CD22-targeted glyco-engineered natural killer cells offer a further treatment option for B-cell acute lymphoblastic leukemia.

Not available.

Superior mesenteric artery embolism after radiofrequency ablation in regularly anticoagulated patients with paroxysmal atrial fibrillation: a case report.

BACKGROUND: Superior mesenteric artery embolism (SMAE) is a rare cause of acute abdomen, and the fatality rate is extremely high if it is not diagnosed and treated in time. Due to the lack of knowledge and experience of nonspecialist physicians, it is easy to misdiagnose. Radiofrequency ablation (RFA) has become the first-line treatment strategy for atrial fibrillation (AF). Thromboembolic events are some of the major complications after RFA, whereas SMAE is rarely reported. CASE PRESENTATION: A 70 year-old woman with paroxysmal AF who regularly took anticoagulant drugs for 3 months experienced abdominal pain after RFA. At the outset, she was misdiagnosed as mechanical intestinal obstruction. When the patient presented with blood in the stool, abdominal enhancement computed tomography was conducted and showed a small bowel perforation. Immediate laparotomy was performed, and the final diagnosis was SMAE. CONCLUSION: It is suggested that for unexplained abdominal pain after RFA of AF, the possibility of SMAE should be considered, and a targeted examination should be carried out in time to confirm the diagnosis and give appropriate treatment.

Enhanced stent visualization system for percutaneous coronary intervention in patients with chronic kidney disease: effects on contrast media volume and radiation exposure.

OBJECTIVE: We aimed to assess the impact of using enhanced stent visualization (ESV) systems on contrast media volume and radiation dose in percutaneous coronary intervention (PCI), especially for patients with chronic kidney disease (CKD). BACKGROUND: Coronary heart disease (CHD) is associated with chronic kidney disease (CKD), as they share a similar pathological pathway. In addition, the iodinated contrast media used for angiography is a risk factor for contrast-associated acute kidney injury (CA-AKI), which could aggravate the progression of CKD. We hypothesized that ESV systems have the potential to reduce the use of contrast media as well as the radiation dose; however, few studies have reported the impact on contrast media with the use of ESV systems. METHODS: We retrospectively collected 124 patients with acute coronary syndrome who underwent PCI from May 2020 to July 2021. The patients were divided into the ESV-guided group (n = 64) and angiography-guided group (n = 60). Procedural parameters, including contrast media volume, radiation exposure (in Air Kerma-AK and Dose Area Product-DAP), number of cines, cine frames, fluoroscopy and procedure time, were recorded and analysed. RESULTS: The groups were comparable regarding the patient characteristics. There was a significant reduction in contrast media volume (174.7 ± 29.6 ml vs.132.6 ± 22.3 ml, p = 0.0001), radiation exposure (776 (499 - 1200) mGy vs. 1065 (791 - 1603) mGy, p = 0.002 in AK; 43 (37 - 73) Gycm2 vs. 80 (64 - 133) Gycm2, p = 0.030 in DAP) and procedure time (53.06 ± 21.20 min vs. 72.00 ± 30.55 min, p = 0.01) with the use of ESV systems. Similar results were observed in the subgroup analysis for the patients with CKD. CONCLUSION: This study suggested that the use of ESV is associated with reduced contrast media usage, radiation dose and procedure time during PCI. The same results were observed in a subgroup analysis in patients with CKD, and this shows that ESV-guided PCI has the potential to reduce renal impairment and mitigate the progression of CKD for those CHD patients with CKD.

Sodium Houttuyfonate Ameliorates ß-amyloid1-42-Induced Memory Impairment and Neuroinflammation through Inhibiting the NLRP3/GSDMD Pathway in Alzheimer's Disease.

OBJECTIVE: Our research is designed to explore the function of sodium houttuyfonate (SH) on Alzheimer's disease (AD) and its potential molecular mechanisms. METHODS: In our study, the Morris water maze (MWM) test was used to assess the role of SH on spatial learning and memory deficiency in amyloid-ß peptide (Aß)1-42-induced AD mice. We explored the functions of SH on proinflammatory cytokines, neuron apoptosis, and damage in vivo and in vitro by using an enzyme-linked immunosorbent assay (ELISA), quantitative real-time polymerase chain reaction (qRT-PCR), flow cytometry, western blot, and Nissl staining. Moreover, the effect of SH on oxidative stress in vivo and in vitro was also detected. To explore the underlying molecular mechanisms of SH on AD, the expressions of proteins and mRNA involved in the NOD-like receptor pyrin domain containing-3/gasdermin D (NLRP3/GSDMD) pathway were determined using western blot, immunofluorescence staining, and qRT-PCR. RESULTS: Our data demonstrated that SH ameliorated spatial learning and memory deficiency in Aß 1-42-induced AD mice. Moreover, SH significantly improved hippocampal neuron damage and inhibited oxidative stress, neuroinflammation, and neuron apoptosis in Aß 1-42-induced AD mice and PC12 cells. The results also revealed that SH protected Aß 1-42-induced AD through inhibiting the NLRP3/GSDMD pathway. CONCLUSION: The present study demonstrated that SH could ameliorate Aß 1-42-induced memory impairment neuroinflammation and pyroptosis through inhibiting the NLRP3/GSDMD pathway in AD, suggesting that SH may be a potential candidate for AD treatment.

