CeR) for photodynamic-triggered breast cancer immunotherapy by macrophage polarization. Among these, ChiP-CeR is composed of the photosensitizer of chlorine e6 (Ce6) and the TLR7/8 agonist of lmiquimod (R837), which is further modified with tumor matrix targeting peptide (Fmoc-K(Fmoc)-PEG8 -CREKA. ChiP-CeR is preferred to actively accumulate at the tumor site via specific recognition of fibronectin, which can eradicate primary tumor growth through photodynamic therapy (PDT). Meanwhile, the destruction of primary tumors would trigger immunogenic cell death (ICD) effects to release high-mobility group box-1(HMGB1) and expose calreticulin (CRT). Moreover, ChiP-CeR can also polarize M2-type tumor-associated macrophages (TAMs) into M1-type TAMs, which can activate T cell antitumor immunity in combination with ICD. Overall, ChiP-CeR possesses superior antitumor effects against primary and lung metastatic tumors, which provide an applicable nanomedicine and a feasible strategy for the systemic management of metastatic breast cancer.

Endonuclease enrichment TAPS for cost-effective genome-wide base-resolution DNA methylation detection.

Whole genome base-resolution methylome sequencing allows for the most comprehensive analysis of DNA methylation, however, the considerable sequencing cost often limits its applications. While reduced representation sequencing can be an affordable alternative, over 80% of CpGs in the genome are not covered. Building on our recently developed TET-assisted pyridine borane sequencing (TAPS) method, we here described endonuclease enrichment TAPS (eeTAPS), which utilizes dihydrouracil (DHU)-cleaving endonuclease digestion of TAPS-converted DNA to enrich methylated CpG sites (mCpGs). eeTAPS can accurately detect 87% of mCpGs in the mouse genome with a sequencing depth equivalent to 4× whole genome sequencing. In comparison, reduced representation TAPS (rrTAPS) detected less than 4% of mCpGs with 2.5× sequencing depth. Our results demonstrate eeTAPS to be a new strategy for cost-effective genome-wide methylation analysis at single-CpG resolution that can fill the gap between whole-genome and reduced representation sequencing.

Effects of xenon anesthesia on postoperative neurocognitive disorders: a systematic review and meta-analysis.

The latest clinical trials have reported conflicting outcomes regarding the effectiveness of xenon anesthesia in preventing postoperative neurocognitive dysfunction; thus, this study assessed the existing evidence. We searched the PubMed, Embase, Cochrane Library, and Web of Science databases from inception to April 9, 2023, for randomized controlled trials of xenon anesthesia in postoperative patients. We included English-language randomized controlled studies of adult patients undergoing surgery with xenon anesthesia that compared its effects to those of other anesthetics. Duplicate studies, pediatric studies, and ongoing clinical trials were excluded. Nine studies with 754 participants were identified. A forest plot revealed that the incidence of postoperative neurocognitive dysfunction did not differ between the xenon anesthesia and control groups (P = 0.43). Additionally, xenon anesthesia significantly shortened the emergence time for time to opening eyes (P < 0.001), time to extubation (P < 0.001), time to react on demand (P = 0.01), and time to time and spatial orientation (P = 0.04). However, the Aldrete score significantly increased with xenon anesthesia (P = 0.005). Postoperative complications did not differ between the anesthesia groups. Egger's test for bias showed no small-study effect, and a trim-and-fill analysis showed no apparent publication bias. In conclusion, xenon anesthesia probably did not affect the occurrence of postoperative neurocognitive dysfunction. However, xenon anesthesia may effectively shorten the emergence time of certain parameters without adverse effects.

Contribution of m5C RNA Modification-Related Genes to Prognosis and Immunotherapy Prediction in Patients with Ovarian Cancer.

Background: 5-Methylcytosine (m5C) RNA modification is closely implicated in the occurrence of a variety of cancers. Here, we established a novel prognostic signature for ovarian cancer (OC) patients based on m5C RNA modification-related genes and explored the correlation between these genes with the tumor immune microenvironment. Methods: Methylated-RNA immunoprecipitation sequencing helped us to identify candidate genes related to m5C RNA modification at first. Based on TCGA database, we screened the differentially expressed candidate genes related to the prognosis and constructed a prognostic model using LASSO Cox regression analyses. Notably, the accuracy of the model was evaluated by Kaplan-Meier analysis and receiver operator characteristic curves. Independent prognostic risk factors were investigated by Cox proportional hazard model. Furthermore, we also analyzed the biological functions and pathways involved in the signature. Finally, the immune response of the model was visualized in great detail. Results: Totally, 2,493 candidate genes proved to be involved in m5C modification of RNA for OC. We developed a signature with prognostic value consisting of six m5C RNA modification-related genes. Specially, samples have been split into two cohorts with low- and high-risk scores according to the model, in which the low-risk OC patients exhibited dramatically better overall survival time than those with high-risk scores. Besides, not only was this model a prognostic factor independent of other clinical characteristics but it predicted the intensity of the immune response in OC. Significantly, the accuracy and availability of the signature were verified by ICGC database. Conclusions: Our study bridged the gap between m5C RNA modification and the prognosis of OC and was expected to provide an effective breakthrough for immunotherapy in OC patients.

