Self-adaptive pyroptosis-responsive nanoliposomes block pyroptosis in autoimmune inflammatory diseases.

Nanoliposomes have a broad range of applications in the treatment of autoimmune inflammatory diseases because of their ability to considerably enhance drug transport. For their clinical application, nanoliposomes must be able to realize on-demand release of drugs at disease sites to maximize drug-delivery efficacy and minimize side effects. Therefore, responsive drug-release strategies for inflammation treatment have been explored; however, no specific design has been realized for a responsive drug-delivery system based on pyroptosis-related inflammation. Herein, we report a pioneering strategy for self-adaptive pyroptosis-responsive liposomes (R8-cardiolipin-containing nanoliposomes encapsulating dimethyl fumarate, RC-NL@DMF) that precisely release encapsulated anti-pyroptotic drugs into pyroptotic cells. The activated key pyroptotic protein, the N-terminal domain of gasdermin E, selectively integrates with the cardiolipin of liposomes, thus forming pores for controlled drug release, pyroptosis, and inflammation inhibition. Therefore, RC-NL@DMF exhibited effective therapeutic efficacies to alleviate autoimmune inflammatory damages in zymosan-induced arthritis mice and dextran sulfate sodium-induced inflammatory bowel disease mice. Our novel approach holds great promise for self-adaptive pyroptosis-responsive on-demand drug delivery, suppressing pyroptosis and treating autoimmune inflammatory diseases.

Highly Strong, Tough, and Cryogenically Adaptive Hydrogel Ionic Conductors via Coordination Interactions.

Despite the promise of high flexibility and conformability of hydrogel ionic conductors, existing polymeric conductive hydrogels have long suffered from compromises in mechanical, electrical, and cryoadaptive properties due to monotonous functional improvement strategies, leading to lingering challenges. Here, we propose an all-in-one strategy for the preparation of poly(acrylic acid)/cellulose (PAA/Cel) hydrogel ionic conductors in a facile yet effective manner combining acrylic acid and salt-dissolved cellulose, in which abundant zinc ions simultaneously form strong coordination interactions with the two polymers, while free solute salts contribute to ionic conductivity and bind water molecules to prevent freezing. Therefore, the developed PAA/Cel hydrogel simultaneously achieved excellent mechanical, conductive, and cryogenically adaptive properties, with performances of 42.5 MPa for compressive strength, 1.6 MPa for tensile strength, 896.9% for stretchability, 9.2 MJ m-3 for toughness, 59.5 kJ m-2 for fracture energy, and 13.9 and 6.2 mS cm-1 for ionic conductivity at 25 and -70 °C, respectively. Enabled by these features, the resultant hydrogel ionic conductor is further demonstrated to be assembled as a self-powered electronic skin (e-skin) with high signal-to-noise ratio for use in monitoring movement and physiological signals regardless of cold temperatures, with hinting that could go beyond high-performance hydrogel ionic conductors.

Comparison of the ability of exosomes and ectosomes derived from adipose-derived stromal cells to promote cartilage regeneration in a rat osteochondral defect model.

BACKGROUND: Extracellular vesicles (EVs) derived from mesenchymal stromal cells (MSCs) offer promising prospects for stimulating cartilage regeneration. The different formation mechanisms suggest that exosomes and ectosomes possess different biological functions. However, little attention has been paid to the differential effects of EV subsets on cartilage regeneration. METHODS: Our study compared the effects of the two EVs isolated from adipose-derived MSCs (ASCs) on chondrocytes and bone marrow-derived MSCs (BMSCs) in vitro. Additionally, we loaded the two EVs into type I collagen hydrogels to optimize their application for the treatment of osteochondral defects in vivo. RESULTS: In vitro experiments demonstrate that ASC-derived exosomes (ASC-Exos) significantly promoted the proliferation and migration of both cells more effectively than ASC-derived ectosomes (ASC-Ectos). Furthermore, ASC-Exos facilitated a stronger differentiation of BMSCs into chondrogenic cells than ASC-Ectos, but both inhibited chondrocyte apoptosis to a similar extent. In the osteochondral defect model of rats, ASC-Exos promoted cartilage regeneration in situ better than ASC-Ectos. At 8 weeks, the hydrogel containing exosomes group (Gel + Exo group) had higher macroscopic and histological scores, a higher value of trabecular bone volume fraction (BV/TV), a lower value of trabecular thickness (Tb.Sp), and a better remodeling of extracellular matrix than the hydrogel containing ectosomes group (Gel + Ecto group). At 4 and 8 weeks, the expression of CD206 and Arginase-1 in the Gel + Exo group was significantly higher than that in the Gel + Ecto group. CONCLUSION: Our findings indicate that administering ASC-Exos may be a more effective EV strategy for cartilage regeneration than the administration of ASC-Ectos.

