Etoposide combined with cytarabine and pegfilgrastim for poorly mobilizing patients with multiple myeloma and lymphoma: A prospective multicentre study.

A chemotherapy-based mobilization regimen in patients who mobilize poorly, based on etoposide, cytarabine and pegfilgrastim (EAP), has recently been introduced. The aim of this prospective study was to investigate the efficacy and safety of the EAP regimen in patients with poorly mobilizing multiple myeloma (MM) or lymphoma. This single-arm clinical trial was performed at eight public hospitals in China and was registered as a clinical trial (NCT05510089). The inclusion criteria were; (1) diagnosis of MM or lymphoma, (2) defined as a 'poor mobilizer' and (3) aged 18-75 years. The EAP regimen consisted of etoposide 75 mg/m2/day on days 1-2, cytarabine 300 mg/m2 every 12 h on days 1-2 and pegfilgrastim 6 mg on day 6. The primary endpoint of the study was the ratio of patients achieving adequate mobilization (≥2.0 × 106 CD34+ cells/kg). From 1 September 2022 to 15 August 2023, a total of 58 patients were enrolled, 53 (91.4%) achieved adequate mobilization, while 41 (70.7%) achieved optimal mobilization with a median number of cumulative collected CD34+ cells was 9.2 (range 2.1-92.7) × 106/kg and the median number of apheresis per patient of 1.2. The median time from administration of the EAP regimen to the first apheresis was 12 days. Approximately 8.6% of patients required plerixa for rescue, which was successful. Twelve (20.7%) of the 58 patients suffered grade 2-3 infections, while 25 (43.1%) required platelet transfusions. The duration of neutrophil and platelet engraftment was 11 days. In conclusion, these results suggest that the EAP mobilization regimen might be a promising option for poorly mobilizing patients with MM or lymphoma.

Nitric Oxide-Releasing Porous Coating with Antibacterial Activity and Blood Compatibility.

Nitric oxide (NO)-releasing coating is promising to enhance the biocompatibility of medical devices. In this study, polyurethane (PU) and S-nitrosated keratin (KSNO) were dissolved with dimethyl sulfoxide (DMSO) and tetrahydrofuran (THF) to prepare a coating solution. This solution is facile to form a porous coating on various substrates based on solvent-evaporation-induced phase separation (SEIPS). The coating could continuously release NO up to 200 h in the presence of ascorbic acid (Asc). In addition, the coating could accelerate endothelialization by promoting the viability of human umbilical vein endothelial cells (HUVECs) while inhibiting the proliferation of human umbilical artery smooth muscle cells (HUASMCs). Furthermore, the coating had good antibacterial activity and blood compatibility. Taken together, this universal coating provides wider potential applications in the field of cardiovascular implants.

Randomized, Single-Blind, Comparative Study of Remimazolam Besylate vs Propofol for Facial Plastic Surgery.

BACKGROUND: Use of local anesthesia and conscious sedation with a combination of a sedative and anesthetic drug during a surgical procedure is an approach designed to avoid intubation, which produces fewer adverse events compared to general anesthesia. In the present study, a comparison was made between the efficacy and safety of remimazolam besylate and propofol for facial plastic surgery. OBJECTIVES: The objective was to evaluate the clinical efficacy, comfort, and incidence of adverse events of remimazolam compared with propofol combined with alfentanil in outpatient facial plastic surgery. METHODS: In this randomized, single-blind, single-center, comparative study, facial plastic surgery patients were randomly divided into remimazolam-alfentanil (n = 50) and propofol-alfentanil (n = 50) groups for sedation and analgesia. The primary endpoint was the incidence of hypoxemia, while secondary endpoints included efficacy and safety evaluations. RESULTS: There were no significant differences regarding the surgical procedure, sedation and induction times, pain and comfort scores, muscle strength recovery, heart rate, respiratory rate, and blood pressure, but the dosage of alfentanil administered to the remimazolam group (387.5 µg) was lower than that for the propofol group (600 µg). The incidence of hypoxemia (P = .046) and towing of the mandibular (P = .028), as well as wake-up (P = .027) and injection pain (P = .008), were significantly higher in the propofol group than the remimazolam group. CONCLUSIONS: Remimazolam and propofol had similar efficacies for sedation and analgesia during facial plastic surgery, but especially the incidence of respiratory depression was significantly lower in patients given remimazolam.