Definition and Characterization of SOX11-Derived T Cell Epitopes towards Immunotherapy of Glioma.

The transcription factor SOX11 is a tumor-associated antigen with low expression in normal cells, but overexpression in glioblastoma (GBM). So far, conventional surgery, chemotherapy, and radiotherapy have not substantially improved the dismal prognosis of relapsed/refractory GBM patients. Immunotherapy is considered a promising strategy against GBM, but there is a fervent need for better immunotargets in GBM. To this end, we performed an in silico prediction study on SOX11, which primarily yielded ten promising HLA-A*0201-restricted peptides derived from SOX11. We defined a novel peptide FMACSPVAL, which had the highest score according to in silico prediction (6.02 nM by NetMHC-4.0) and showed an exquisite binding affinity to the HLA-A*0201 molecule in the peptide-binding assays. In the IFN-γ ELISPOT assays, FMACSPVAL demonstrated a high efficiency for generating SOX11-specific CD8+ T cells. Nine out of thirty-two healthy donors showed a positive response to SOX11, as assessed by the ELISPOT assays. Therefore, this novel antigen peptide epitope seems to be promising as a target for T cell-based immunotherapy in GBM. The adoptive transfer of in vitro elicited SOX11-specific CD8+ T cells constitutes a potential approach for the treatment of GBM patients.

Research Advances in Clinical Applications, Anticancer Mechanism, Total Chemical Synthesis, Semi-Synthesis and Biosynthesis of Paclitaxel.

Paclitaxel, a natural secondary metabolite isolated and purified from the bark of the Taxus tree, is considered one of the most successful natural anticancer drugs due to its low toxicity, high potency and broad-spectrum anticancer activity. Taxus trees are scarce and slow-growing, and with extremely low paclitaxel content, the contradiction between supply and demand in the market is becoming more and more intense. Therefore, researchers have tried to obtain paclitaxel by various methods such as chemical synthesis, artificial culture, microbial fermentation and tissue cell culture to meet the clinical demand for this drug. This paper provides a comprehensive overview of paclitaxel extraction, combination therapy, total synthesis, semi-synthesis and biosynthesis in recent years and provides an outlook, aiming to provide a theoretical basis and reference for further research on the production and application of paclitaxel in the future.

Inhibition of circ_0081234 reduces prostate cancer tumor growth and metastasis via the miR-1/MAP 3 K1 axis.

INTRODUCTION: Circular RNAs (circRNAs) are crucial regulators of tumor occurrence and progression, and circRNAs are enriched and stable in exosomes. The present study aimed to explore the role and potential mechanism of cancer-derived exosomal circ_0081234 in prostate cancer (PCa). METHODS: Exosomes were extracted using the ExoQuick Precipitation Kit (System Biosciences, Mountain View, CA, USA). The levels of circ_0081234, miR-1 and mitogen-activated protein kinase kinase kinase 1 (MAP 3 K1) were examined using a quantitative real-time polymerase chain reaction or western blotting. Cell migration and invasion were evaluated via a transwell assay. The protein levels of N-cadherin, vimentin and E-cadherin were detected by western blotting. The interaction between miR-1 and circ_0081234 or MAP 3 K1 was verified via a dual-luciferase reporter assay and an RNA pull-down assay. RESULTS: The circ_0081234 level was increased in PCa tissues with spinal metastasis in comparison to primary PCa tissues without spinal metastasis. Exosomal circ_0081234 promoted the migration, invasion and epithelial-mesenchymal transition of PCa cells. Knockdown of circ_0081234 blocked PCa cell progression by regulating miR-1. In addition, miR-1 overexpression suppressed PCa cell progression by repressing MAP 3 K1. Moreover, circ_0081234 increased MAP 3 K1 level via sponging miR-1. Depletion of circ_0081234 inhibited tumor growth in vivo. CONCLUSIONS: Exosomal circ_0081234 promoted migration, invasion and epithelial-mesenchymal transition of PCa cells by regulating the miR-1/MAP 3 K1 axis.