Local Injection of Rapamycin-Loaded Pcl-Peg Nanoparticles for Enhanced Tendon Healing in Rotator Cuff Tears via Simultaneously Reducing Fatty Infiltration and Drug Toxicity.

As a common cause of shoulder pain, rotator cuff tears (RCTs) are difficult to treat clinically because of their unsatisfactory prognosis due to the fatty infiltration caused by muscle-derived stem cells (MDSCs). Previous studies have found that rapamycin (RAPA) can inhibit fatty infiltration. However, systemic administration of RAPA may cause complications such as infection and nausea, while local administration of RAPA may lead to the cytotoxicity of tendon cells, affecting the healing of rotator cuffs. In this study, biocompatible and clinically approved polycaprolactone-polyethylene glycol (PCL-PEG) is formulated into an injectable nanoparticle for the sustained release of RAPA. The results indicate that the RAPA/PCL-PEG nanoparticles (NPs) can efficiently prolong the release of RAPA and significantly reduce the cytotoxicity of tendon cells caused by RAPA. The study of the fatty infiltration model in rats with delayed rotator cuff repair shows that weekly intraarticular injection of RAPA/PCL-PEG NPs can more effectively reduce the fatty infiltration and muscle atrophy of rat rotator cuffs and leads to better mechanical properties and gait improvements than a daily intraarticular injection of RAPA. These findings imply that local injection of RAPA/PCL-PEG NPs in the shoulder joints can be a potential clinical option for RCTs patients with fatty infiltration.

Externally Heated Diamond ANvil Cell Experimentation (EH-DANCE) for studying materials and processes under extreme conditions.

Externally heated diamond anvil cells provide a stable and uniform thermal environment, making them a versatile device to simultaneously generate high-pressure and high-temperature conditions in various fields of research, such as condensed matter physics, materials science, chemistry, and geosciences. The present study features the Externally Heated Diamond ANvil Cell Experimentation (EH-DANCE) system, a versatile configuration consisting of a diamond anvil cell with a customized microheater for stable resistive heating, bidirectional pressure control facilitated by compression and decompression membranes, and a water-cooled enclosure suitable for vacuum and controlled atmospheres. This integrated system excels with its precise control of both pressure and temperature for mineral and materials science research under extreme conditions. We showcase the capabilities of the system through its successful application in the investigation of the melting temperature and thermal equation of state of high-pressure ice-VII at temperatures up to 1400 K. The system was also used to measure the elastic properties of solid ice-VII and liquid H2O using Brillouin scattering and Raman spectra of carbonates using Raman spectroscopy, highlighting the potential of the EH-DANCE system in high-pressure research.

A comparative study of intestinal Pseudomonas aeruginosa in healthy individuals and ICU inpatients.

