Probing Interfacial Aging of Model Adhesion Joints under a Hygrothermal Environment at a Molecular Level.

Generally, for adhesive joints, the polar water molecules in humid environments can have a critical effect on the interfacial structures and structural evolution adjacent to the solid substrates. Regarding this, it is still a big challenge to detect and understand the interfacial hygrothermal aging process at the molecular level in real time and in situ. In this study, to trace the interfacial hygrothermal aging process of a classical epoxy formula containing diglycidyl ether of biphenyl A (DGEBA) and 2,2'-(ethylenedioxy) diethylamine (EDDA) with sapphire and fused silica in a typical hygrothermal environment (85 °C and 85% RH), sum frequency generation (SFG) vibrational spectroscopy was used to probe the molecular-level interfacial structural change over the time. The structural evolution dynamics at the buried epoxy/sapphire and epoxy/silica interfaces upon hygrothermal aging were revealed directly in situ. The interfacial delamination during hygrothermal aging was also elucidated from the molecular level. Upon hygrothermal aging, the interfacial CH signals, such as the ones from methyl, methylene, and phenyl groups, decreased significantly and the water OH signals increased substantially, indicating the water molecules had diffused into the interfaces and destroyed the original interactions between the epoxy formula and the substrates. Further analysis indicates that when the integrated signals in the CH range declined to their minimum and leveled off, the interfacial delamination happened. The tensile experiment proved the validity of these spectroscopic experimental results. Our study provides first-hand and molecular-level evidence on a direct correlation between the diffusion of the surrounding water molecules into the interface and the evolution/destruction of the interfacial structures during hygrothermal aging. More importantly, it is proved, SFG can be developed into a powerful tool to noninvasively reveal the local interfacial delamination in real time and in situ under extreme hygrothermal conditions, complemented by the mechanic test.

Nanoparticle-Mediated Multiple Modulation of Bone Microenvironment To Tackle Osteoarthritis.

Development of nanomedicines that can collaboratively scavenge reactive oxygen species (ROS) and inhibit inflammatory cytokines, along with osteogenesis promotion, is essential for efficient osteoarthritis (OA) treatment. Herein, we report the design of a ROS-responsive nanomedicine formulation based on fibronectin (FN)-coated polymer nanoparticles (NPs) loaded with azabisdimethylphoaphonate-terminated phosphorus dendrimers (G4-TBP). The constructed G4-TBP NPs-FN with a size of 268 nm are stable under physiological conditions, can be specifically taken up by macrophages through the FN-mediated targeting, and can be dissociated in the oxidative inflammatory microenvironment. The G4-TBP NPs-FN loaded with G4-TBP dendrimer having intrinsic anti-inflammatory property and FN having both anti-inflammatory and antioxidative properties display integrated functions of ROS scavenging, hypoxia attenuation, and macrophage M2 polarization, thus protecting macrophages from apoptosis and creating designed bone immune microenvironment for stem cell osteogenic differentiation. These characteristics of the G4-TBP NPs-FN lead to their effective treatment of an OA model in vivo to reduce pathological changes of joints including synovitis inhibition and cartilage matrix degradation and simultaneously promote osteogenic differentiation for bone repair. The developed nanomedicine formulation combining the advantages of both bioactive phosphorus dendrimers and FN to treat OA may be developed for immunomodulatory therapy of different inflammatory diseases.

Effective elimination of bacteria on hard surfaces by the combined use of bacteriophages and chemical disinfectants.