Carrier Free O2 -Economizer for Photodynamic Therapy Against Hypoxic Tumor by Inhibiting Cell Respiration.

Abnormal tumor metabolism causes the hypoxic microenvironment, which greatly limits the efficacy of photodynamic therapy (PDT). In this work, a strategy of metabolic reprogramming is proposed to economize O2 for enhanced PDT against hypoxic tumors. The carrier-free O2 -economizer (designated as LonCe) is prepared based on the metabolic antitumor drug of Lonidamine (Lon) and the photosensitizer of chlorin e6 (Ce6). By virtue of intermolecular interactions, Lon and Ce6 self-assemble into nanosized LonCe with favorable stability and high drug contents. Compared with Ce6, LonCe exhibits an improved cellular uptake and photodynamic property for tumor treatment. Moreover, LonCe is capable of inhibiting cell metabolism and mitochondrial respiration to remit the tumor hypoxia, which would promote reactive oxygen species (ROS) production and elevate the PDT efficacy on tumor suppression. In vivo experiments indicate that intravenously injected LonCe prefers to accumulate at the tumor site for highly efficient PDT regardless of the hypoxic environment. Besides, the self-delivery LonCe is fabricated without any carriers, which avoids the excipients induced system toxicity and immunogenicity in vivo. This carrier-free nanomedicine with cell respiratory inhibition mechanism would expedite the development and clinical translation of photodynamic nanoplatforms in tumor treatment.

All-Organic Superhydrophobic Coating Comprising Raspberry-Like Particles and Fluorinated Polyurethane Prepared via Thiol-Click Reaction.

Mechanically robust superhydrophobic coatings have been extensively reported using chemically susceptible inorganic fillers like slica, titanium dioxide, and zinc oxide for constructing micro-nano structures. Organic particles are good candidates for improving chemical resistance, whereas the synthesis of organic particles with well-defined and stable micro-nano structures remains exclusive. Here, an all-organic, cross-linked superhydrophobic coating comprising raspberry-like fluorinated micro particles (RLFMP) and fluorinated polyurethane (FPU) is prepared via thiol-click reaction. Benefiting from the robust micro-nano structure of RLFMP and the excellent flexibility of FPU, the coating can maintain superhydrophobicity after severe alkali corrosion or mechanical damage, while the superhydrophobicity can be repaired readily by the fast recovery of micro-nano roughness and migration of branched fluoroalkyl chains to the coating surface. This design strategy is expected to provide a good application of thiol-click chemistry.

Predictive value of single-nucleotide polymorphisms in curve progression of adolescent idiopathic scoliosis.

PURPOSE: Genetic diagnosis is a promising approach because several single-nucleotide polymorphisms (SNPs) associated with adolescent idiopathic scoliosis (AIS) progression have been reported. We review the predictive value of SNPs in curve progression of adolescent idiopathic scoliosis. METHODS: We reviewed DNA-based prognostic testing to predict curve progression. Then, the multiple polymorphisms in loci related to AIS progression were also reviewed, and we elucidated the predictive value of SNPs from four functional perspectives, including endocrine metabolism, neuromuscular system, cartilage and extracellular matrix, enzymes, and cytokines. RESULTS: The ScoliScores were less successful predictors than expected, and the weak power of predictive SNPs might account for its failure. Susceptibility loci in ESR1, ESR2, GPER, and IGF1, which related to endocrine metabolism, have been reported to predict AIS progression. Neuromuscular imbalance might be a potential mechanism of scoliosis, and SNPs in LBX1, NTF3, and SOCS3 have been reported to predict the curve progression of AIS. Susceptibility loci in SOX9, MATN1, AJAP1, MMP9, and TIMP2, which are related to cartilage and extracellular matrix, are also potentially related to AIS progression. Enzymes and cytokines play essential roles in regulating bone metabolism and embryonic development. SNPs in BNC2, SLC39A8, TGFB1, IL-6, IL-17RC, and CHD7 were suggested as predictive loci for AIS curve progression. CONCLUSIONS: Many promising SNPs have been identified to predict the curve progression of AIS. However, conflicting results from replication studies and different ethnic groups hamper their reliability. Convincing SNPs from multiethnic populations and functional verification are needed.

On-line monitoring of the dopamine-based molecular imprinting processes for protein templates with the assistance of a fluorescent indicator.