The human intestinal tract is considered the most important reservoir of the opportunistic pathogens, including Pseudomonas aeruginosa, which is often overlooked but critical due to its antimicrobial resistance and virulence. Public health interventions to control this pathogen require a comprehensive understanding of its epidemiology and genomics.  In the current study, we identified P. aeruginosa strains from 2,605 fecal samples collected between 2021 to 2022. Among these samples, 574 were from ICU inpatients in Zhejiang province, while 2,031 were obtained from healthy individuals residing in ten different provinces in China. The prevalence of P. aeruginosa intestinal carriage was found to be higher in ICU inpatients (10.28%, 95% CI: 7.79%-12.76%) than that in healthy individuals (3.99%, 81/2,031, 95% CI: 3.14%-4.84%). Similarly, the prevalence of carbapenem-resistant P. aeruginosa (CRPA) was higher in ICU inpatients (32.2%) compared to healthy individuals (7.41%). The population structure analysis of our isolates revealed a predominantly non-clonal distribution, with 41 distinct sequence types identified among 59 P. aeruginosa isolates from ICU inpatients and 38 different STs among 81 P. aeruginosa isolates from healthy individuals. These findings suggest that the individual acquisition of P. aeruginosa is more frequent than patient-to-patient transmission, as evidenced by the polyclonal population structure. Antimicrobial susceptibility testing and genome analysis indicated that P. aeruginosa strains from ICU inpatients exhibited significantly higher resistance rates to most antimicrobials and harbored a greater number of acquired resistance genes compared to strains from healthy individuals. Notably, in ICU inpatients, we identified three isolates of ST463, all of which shared the conserved Tn3-TnpR-ISKpn8-blaKPC-ISKpn6 genetic context. Additionally, five isolates carrying the qacE gene were also identified, these findings suggest that small-scale transmission events may still occur within the ICU setting, posing significant challenges for clinical management. With regard to virulence factors, we observed similar profiles between the two groups, except for phzA2, phzB2, and pilA, which were statistically higher in isolates from healthy individuals. This may be because the accumulating resistance mutations in ICU-derived P. aeruginosa are linked to a decrease in virulence.

Temperature-Mediated Phase Separation Enables Strong yet Reversible Mechanical and Adhesive Hydrogels.

Hydrogels with strong yet reversible mechanical and adhesive properties fabricated in a facile and friendly manner are important for engineering and intelligent electronics applications but are challenging to create and control. Existing approaches for preparing hydrogels involve complicated pretreatments and produce hydrogels that suffer from limited skin applicability. Copolymerized hydrogels are expected to present an intriguing target in this field by means of thermoresponsive features, while the perceived intrinsic flaws of brittleness, easy fracture, and weak adhesion enervate the development prospects. Herein, we report a hydrogel with strong yet reversible mechanical and adhesive properties using cellulose nanofibrils to simultaneously address multiple dilemmas inspired by a temperature-mediated phase separation strategy. This strategy applies temperature-driven formation and dissociation of hydrogen bonds between common copolymers and cellulose nanofibrils to trigger the onset and termination of phase separation for dynamically reversible on-demand properties. The resulting hydrogel exhibits up to 96.0% (117.2 J/m2 vs 4.8 J/m2 for interfacial toughness) and 85.7% (0.02 MPa vs 0.14 MPa for mechanical stiffness) adhesive and mechanical tunability when worked on skin, respectively. Our strategy offers a promising, simple, and efficient way to directly achieve robust adhesion performance in one step using common copolymers and biomass resources, with implications that could go beyond strong yet adhesive hydrogels.

A sweat-pH-enabled strongly adhesive hydrogel for self-powered e-skin applications.

On-skin hydrogel electrodes are poorly conformable in sweaty scenarios due to low electrode-skin adhesion resulting from the sweat film formed on the skin surface, which seriously hinders practical applications. In this study, we fabricated a tough adhesive cellulose-nanofibril/poly(acrylic acid) (CNF/PAA) hydrogel with tight hydrogen-bond (H-bond) networks based on a common monomer and a biomass resource. Furthermore, inherent H-bonded network structures can be disrupted through judicious engineering using excess hydronium ions produced through sweating, which facilitate the transition to protonation and modulate the release of active groups (i.e., hydroxyl and carboxyl groups) accompanied by a pH drop. The lower pH enhances adhesive performance, especially on skin, with a 9.7-fold higher interfacial toughness (453.47 vs. 46.74 J m-2), an 8.6-fold higher shear strength (600.14 vs. 69.71 kPa), and a 10.4-fold higher tensile strength (556.44 vs. 53.67 kPa) observed at pH 4.5 compared to the corresponding values at pH 7.5. Our prepared hydrogel electrode remains conformable on sweaty skin when assembled as a self-powered electronic skin (e-skin) and enables electrophysiological signals to be reliably collected with high signal-to-noise ratios when exercising. The strategy presented here promotes the design of high-performance adhesive hydrogels that may serve to record continuous electrophysiological signals under real-life conditions (beyond sweating) for various intelligent monitoring systems.

Epidemiology and Molecular Characteristics of mcr-9 in Citrobacter spp. from Healthy Individuals and Patients in China.