Multiresponsive Keratin-Polysulfobetaine Conjugate-Based Micelles as Drug Carriers with a Prolonged Circulation Time.

A protein-polymer conjugate combines the chemical properties of a synthetic polymer chain with the biological properties of a protein. In this study, the initiator terminated with furan-protected maleimide was first synthesized through three steps. Then, a series of zwitterionic poly[3-dimethyl(methacryloyloxyethyl)ammonium propanesulfonate] (PDMAPS) was synthesized via atom transfer radical polymerization (ATRP) and optimized. Subsequently, well-controlled PDMAPS was conjugated with keratin via thiol-maleimide Michael addition. The keratin-PDMAPS conjugate (KP) could self-assemble in an aqueous solution to form micelles with low critical micelle concentration (CMC) values and good blood compatibility. The drug-loaded micelles exhibited triple responsiveness to pH, glutathione (GSH), and trypsin under tumor microenvironments. In addition, these micelles showed high toxicity against A549 cells while low toxicity on normal cells. Furthermore, these micelles performed prolonged blood circulation.

pH/enzyme dual sensitive and nucleus-targeting dendrimer nanoparticles to enhance the antitumour activity of doxorubicin.

Direct delivery of drugs into the nucleus is a promising nanotechnology therapy, since the nucleus is one of the most important organelles controlling cell proliferation and apoptosis. Here, we report a nucleus-targeting nanocarrier for nuclear drug delivery using a pH/enzyme dual sensitive strategy. The specific ligand PGM (PKKKRKV-GFLG-Mp), composed of nuclear localization sequence (PKKKRKV), enzyme-sensitive tetrapeptide (Gly-Phe-Leu-Gly, GFLG), and pH-sensitive molecules morpholine (Mp), was modified on poly (amidoamine) (PAMAM) by maleimide active polyethylene glycol ester (NHS-PEG-MAL) to form PAMAM-PEG-PGM. Doxorubicin (DOX) was loaded into the cavity of PAMAM to prepare DOX/PAMAM-PEG-PGM. In vitro release study suggested DOX release from DOX/PAMAM-PEG-PGM nanoparticles followed pH and enzyme-triggered manner. In vitro studies showed DOX/PAMAM-PEG-PGM nanoparticles could not only promote cell internalization through the charge switching of morpholine, but also achieve nuclear internalization by the mediation of composite formed by NLS and importin α/ß receptor. Further, employing H22 tumour-bearing BALB/c mice as a model, the systemic distribution and anticancer effects of nanoparticles were studied in vivo. The results indicated the nanoparticles could preferentially accumulate in the tumour site in vivo, and the tumour inhibition rate was 88.47%. In short, the nanoparticles developed could be promising in application to nucleus-targeting therapy to enhance antitumour activity.

Neutrophil-mediated clinical nanodrug for treatment of residual tumor after focused ultrasound ablation.

BACKGROUND: The risk of local recurrence after high-intensity focused ultrasound (HIFU) is relatively high, resulting in poor prognosis of malignant tumors. The combination of HIFU with traditional chemotherapy continues to have an unsatisfactory outcome because of off-site drug uptake. RESULTS: Herein, we propose a strategy of inflammation-tendency neutrophil-mediated clinical nanodrug targeted therapy for residual tumors after HIFU ablation. We selected neutrophils as carriers and PEGylated liposome doxorubicin (PLD) as a model chemotherapeutic nanodrug to form an innovative cell therapy drug (PLD@NEs). The produced PLD@NEs had a loading capacity of approximately 5 µg of PLD per 106 cells and maintained the natural characteristics of neutrophils. The targeting performance and therapeutic potential of PLD@NEs were evaluated using Hepa1-6 cells and a corresponding tumor-bearing mouse model. After HIFU ablation, PLD@NEs were recruited to the tumor site by inflammation (most in 4 h) and released PLD with inflammatory stimuli, leading to targeted and localized postoperative chemotherapy. CONCLUSIONS: This effective integrated method fully leverages the advantages of HIFU, chemotherapy and neutrophils to attract more focus on the practice of improving existing clinical therapies.