Equipping Natural Killer Cells with Cetuximab through Metabolic Glycoengineering and Bioorthogonal Reaction for Targeted Treatment of KRAS Mutant Colorectal Cancer.

While Cetuximab can be used to treat KRAS wild-type colon cancer cells by targeting EGFR and inhibiting the activation of downstream signaling pathways, it exhibits little therapeutic effect on KRAS mutant colon cancer cells. Natural killer (NK) cells are a class of powerful immune cells with anticancer activities. However, NK cells typically lack inherent tumor targeting abilities. Here, a new method is established to bestow NK-92 cells with tumor targeting abilities by installing cetuximab on the cell surface. Through metabolic glycoengineering, azide groups were introduced onto the surface of NK-92 cells. Bioorthogonal strain promoted the azide-alkyne cycloaddition click reaction of engineered NK-92 cells with alkyne modified cetuximab functionalized NK cells with the antibody. The resulting NK-92 cells were significantly more effective than the parent NK-92 cells in protecting against tumor development in a KRAS mutant mouse tumor model resistant to cetuximab treatment. Thus, NK cell functionalization with antibodies enabled by metabolic glycoengineering is a promising strategy to enhance anticancer immune therapy.

Acupuncture for persistent atrial fibrillation after catheter ablation: study protocol for a pilot randomized controlled trial.

BACKGROUND: Atrial fibrillation (AF) is a common arrhythmia, which is closely related to cardiovascular morbidity and mortality. Although acupuncture is used in the treatment of AF, the evidence is insufficient. The objective of this pilot trial is to evaluate the feasibility, preliminary efficacy, and safety of acupuncture in reducing AF burden for persistent AF after catheter ablation (CA). METHODS AND DESIGN: This will be a multi-center, 3-arm, pilot randomized controlled trial in China. Sixty patients in total will be randomly assigned to the specific acupoints group, the non-specific acupoints group, or the non-acupoints group in a 1:1:1 ratio. The whole study period is 6 months, including a 3-month treatment period and a 3-month follow-up period. All patients will receive 18 sessions of acupuncture over 12 weeks after CA and appropriate post-ablation routine treatment. The primary outcome is AF burden at 6 months after CA measured by electrocardiography patch that can carry out a 7-day continuous ambulatory electrocardiographic monitoring. The secondary outcomes include AF burden at 3 months after CA, recurrence of AF, quality of life, etc. The adverse events will also be recorded. DISCUSSION: This pilot study will contribute to evaluating the feasibility, preliminary efficacy, and safety of acupuncture in reducing AF burden for persistent AF after CA. The results will be used for the sample size calculation of a subsequent large-scale trial. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR2000030576 . Registered on 7 March 2020.

Galectin-3 inhibition attenuates doxorubicin-induced cardiac dysfunction by upregulating the expression of peroxiredoxin-4.

Doxorubicin (DOX) is a highly efficient chemotherapeutic drug limited by its cardiotoxicity. Galectin-3 (Gal-3) overexpression is associated with several cardiovascular diseases. In this study, the in vivo models of DOX-treated rats and the in vitro model of DOX-treated H9C2 cells were used. DOX induced cardiac injury and dysfunction accompanied with the upregulation of Gal-3 at the end of the experiment, while inhibition of Gal-3 with modified citrus pectin (MCP) exhibited a dramatic improvement in cardiac function of the DOX-treated rats, as manifested by increased left ventricular systolic pressure and ±dp/dtmax and decreased left ventricular end-diastolic pressure. The plasma levels of myocardial injury markers such as lactate dehydrogenase, creatine kinase, creatine kinase-MB, and cardiac troponin I were decreased after MCP treatment. In parallel, MCP attenuated myocardial tissue markers of oxidative stress such as hydrogen peroxide and malondialdehyde restored the activities of superoxide dismutase, catalase, and glutathione peroxidase and upregulated antioxidant peroxiredoxin-4 (Prx-4). To further verify the role of Prx-4, it was downregulated by siRNA-mediated knockdown in H9C2 cells. MCP could not reverse DOX-induced oxidative stress in Prx-4-knock-down cells. In conclusion, Gal-3 mediated DOX-induced cardiotoxicity and Gal-3 inhibition attenuated DOX-induced cardiac dysfunction by upregulating the expression of Prx-4 to reduce myocardial oxidative stress.