With the globally prevailing carbapenemase-producing (CP) Citrobacter spp., polymyxin antibiotics have been reconsidered as one of the last-resort treatment options. Our study was conducted to investigate the prevalence of mcr-9 in Citrobacter species. From October to November 2021, 650 fecal samples and 215 Citrobacter isolates were collected from healthy individuals and infected patients, respectively. Isolates were screened for the presence of the mcr-9 gene by the PCR method. mcr-9-carrying strains were identified by matrix-assisted laser desorption ionization-time of flight (MALDI-TOF) mass spectrometry. Due to the susceptibility to colistin, Citrobacter spp. isolates were first induced to increase the expression of mcr-9 on China blue agar plates containing colistin and were then subjected to conjugation experiments. Whole-genome sequencing was performed on the Illumina NovaSeq PE150 system. The prevalence of mcr-9 in the Citrobacter genus from healthy guts and infected patients was 0.62% and 1.86%, respectively. In all mcr-9-positive strains, MICs of polymyxin B were observed at ≤2 µg/mL, displaying a nonresistant phenotype. As for conjugation experiments, only one isolate successfully transferred the mcr-9 gene to Escherichia coli C600. Whole-genome sequencing showed that eight mcr-9-positive Citrobacter isolates carried mcr-9 and genes encoding resistance to beta-lactam antibiotics, including blaCMY, blaDHA, blaSHV, blaTEM, and blaCTX-M. We also discovered that mcr-9 could be located on the pKPC-CAV1321 plasmid. Our study investigated the prevalence of mcr-9 in Citrobacter spp. in both healthy individuals and infected patients and described the carriage of mcr-9 on the pKPC-CAV1321 plasmid for the first time. IMPORTANCE The emergence of mcr homologues posed a serious threat to the therapeutic efficiency of polymyxin antibiotics. Citrobacter freundii is generally regarded as an opportunistic pathogen associated with a variety of nosocomial infections. In this study, we investigated the prevalence of mcr-9 in Citrobacter spp. isolates from healthy individuals and infected patients and highlighted the importance of the rational use of antibiotics. In addition, this epidemiological investigation is the first to describe the carriage of mcr-9 on plasmid pKPC-CAV1321 and confirms the horizontal transfer of this plasmid. Our research may shed new light on further studies of mcr-9 dissemination in humans.

Scalable Production of Biodegradable, Recyclable, Sustainable Cellulose-Mineral Foams via Coordination Interaction Assisted Ambient Drying.

Heavy reliance on petrochemical-based plastic foams in both industry and society has led to severe plastic pollution (the so-called "white pollution"). In this work, we develop a biodegradable, recyclable, and sustainable cellulose/bentonite (Cel/BT) foam material directly from resource-abundant natural materials (i.e., lignocellulosic biomass and minerals) via ambient drying. The strong resistance to the capillary force-driven structural collapse of the preformed three-dimensional (3D) network during the ambient drying process can be ascribed to the purpose-designed cellulose-bentonite coordination interaction, which provides a practical way for the locally scalable production of foam materials with designed shapes without complex processing and intensive energy consumption. Benefiting from the strong cellulose-bentonite coordination interaction, the Cel/BT foam material demonstrates high mechanical strength and outstanding thermal stability, outperforming commercial plastic polystyrene foam. Furthermore, the Cel/BT foam presents environmental impacts much lower than those of petrochemical-based plastic foams as it can be 100% recycled in a closed-loop recycling process and easily biodegraded in the environment (natural cellulose goes back to the carbon cycle, and bentonite minerals return to the geological cycle). This study demonstrates an energy-efficient ambient drying approach for the local and scalable production of an all-natural cellulose/bentonite foam for sustainable packaging, buildings, and beyond, presenting great potential in response to "white pollution" and resource shortage.

Comparative Effects of Exosomes and Ectosomes Isolated From Adipose-Derived Mesenchymal Stem Cells on Achilles Tendinopathy in a Rat Model.