Biosafety, Functionalities, and Applications of Biomedical Micro/nanomotors.

Due to their unique ability to actively move, micro/nanomotors offer the possibility of breaking through the limitations of traditional passive drug delivery systems for the treatment of many diseases, and have attracted the increasing attention of researchers. However, at present, the realization of many advantages of micro/nanomotors in disease treatment in vivo is still in its infancy, because of the complexity and particularity of diseases in different parts of human body. In this Minireview, we first focus on the biosafety and functionality of micro/nanomotors as a biomedical treatment system. Then, we address the treatment difficulties of various diseases in vivo (such as ophthalmic disease, orthopedic disease, gastrointestinal disease, cardiovascular disease, and cancer), and then review the research progress of biomedical micro/nanomotors in the past 20 years, Finally, we propose the challenges in this field and possible future development directions.

Catalytic Generation of Nitric Oxide from Poly(ε-caprolactone)/Phosphobetainized Keratin Mats for a Vascular Tissue Engineering Scaffold.

Tissue-engineered vascular graft (TEVG) is a promising alternative to meet the clinical demand of organ shortages. Herein, human hair keratin was extracted by the reduction method, followed by modification with zwitterionic 2-methacryloyloxyethyl phosphorylcholine (MPC) through thiol-Michael addition to improve blood clotting nature. Then, phosphobetainized keratin (PK) was coelectrospun with poly(ε-caprolactone) (PCL) to afford PCL/PK mats with a ratio of 7:3. The surface morphology, chemical structure, and wettability of these mats were characterized. The biocomposite mats selectively enhanced adhesion, migration, and growth of endothelial cells (ECs) while suppressed proliferation of smooth muscle cells (SMCs) in the presence of glutathione (GSH) and GSNO due to the catalytic generation of NO. In addition, these mats exhibited good blood anticoagulant activity by reducing platelet adhesion, prolonging blood clotting time, and inhibiting hemolysis. Taken together, these NO-generating PCL/PK mats have potential applications as a scaffold for vascular tissue engineering with rapid endothelialization and reduced SMC proliferation.

Coronary Stents Decorated by Heparin/NONOate Nanoparticles for Anticoagulant and Endothelialized Effects.

In the treatment of coronary artery disease (CAD), the use of stent implantation often leads to clinical complications such as restenosis, delayed endothelial healing, and thrombosis. Here, we develop a double drug sustained-release coating for the stent surface by grafting heparin/NONOate nanoparticles (Hep/NONOates). The Hep/NONOates and surface modification of the stent were characterized by X-ray photoelectron spectroscopy, attenuated total reflection Fourier-transform infrared spectroscopy, static water contact angle, and scanning electron microscopy (SEM), and the release behaviors of the anticoagulant, heparin (Hep) and the bioactive molecule, nitric oxide (NO) were studied. Furthermore, the blood compatibility and cytotoxicity of the modified stent were evaluated by whole blood adhesion and platelet adhesion tests, hemolysis assay, morphological changes of red blood cells, plasma recalcification time assay, in vitro coagulation time tests, and MTT assay. Finally, the results of a rabbit carotid artery stent implantation experiment showed that the double drug sustained-release coating for the stent can accelerate regeneration of endothelial cells and keep good anticoagulant activity. This study can provide new design ideas based on nanotechnology for improving the safety and effectiveness of drug-eluting stents.

Biodegradable Zwitterion/PLGA Scaffold Enables Robust Healing of Rat Calvarial Defects with Ultralow Dose of rhBMP-2.

Designing smart scaffolds to reduce administration dosage under the premise of functional healing of bone defects to avoid the severe side effects associated with BMP-2 treatments is one of the essential goals in bone tissue engineering. Here, we report a novel biodegradable PLGA/PSBMA composite as the scaffold for bone tissue engineering. The introduction of zwitterionic PSBMA components can alter the intrinsic burst degradation behavior of PLGA and enable a sustained degradation of the scaffold over the time. The PLGA/PSBMA scaffold can sequester rhBMP-2 and enable a sustained release of the sequestered rhBMP-2 with preserved bioactivity. Furthermore, PLGA/PSBMA scaffolds were able to guide robust healing of critical-sized nonunion calvarial defects (5 mm) at an ultralow dose of 400 ng/scaffold, at which level successful healing of critical-sized bone defects has never been reported. These findings indicate the PLGA/PSBMA scaffolds as novel high-efficiency rhBMP-2 delivery vehicles for bone tissue engineering, and the concept of utilizing the material, which is capable of maintaining the bioactivity of the proteins in the preparation of scaffolds, may open a new avenue for the design of smart scaffolds/vehicles for high-efficiency protein/bioactive drug therapies.