Glycoengineering of Natural Killer Cells with CD22 Ligands for Enhanced Anticancer Immunotherapy.

Adoptive transfer of immune cells is being actively pursued for cancer treatment. Natural killer (NK) cells, a class of cytotoxic immune cells, generally lack inherent selectivities toward cancer. To bestow tumor-targeting abilities and enhance anticancer efficacy, a new strategy is established to glycoengineer NK cells. Carbohydrate-based ligands for CD22, a marker for B cell lymphoma, are introduced onto NK cells through either metabolic engineering or glyco-polymer insertion. Such NK cells exhibited greatly enhanced cytotoxicities toward CD22+ lymphoma cells in a CD22-dependent manner. Importantly, both CD22+ lymphoma cell lines and primary lymphoma cells from human cancer patients can be effectively killed by the engineered NK cells. Furthermore, glycoengineered NK cells provided significant protection to tumor-bearing mice. Thus, NK cell glycoengineering is an exciting new approach for cancer treatment complementing the current immune cell genetic engineering strategy.

Synthesis of a New Water-Soluble Melatonin Derivative with Low Toxicity and a Strong Effect on Sleep Aid.

A new melatonin sulfonate derivative sodium 4-(3-(2-acetamidoethyl)-5-methoxy-1H-indol-1-yl) butane-1-sulfonate (MLTBS) with higher water solubility (695 times) and lower cytotoxicity than natural melatonin (MLT) was synthesized, yet with the same sleep aid function. The poor solubility of MLT in water has been improved with a simple chemical reaction, which solves the poor solubility of melatonin in water, overcoming the safety problem caused by adding organic reagents such as dimethyl sulfoxide (DMSO) and ethanol to increase the solubility. Moreover, the modified MLT still has the same sleep aid effect as the natural MLT and higher biological safety. As a novel potential drug for sleep aid, the new MLT derivative could also flourish the application and research of this molecule in medicine and biology.

LATS2 promotes cardiomyocyte H9C2 cells apoptosis via the Prx3-Mfn2-mitophagy pathways.

Context: The pathogenesis of cardiomyocyte death is closely associated with mitochondrial homeostasis via poorly understood mechanisms.Objective: The aim of our study is to explore the contribution of large tumor suppressor kinase 2 (LATS2) to the apoptosis of cardiomyocyte H9C2 cells.Materials and Methods: Adenovirus-mediated LATS2 overexpression was carried out in H9C2 cells. The cell viability and apoptosis rate were measured via an MTT assay, TUNEL staining, western blotting, an ELISA, and an LDH release assay. Mitophagy was quantified using immunofluorescence and western blotting.Results: The overexpression of LATS2 in H9C2 cells drastically promoted cell death. Molecular investigations showed that LATS2 overexpression was associated with mitochondrial injury, as evidenced by increased mitochondrial ROS production, reduced antioxidant factor levels, increased cyt-c liberation into the nucleus and activated mitochondrial caspase-9-dependent apoptotic pathway activity. Furthermore, our results demonstrated that LATS2-mediated mitochondrial malfunction by repressing mitophagy and that the reactivation of mitophagy could sustain mitochondrial integrity and homeostasis in response to LATS2 overexpression. Furthermore, we found that LATS2 inhibited mitophagy by inactivating the Prx3-Mfn2 axis. The reactivation of Prx3-Mfn2 pathways abrogated the LATS2-mediated inhibition of mitochondrial apoptosis in H9C2 cells.Conclusions: The overexpression of LATS2 induces mitochondrial stress by repressing protective mitophagy in a manner dependent on Prx3-Mfn2 pathways, thus reducing the survival of H9C2 cells.

Redirecting immunity via covalently incorporated immunogenic sialic acid on the tumor cell surface.

Techniques eliciting anti-tumor immunity are of interest for immunotherapy. We herein report the covalent incorporation of a non-self immunogen into the tumor glycocalyx by metabolic oligosaccharide engineering with 2,4-dinitrophenylated sialic acid (DNPSia). This enables marked suppression of pulmonary metastasis and subcutaneous tumor growth of B16F10 melanoma cells in mice preimmunized to produce anti-DNP antibodies. Located on the exterior glycocalyx, DNPSia is well-positioned to recruit antibodies. Given the high levels of natural anti-DNP antibodies in humans and ubiquitous sialylation across many cancers, DNPSia offers a simplified route to redirect immunity against diverse tumors without recourse to preimmunization.