BACKGROUND: Extracellular vesicles derived from mesenchymal stem cells (MSC-EVs) have gained momentum as a treatment for tendinopathy. Multiple studies have demonstrated significant differences in cargo composition between the 2 subtypes of MSC-EVs (ie, exosomes and ectosomes), which may result in different therapeutic effects. However, the effects of the 2 EV subtypes on tendinopathy have not yet been compared. PURPOSE: To compare the effects of adipose stem cell-derived exosomes (ASC-Exos) and ectosomes (ASC-Ectos) on Achilles tendinopathy. STUDY DESIGN: Controlled laboratory study. METHODS: Rats were administered collagenase injections to generate a model of Achilles tendinopathy. A week later, 36 rats were randomly assigned to 3 groups. In each group, Achilles tendons were injected with equal volumes of ASC-Exos, ASC-Ectos, or saline (12 legs/group). The healing outcomes were evaluated by magnetic resonance imaging, histology, immunohistochemistry, transmission electron microscopy, and biomechanical testing at 3 and 5 weeks after collagenase injection. RESULTS: At 3 and 5 weeks, the ASC-Exo group had better histological scores (P = .0036 and P = .0276, respectively), a lower fibril density (P < .0001 and P = .0310, respectively), and a larger collagen diameter (P = .0052 and P < .0001, respectively) than the ASC-Ecto group. At 5 weeks, the expression of collagen type 1 and CD206 in the ASC-Exo group was significantly higher than that in the ASC-Ecto group (P = .0025 and P = .0010, respectively). Regarding biomechanical testing, the ASC-Exo group showed higher failure load (P = .0005), tensile stress (P < .0001), and elastic modulus (P < .0001) than the ASC-Ecto group. CONCLUSION: ASC-Exos had more beneficial effects on tendon repair than ASC-Ectos in a rat model of Achilles tendinopathy. CLINICAL RELEVANCE: Administration of ASC-EVs may have the potential to treat Achilles tendinopathy, and delivery of ASC-Exos could provide additional benefits. It is necessary to compare the healing responses caused by different EV subtypes to further understand their effects on tendinopathy and to aid clinical decision making.

Carriage of the mcr-9 and mcr-10 genes in clinical strains of the Enterobacter cloacae complex in China: a prevalence and molecular epidemiology study.

OBJECTIVES: Enterobacter cloacae complex (ECC) is among the most common carbapenem-resistant Enterobacteriaceae (CRE) in China. The emergence of mcr has rendered CRE strains resistant to the last-line antibiotic colistin. This study investigated the prevalence of mcr-9 and mcr-10 in carbapenem-resistant ECC (CRECC) and carbapenem-susceptible ECC (CSECC) in China. METHODS: The CRECC and CSECC strains were collected from different regions of China. Antimicrobial susceptibility tests, conjugation experiments, whole genome sequencing, bioinformatic analysis, and quantitative RT-PCR were performed to understand the mechanisms of resistance and transmission of mcr in ECC. RESULTS: A total of 534 ECC were collected, among which 57 (10.7%) and 23 (4.3%) were positive for mcr-9 and mcr-10, respectively. The prevalence of mcr-9 in CRECC was significantly higher than that in CSECC (31.8% vs. 3.7%; P < 0.001), while the prevalence of mcr-10 in CRECC was significantly lower (0.8% vs. 5.5%; P < 0.05). Most mcr-9-positive strains (n = 45, 78.9%) exhibited multidrug-resistant phenotype, and four (17.4%) of the mcr-10-positive strains exhibited multi-drug resistance. Coexistence of mcr and carbapenemase genes was commonly observed, including 41 (71.9%) mcr-9-positive strains and one (4.3%) mcr-10-positive strain, and the possibility of co-transfer was confirmed by conjugation experiments. The mcr-positive ECC were highly diverse, while most mcr genes were plasmid-encoded, indicating the important role of plasmids in the transmission of mcr in ECC. Furthermore, the expression of mcr-9 was increased after induction by colistin. CONCLUSIONS: The widespread mcr genes and co-transfer with carbapenemase genes among ECC strains pose an urgent threat to public health.

Strong, tough, ionic conductive, and freezing-tolerant all-natural hydrogel enabled by cellulose-bentonite coordination interactions.