MicroRNA-212 suppresses nonsmall lung cancer invasion and migration by regulating ubiquitin-specific protease-9.

MicroRNAs (miRNAs) play crucial roles in various biological processes, including migration, proliferation, differentiation, cell cycling, and apoptosis. Epithelial-mesenchymal transition (EMT) has been shown to be related to the capability of migration and invasion in many tumor cells. In this study, we used wound-healing assay and transwell invasion to analysis the capability of migration and invasion in non-small-cell lung carcinoma (NSCLC), respectively. The expression of ubiquitin-specific protease-9-X-linked (USP9X) and miR-212 messenger RNA (mRNA) was determined by quantitative real-time polymerase chain reaction and Western blot analysis was used to determine the E-cadherin and vimentin expression. Our results showed that miR-212 mimic inhibited cell migration and invasion, while miR-212 inhibitor increased cell migration and invasion. There was no significant difference between WP1130 and miR-212 mimic combined with WP1130 groups. Moreover, WP1130 inhibited the capability of the migration and invasion of NSCLC cells. Western blot analysis displayed that miR-212 mimic upregulated E-cadherin expression and downregulated vimentin expression, while miR-212 inhibitor downregulated E-cadherin and upregulated vimentin expression. These data showed that miR-212 regulated NSCLC cell invasion and migration by regulating USP9X expression. Taken together, these findings indicated that miR-212 regulated NSCLC cells migration and invasion through targeting USP9X involved in EMT.

Mussel-Inspired Surface Functionalization of PET with Zwitterions and Silver Nanoparticles for the Dual-Enhanced Antifouling and Antibacterial Properties.

Herein, we designed and constructed a dual functional surface with antimicrobial and antifouling abilities to prevent protein and bacterial attachment that are significant challenges in biomedical devices. Primary amino-group-capped sulfobetaine of DMMSA was synthesized and then grafted onto polydopamine pretreated PET sheets via click chemistry. The sheets were subsequently immersed into silver ion solution, in which the absorbed silver ions were reduced to silver nanoparticles (AgNPs) in situ by a polydopamine layer. The antifouling assays demonstrated that the resultant PET/DMMSA/AgNPs sheets exhibited great antifouling performances against bovine serum albumin (BSA), bovine fibrinogen (BFG), platelets, and bacteria, the critical proteins/microorganisms leading to implant failure. The antibacterial data suggested that the sheets had dual functions as inhibitors of bacterial growth and bactericide and could efficiently delay the biofilm formation. This repelling and killing approach is green and simple, with potential biomedical applications.

Layer-by-layer assembled PEI-based vector with the upconversion luminescence marker for gene delivery.

The upconversion luminescence (UCL) marker based on upconversion nanoparticles (UCNPs) shows unique advantages over traditional fluorescence markers, such as enhanced tissue penetration, better photostability, and less autofluorescence. Herein, we constructed a new UCL gene-delivery nonviral vector via layer-by-layer self-assembly of poly(ethylene imine) (PEI) with UCNPs. To reduce the cytotoxicity of PEI, citric acid (CA) was introduced for aqueous modification, and PEI assembly was introduced on the UCNP surface. Our data show that the nonviral vector for UCL gene-delivery demonstrates excellent photostability, low toxicity, and good stability under physiological or serum conditions and can strongly bind to DNA. Moreover, this UCL PEI-based vector could serve as a promising fluorescent gene-delivery carrier for theranostic applications.

Mesoporous Silica Nanoparticles-Encapsulated Agarose and Heparin as Anticoagulant and Resisting Bacterial Adhesion Coating for Biomedical Silicone.