On-line monitoring of the dopamine (DA)-based molecular imprinting processes over Fe3O4@SiO2-NH2 nanoparticles (SiMNPs) is reported by using a real-time quantitative PCR machine. Taking advantages of the efficient fluorescence quenching capability of polydopamine (PDA) and its high binding affinity to rhodamine B (RhB), we performed molecular imprinting against different proteins with free dopamine as the functional monomer and RhB as a fluorescent indicator. Along with the template molecules, the fluorescent indicators were continuously encapsulated into the PDA layer formed on the surface of the SiMNPs, resulting in immediate quenching of the fluorescence, which can be conveniently monitored in real time. As proteins showed sequence-dependent influences on the oxidation of dopamine and subsequent self-assembly on the surface of the SiMNPs, the observed fluorescence signals clearly indicated the polymerization progress in the presence of the template proteins, allowing precise control of the reaction time for different templates at a given initial concentration. The optimum end point of the reaction was found to be when 90 ± 3% of the templates had been encapsulated into the polymer, which offered the highest imprinting factor and selectivity. We applied the approach to prepare a primary PDA-based surface imprinted polymer for a multifunctional protein apurinic/apyrimidinic endonuclease/redox effector factor 1 (APE1). After further introduction of 3-hydroxyphenylboronic acid to the interfaces between APE1 and PDA, the resultant molecularly imprinted polymers (MIP-II) enabled quantitative isolation APE1 from cell lysate samples. The developed approach will be useful for the quantitative preparation of PDA-based MIPs for precious template proteins with limited input quantity. It is also applicable for further study on the effects of different proteins or peptides on the PDA formation reactions.

PO4 3- Coordinated Robust Single-Atom Platinum Catalyst for Selective Polyol Oxidation.

Achieving efficient catalytic conversion over a heterogeneous catalyst with excellent resistance against leaching is still a grand challenge for sustainable chemical synthesis in aqueous solution. Herein, we devised a single-atom Pt1 /hydroxyapatite (HAP) catalyst via a simple hydrothermal strategy. Gratifyingly, this robust Pt1 /HAP catalyst exhibits remarkable catalytic selectivity and catalyst stability for the selective oxidation of C2 -C4 polyols to corresponding primary hydroxy acids. It is found that the Pt-(O-P) linkages with strong electron-withdrawing function of PO4 3- (Pt1 -OPO4 3- pair active site) not only realize the activation of the C-H bond, but also destabilize the transition state from adsorbed hydroxy acids toward the C-C cleavage, resulting in the sharply increased selectivity of hydroxy acids. Moreover, the strong PO4 3- -coordination effect provides electrostatic stabilization for single-atom Pt, ensuring the highly efficient catalysis of Pt1 /HAP for over 160 hours with superior leaching resistance.

Ibrutinib for improved chimeric antigen receptor T-cell production for chronic lymphocytic leukemia patients.

Chimeric antigen receptor T (CART) cells targeting CD19 have shown promising results in the treatment of chronic lymphocytic leukemia (CLL). However, efficacy seems to be inferior compared to diffuse large B-cell lymphoma or acute lymphoblastic leukemia. Impaired T-cell fitness of CLL patients may be involved in treatment failure. Less-differentiated naïve-like T cells play an important role in CART expansion and long-term persistence in vivo. These cells are sparse in CLL patients. Therefore, optimization of CART cell production protocols enriching less differentiated T cell subsets may overcome treatment resistance. The B-cell receptor inhibitor ibrutinib targeting Bruton's tyrosine kinase (BTK) is approved for the treatment of CLL. Besides BTK, ibrutinib additionally inhibits interleukin-2-inducible T-cell kinase (ITK) which is involved in T-cell differentiation. To evaluate the effect of ibrutinib on CART cell production, peripheral blood mononuclear cells from nine healthy donors and eight CLL patients were used to generate CART cells. T-cell expansion and phenotype, expression of homing and exhaustion makers as well as functionality of CART cells were evaluated. CART cell generation in the presence of ibrutinib resulted in increased cell viability and expansion of CLL patient-derived CART cells. Furthermore, ibrutinib enriched CART cells with less-differentiated naïve-like phenotype and decreased expression of exhaustion markers including PD-1, TIM-3 and LAG-3. In addition, ibrutinib increased the cytokine release capacity of CLL patient-derived CART cells. In summary, BTK/ITK inhibition with ibrutinib during CART cell culture can improve yield and function of CLL patient-derived CART cell products.