Ionic conductive hydrogels prepared from naturally abundant cellulose are ideal candidates for constructing flexible electronics from the perspective of commercialization and environmental sustainability. However, cellulosic hydrogels featuring both high mechanical strength and ionic conductivity remain extremely challenging to achieve because the ionic charge carriers tend to destroy the hydrogen-bonding network among cellulose. Here we propose a supramolecular engineering strategy to boost the mechanical performance and ionic conductivity of cellulosic hydrogels by incorporating bentonite (BT) via the strong cellulose-BT coordination interaction and the ion regulation capability of the nanoconfined cellulose-BT intercalated nanostructure. A strong (compressive strength up to 3.2 MPa), tough (fracture energy up to 0.45 MJ m-3), yet highly ionic conductive and freezing tolerant (high ionic conductivities of 89.9 and 25.8 mS cm-1 at 25 and -20 °C, respectively) all-natural cellulose-BT hydrogel is successfully realized. These findings open up new perspectives for the design of cellulosic hydrogels and beyond.

Metapone: a Bioconductor package for joint pathway testing for untargeted metabolomics data.

MOTIVATION: Testing for pathway enrichment is an important aspect in the analysis of untargeted metabolomics data. Due to the unique characteristics of untargeted metabolomics data, some key issues have not been fully addressed in existing pathway testing algorithms: (i) matching uncertainty between data features and metabolites; (ii) lacking of method to analyze positive mode and negative mode liquid chromatography-mass spectrometry (LC/MS) data simultaneously on the same set of subjects; (iii) the incompleteness of pathways in individual software packages. RESULTS: We developed an innovative R/Bioconductor package: metabolic pathway testing with positive and negative mode data (metapone), which can perform two novel statistical tests that take matching uncertainty into consideration-(i) a weighted gene set enrichment analysis-type test and (ii) a permutation-based weighted hypergeometric test. The package is capable of combining positive- and negative-ion mode results in a single testing scheme. For comprehensiveness, the built-in pathways were manually curated from three sources: Kyoto Encyclopedia of Genes and Genomes, Mummichog and The Small Molecule Pathway Database. AVAILABILITY AND IMPLEMENTATION: The package is available at https://bioconductor.org/packages/devel/bioc/html/metapone.html. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

In vitro Activity of Contezolid Against Methicillin-Resistant Staphylococcus aureus, Vancomycin-Resistant Enterococcus, and Strains With Linezolid Resistance Genes From China.

Contezolid is a novel oxazolidinone, which exhibits potent activity against gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus (VRE), and penicillin-resistant Streptococcus pneumoniae (PRSP). In this study, the in vitro activity of contezolid was compared with linezolid (LZD), tigecycline (TGC), teicoplanin (TEC), vancomycin (VA), daptomycin (DAP), and florfenicol (FFC) against MRSA and VRE strains isolated from China. Contezolid revealed considerable activity against MRSA and VRE isolates with MIC90 values of 0.5 and 1.0 µg/mL, respectively. For VRE strains with different resistance genotypes, including vanA- and vanM-type strains, contezolid did not exhibit significantly differential antibacterial activity. Furthermore, the antimicrobial activity of contezolid is similar to or slightly better than that of linezolid against MRSA and VRE strains. Subsequently, the activity of contezolid was tested against strains carrying linezolid resistance genes, including Staphylococcus capitis carrying cfr gene and Enterococcus faecalis carrying optrA gene. The results showed that contezolid exhibited similar antimicrobial efficacy to linezolid against strains with linezolid resistance genes. In general, contezolid may have potential benefits to treat the infections caused by MRSA and VRE pathogens.

Modified cellulose nanocrystals are used to enhance the performance of self-healing siloxane elastomers.

Self-healing siloxane elastomers with high ductility can be developed for the manufacture of wearable and flexible electronic devices. However, the poor mechanical properties of self-healing siloxane elastomers limit their industrial applications. Herein, the mechanical and self-healing properties of siloxane elastomers were improved using 3-isocyanatepropyltrimethoxysilane modified (ICNCs) as a crosslinking agent and nanofiller. ICNCs increased the tensile strength and shear strength of siloxane elastomers by 54% and 68.6%, respectively. Significantly, ICNCs decreased the relaxation time for siloxane elastomers and reduced the activation energy for reversible siloxane equilibration from 68 kJ/mol to 38 kJ/mol. Therefore, ICNCs improve the self-healing and welding efficiency of siloxane elastomers. Furthermore, the self-healing siloxane elastomer maintained excellent mechanical properties and thermal properties after three cycles of recycling. Our research reveals that such a material can be applied to the field of recyclable self-healing products and surface adhesives.