Silicone catheter has been widely used in peritoneal dialysis. The research missions of improving blood compatibility and the ability of resisting bacterial adhesion of silicone catheter have been implemented for the biomedical requirements. However, most of modification methods of surface modification were only able to develop the blood-contacting biomaterials with good hemocompatibility. It is difficult for the biomaterials to resist bacterial adhesion. Here, agarose was selected to resist bacterial adhesion, and heparin was chosen to improve hemocompatibility of materials. Both of them were loaded into mesoporous silica nanoparticles (MSNs), which were successfully modified on the silicone film surface via electrostatic interaction. Structures of the mesoporous coatings were characterized in detail by dynamic light scattering, transmission electron microscopy, Brunauer-Emmett-Teller surface area, thermogravimetric analysis, Fourier transform infrared spectroscopy, scanning electron microscope, and water contact angle. Platelet adhesion and aggregation, whole blood contact test, hemolysis and related morphology test of red blood cells, in vitro clotting time tests, and bacterial adhesion assay were performed to evaluate the anticoagulant effect and the ability of resisting bacterial adhesion of the modified silicone films. Results indicated that silicone films modified by MSNs had a good anticoagulant effect and could resist bacterial adhesion. The modified silicone films have potential as blood-contacting biomaterials that were attributed to their biomedical properties.

Preparation and Biocompatibility of Gold@ Polypyrrole-Chitosan with Core-Shell Nanostructure.

A two-step method for preparing Au@polypyrrole-chitosan core-shell nanoparticles (Au @ PPy-CS NPs) was fabricated by in situ polymerization of pyrrole monomer on the surface of Au spheres in chitosan solution. Transmission electron microscopy (TEM) images showed the presence of core-shell structure of nanoparticles. Energy-Dispersive Spectroscopy (EDS) and Fourier transform infrared (FTIR) spectroscopy were adopted to verify the shell is polypyrrole-chitosan. Ultraviolet-visible (UV-vis) and X-ray diffraction (XRD) showed that Au was present in the core-shell nanoparticles. The biocompatibility of Au @ PPy-CS NPs was characterized by in vitro for hemolysis assay and cytotoxicity experiments. Results indicated the Au @ PPy-CS NPs had good blood compatibility and low cytotoxicity. The Au @ PPy-CS NPs we proposed provide a promising platform of blood circulation system for early illness diagnosis and therapy.

Preparation and Biosafety Assessment of Water-Soluble Hyperbranched Polyester Nanoparticles with Carboxylic Acid Functional Groups.

Biosafety assessment of nanoparticles has been of great interest in the development of nanoscience and nanotechnology. Here, the water-soluble hyperbranched polyester nanoparticles with carboxylic acid functional group (HBPE-CA NPs) are synthesized and characterized. They have amphiphilic structure that include hydrophobic hyperbranched polyester (HBPE) core and hydrophilic carboxylated terminal groups. Biosafety assessment tests of the HBPE-CA NPs include coagulation times, hemolysis, complement activation, platelet activation and cytotoxicity (MTT) are performed. The results show that the HBPE-CA NPs exhibit good hemocompatibility that strongly depend on the amphiphilic structure. Moreover, the results also indicate the non-cytotoxicity of the HBPE-CA NPs. So the HBPE-CA NPs provide a promising platform of blood circulation system for illness therapy with the help of the drug-loaded capacity of-HBPE.

Mild Anticoagulant Effect of Heparin-Loaded Polycaprolactone Microspheres.

This development of the micro- and nanoparticle technology will bring a new momentum to drug delivery and biomedical therapy. In this case, heparin-loaded polycaprolactone microspheres (PCL-Hep MSs) were prepared by a single-step phase separation method, and characterized by transmission electron microscopy (TEM), dynamic light scattering (DLS), and fourier transform infrared spectroscopy (FTIR). The hemocompatibility and anticoagulant effect of the PCL-Hep MSs were investigated for heparin loading and release study, coagulation tests, hemolysis assay, morphological changes of red blood cells, complement activation, and cytotoxicity experiments. The results showed that the PCL-Hep MSs are hemocompatible with low level of cytotoxicity. Moreover, they have the potential to be used as a mild anticoagulant compared to pure heparin.

A chitosan-Au-hyperbranched polyester nanoparticles-based antifouling immunosensor for sensitive detection of carcinoembryonic antigen.