Optical tracking of phagocytosis with an activatable profluorophore metabolically incorporated into bacterial peptidoglycan.

Phagocytosis is critical for immunity against pathogens. Prior imaging using dye-labeled synthetic beads or green fluorescent protein-expressing bacteria is limited by "always-on" signals which compromise discerning phagocytosed particles from adherent particles. Targeting cellular internalization of pathogens into acidic phagolysosomes, we herein report "turn-on" fluorescence imaging of phagocytosis with viable bacteria featuring peptidoglycans covalently modified with rhodamine-lactam responsive to acidic pH. Culturing of Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus) with d-lysine conjugated rhodamine-lactam and fluorescein isocyanate (FITC) leads to efficient metabolic incorporation of FITC and rhodamine-lactam into bacterial peptidoglycan. E. coli and S. aureus become red-emissive upon phagocytosis into Raw 264.7 macrophages. With FITC as the reference signal, the mono- and dual-color emission allow efficient in situ distinction of ingested bacteria from extracellular bacteria. Given the ease of optical peptidoglycan labeling, the prevalence of microbial peptidoglycan and preservation of microbial surface landscape, this approach would be of use for investigation on microbial pathogenesis and high-throughput screening of immunomodulators of phagocytosis.

Aqueous Extract of Terminalia chebula Induces Apoptosis in Lung Cancer Cells Via a Mechanism Involving Mitochondria-mediated Pathways

The current study was designed to evaluate the aqueous extract of Terminalia chebula activity, and the main pathway was detected on lung cancer by extracts of T. chebula. Aqueous extract of T. chebula was separated using a zeolite, and five fractions of T. chebula extract were obtained and analyzed by ultraviolet (UV) and infrared (IR) spectroscopy. Antiproliferative activity was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) methods against human lung cancer (A549) and mouse lung cancer cell line LLC. T. chebula acts by regulating the Bcl-2 family protein-mediated mitochondrial pathway detected by western blot. Fraction 4 of the T. chebula extract showed much function and was thus studied further. Fraction 4 increased the activation of caspase-3, induced PARP cleavage, and promoted cytochrome c release into the cytoplasm. These data suggest that T. chebula acts by regulating the Bcl-2 family protein-mediated mitochondrial pathway and provide evidence that T. chebula deserves further investigation as a natural agent for treating and preventing cancer.

A targetable acid-responsive micellar system for signal activation based high performance surgical resolution of tumors.

Tumor-reporting probes are valuable to guide surgical resection of tumor foci elusive to visual inspection. As tumors display distinct arrays of lectins, we herein report the construction and screening of a panel of glycan-displaying smart micelles for tumor illumination in mice. These micelles consist of cores of rhodamine-sultam (RST) responsive to lysosomal acidity and a corona of poly[styrene-alter-(maleic acid)] glycosylated with d-glucosamine, d-mannosamine or d-galactosamine. These nanoscale micelles are nonfluorescent extracellularly and become luminescent within acidic lysosomes, enabling optical tracking of tumor endocytosis of the micelles. In vivo screening revealed high-efficiency uptake and fluorescence activation of galactosylated micelles (RST@P-Gal) by subcutaneous tumor and disseminated liver tumor foci with diameters of 0.1-10 mm, which is significantly below minimal residual cancer (a minimum of 1 cm clearance). This system is readily adapted to illuminate different tumors by expanding the diversity of glycans on the shell. Given the robustness and high performance of this system, lectin-targeted responsive micelles are attractive for diagnosis or surgical ablation of tumors.

A fluorescently labelled sialic acid for high performance intraoperative tumor detection.

Surgical resection is widely used for tumor treatment, necessitating approaches for the precise locating of elusive tumor foci. We report the high performance detection of tumors in mice with fluorescein-isothiocyanate (FITC) labelled sialic acid (FITC-SA), a fluorescent monosaccharide with low cytoxicity. Analysis of mice intravenously injected with FITC-SA revealed high target-to-background fluorescence ratios in subcutaneous tumors and liver tumor implants with 0.2-5 mm diameters, which are significantly below the clinical threshold of minimal residual cancer (∼1 cm clearance). Extracellular FITC-SA is quickly cleared from circulation whereas the intracellular FITC-SA could be metabolically incorporated into glycoproteins via a cellular sialylation pathway. Compared with FITC-SA-laden nanoparticles, free FITC-SA is preferentially and quickly taken up by tumors in mice and displays high tumor-to-background signal contrast, suggesting the potential for fluorescence directed surgical ablation of tumors.