Short- to Midterm Clinical and Radiological Outcomes After Matrix-Associated Autologous Chondrocyte Implantation for Chondral Defects in Knees.

BACKGROUND: Matrix-associated autologous chondrocyte implantation (MACI) has been proven to provide favorable short-term results for chondral defects in knees. However, it remains unclear whether the clinical benefits of MACI persist in the longer term. PURPOSE: The purpose of this prospective study was to evaluate the clinical and radiological outcomes, at short- and midterm follow-up, for patients undergoing MACI for focal chondral defects of the knee. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: A total of 30 consecutive patients (31 knees) were treated using MACI between October 2010 and March 2018. There were 24 male patients and 6 female patients with an average age of 26 years (range, 12-48 years). The areas of the cartilage defect were consistently >2 cm2. All patients underwent MACI for a focal chondral defect of the femoral condyles or trochlea in the knee. These patients had been evaluated for up to 5 years, with an average follow-up of 44 months (range, 6-60 months) postoperatively.The International Knee Documentation Committee (IKDC) score, Lysholm score, and magnetic resonance imaging (MRI) with T2 mapping were used to assess the outcomes. RESULTS: No patients were lost to follow-up. Mean IKDC scores improved from 58.6 (range, 40.2-80.5) to 79.1 (range, 39.1-94.3) at 12 months and up to 88.4 (range, 83.9-100) at 5 years; mean Lysholm scores improved from 67.3 (range, 46-95) to 90.6 (range, 71-100) at 12 months and up to 95.9 (range, 85-100) at 5 years. The MRI with T2 mapping value of the transplanted area was evaluated for 21 knees, which revealed no differences compared with the normal area at 12 months postoperatively. CONCLUSION: From the first year onward, the clinical outcome scores and MRI with T2 mapping values showed continuous and marked improvement, suggesting that MACI is a valid option for localized cartilage defects in the knee.

Primaquine phosphate induces the apoptosis of ATRA-resistant acute promyelocytic leukemia cells by inhibition of the NF-κB pathway.

As a subtype of acute myeloid leukemia (AML), acute promyelocytic leukemia (APL) is characterized by a chromosomal translocation, most of which result in the production of a PML-RAR alpha fusion protein. Although the overall survival rate of APL patients has improved dramatically due to all-trans retinoic acid (ATRA) treatment, ATRA-resistance remains a clinical challenge in the management of APL. Therefore, alternative agents should be considered for ATRA-resistant APL patients. Here, we report that antimalaria drug primaquine phosphate (PRQ) exhibits an anti-leukemia effect on both ATRA-sensitive cell line NB4 and ATRA-resistant APL cell lines, NB4-LR2, NB4-LR1, and NB4-MR2. Moreover, PRQ significantly inhibited primary colony formation of untreated or relapsed APL patients. Further study showed that PRQ could induce the apoptosis of APL cells by inhibiting NF-κB signaling pathway. The in vivo study showed that PRQ significantly inhibited NB4-LR2 xenograft tumors growth. These results suggest that PRQ is a potential therapeutic agent for ATRA-resistant APL patients.

Mechanical reinforcement of room-temperature-vulcanized silicone rubber using modified cellulose nanocrystals as cross-linker and nanofiller.

Despite the excellent properties of room-temperature-vulcanized silicone rubber (RTVSR), such as good temperature resistance, low toxicity, and low cost, its industrial application is limited owing to its poor mechanical properties. Herein, we employed cellulose nanocrystals modified by acid hydrolysis and reaction with 3-isocyanatopropyltrimethoxysilane (ICNCs) as the cross-linking agent to reinforce RTVSR. Structural analyses of ICNCs confirmed the chemical modification of the cellulose nanocrystal surface and preservation of the crystalline structure. The ICNCs improved the thermostability of RTVSR and also acted as a nanoscale filler in the RTVSR/ICNCs nanocomposite. The thermostability and mechanical properties of RTVSR/ICNCs expectedly improved with increased ICNC content. Moreover, compared with unmodified silicone rubber, RTVSR/ICNCs nanocomposites exhibited high haze and high transparency. Our work indicates that ICNCs are well dispersed in the RTVSR matrix and effectively improve its properties.