Analysts are always interested in finding new functional nanomaterials and devices with good properties for electrochemical sensor applications. In this paper, hyperbranched polyester nanoparticles with carboxylic acid functional groups (HBPE-CA NPs) were synthesized and combined with chitosan wrapped around Au nanoparticles (CS-Au NPs) to prepare a novel and sensitive electrochemical immunosensor by adsorption of carcinoembryonic antibody (anti-CEA) on the (HBPE-CA)/CS-Au NPs modified glass carbon electrode (GCE). Under the optimized conditions, the proposed immunosensor displayed a good amperometric response to carcinoembryonic antigen (CEA). Moreover, based on the antibiofouling properties, the immunosensor could be used for the direct detection of CEA in whole blood, and exhibited a wide detection range (1-10(7) fg mL(-1)), and a low detection limit of 0.251 fg mL(-1) (signal/noise = 3). Control experiments were also carried out by using ascorbic acid (AA), uric acid (UA), human immunoglobulin G (IgG), BSA and glucose in the absence of CEA. The good stability and repeatability of this immunosensor were also proven. Importantly, the results of the detection of clinical whole blood specimens with the proposed immunosensor showed good consistency with the data determined by enzyme-linked immunosorbent assay (ELISA) in serum samples. Furthermore, the developed immunosensor could provide a promising immunoassay strategy for clinical applications, since the values we measured in whole blood directly are likely closer to the real values.

Removal of total cyanide in coking wastewater during a coagulation process: significance of organic polymers.

Whether a cationic organic polymer can remove more total cyanide (TCN) than a non-ionic organic polymer during the same flocculation system has not been reported previously. In this study, the effects of organic polymers with different charge density on the removal mechanisms of TCN in coking wastewater are investigated by polyferric sulfate (PFS) with a cationic organic polymer (PFS-C) or a non-ionic polymer (PFS-N). The coagulation experiments results show that residual concentrations of TCN (Fe(CN)6(3-)) after PFS-C flocculation (TCN < 0.2 mg/L) are much lower than that after PFS-N precipitation. This can be attributed to the different TCN removal mechanisms of the individual organic polymers. To investigate the roles of organic polymers, physical and structural characteristics of the flocs are analyzed by FT-IR, XPS, TEM and XRD. Owing to the presence of N+ in PFS-C, Fe(CN)6(3-) and negative flocs (Fe(CN)6(3-) adsorbed on ferric hydroxides) can be removed via charge neutralization and electrostatic patch flocculation by the cationic organic polymer. However, non-ionic N in PFS-N barely reacts with cyanides through sweeping or bridging, which indicates that the non-ionic polymer has little influence on TCN removal.

PLA inhibits TNF-α-induced PANoptosis of prostate cancer cells through metabolic reprogramming.

Previous studies have shown that phenyllactic acid (alpha-Hydroxyhydrocinnamic acid, 2-Hydroxy-3-phenylpropionic acid, PLA), a type of organic acid metabolite, has excellent diagnostic efficacy when used to differentiate between prostate cancer, benign prostatic hyperplasia, and prostatitis. This research aims to explore the molecular mechanism by which PLA influences the PANoptosis of prostate cancer (PCa) cell lines. First, we found that PLA was detected in all prostate cancer cell lines (PC-3, PC-3 M, DU145, LNCAP). Further experiments showed that the addition of PLA to prostate cancer cells could promote ATP generation, enhance cysteine desulfurase (NFS1) expression, and reduce tumor necrosis factor alpha (TNF-α) levels, thereby inhibiting apoptosis in prostate cancer cells. Notably, overexpression of NFS1 can inhibit the binding of TNF-α to serpin mRNA binding protein 1 (SERBP1), suggesting that NFS1 competes with TNF-α for binding to SERBP1. Knockdown of SERBP1 significantly reduced the level of small ubiquity-related modifier (SUMO) modification of TNF-α. This suggests that NFS1 reduces the SUMO modification of TNF-α by competing with SERBP1, thereby reducing the expression and stability of TNF-α and ultimately inhibiting apoptosis in prostate cancer cell lines. In conclusion, PLA inhibits TNF-α induced panapoptosis of prostate cancer cells through metabolic reprogramming, providing a new idea for targeted treatment of prostate cancer.