Hospital-acquired infections (HAIs) represent one of the significant causes of morbidity and mortality worldwide, and controlling pathogens in the hospital environment is of great importance. Currently, the standard disinfection method in the hospital environment is chemical disinfection. However, disinfectants are usually not used strictly according to the label, making them less effective in disinfection. Therefore, there is an emergent need to find a better approach that can be used in hospitals to control pathogenic bacteria in the clinical environment. Bacteriophages (phages) are effective in killing bacteria and have been applied in the treatment of bacterial infections but have not received enough attention regarding the control of contamination in the clinical environment. In this study, we found that various phages remain active in the presence of chemical disinfectants. Moreover, the combined use of specific phages and chemical disinfectants is more effective in removing bacterial biofilms and eliminating bacteria on hard surfaces. Thus, this proof-of-concept study indicates that adding phages directly to chemical disinfectants might be an effective and economical approach to enhance clinical environment disinfection. IMPORTANCE: In this study, we investigated whether the combination of bacteriophages and chemical disinfectants can enhance the efficacy of reducing bacterial contamination on hard surfaces in the clinical setting. We found that specific phages are active in chemical disinfectants and that the combined use of phages and chemical disinfectants was highly effective in reducing bacterial presence on hard surfaces. As a proof-of-concept, we demonstrated that adding specific phages directly to chemical disinfectants is an effective and cost-efficient strategy for clinical environment disinfection.

Proportions of Pseudomonas aeruginosa and Antimicrobial-Resistant P aeruginosa Among Patients With Surgical Site Infections in China: A Systematic Review and Meta-analysis.

Background: Pseudomonas aeruginosa is one of the most common pathogens in surgical site infections (SSIs). However, comprehensive epidemiological and antibiotic resistance details for P aeruginosa in Chinese SSIs are lacking. We evaluated the proportions and antimicrobial resistance of P aeruginosa among patients with SSIs in China. Methods: Relevant papers from January 2010 to August 2022 were searched in databases including PubMed, Embase, Web of Science, China Biomedical Literature Database, China National Knowledge Infrastructure, Wanfang, and Weipu. A meta-analysis was performed to analyze the proportions and 95% confidence interval (CIs) of P aeruginosa among patients with SSIs. Meta-regression analysis was used to investigate the proportion difference among different subgroups and antimicrobial resistance. Results: A total of 72 studies met inclusion criteria, involving 33 050 isolated strains. The overall proportion of P aeruginosa among patients with SSIs was 16.0% (95% CI, 13.9%-18.2%). Subgroup analysis showed higher proportions in orthopedic (18.3% [95% CI, 15.6%-21.0%]) and abdominal surgery (17.3% [95% CI, 9.9%-26.2%]). The proportion in the central region (18.6% [95% CI, 15.3%-22.1%]) was slightly higher than that in other regions. Antibiotic resistance rates significantly increased after 2015: cefoperazone (36.2%), ceftriaxone (38.9%), levofloxacin (20.5%), and aztreonam (24.0%). Notably, P aeruginosa resistance to ampicillin and cefazolin exceeded 90.0%. Conclusions: The proportion of P aeruginosa infection among patients with SSIs was higher than the data reported by the Chinese Antimicrobial Resistance Surveillance System, indicating rising antimicrobial resistance. The existing antimicrobial drug management plan should be strengthened to prevent a hospital epidemic of drug-resistant P aeruginosa strains.

Exercise-induced Musclin determines the fate of fibro-adipogenic progenitors to control muscle homeostasis.

The effects of exercise on fibro-adipogenic progenitors (FAPs) are unclear, and the direct molecular link is still unknown. In this study, we reveal that exercise reduces the frequency of FAPs and attenuates collagen deposition and adipose formation in injured or disused muscles through Musclin. Mechanistically, Musclin inhibits FAP proliferation and promotes apoptosis in FAPs by upregulating FILIP1L. Chromatin immunoprecipitation (ChIP)-qPCR confirms that FoxO3a is the transcription factor of FILIP1L. In addition, the Musclin/FILIP1L pathway facilitates the phagocytosis of apoptotic FAPs by macrophages through downregulating the expression of CD47. Genetic ablation of FILIP1L in FAPs abolishes the effects of exercise or Musclin on FAPs and the benefits on the reduction of fibrosis and fatty infiltration. Overall, exercise forms a microenvironment of myokines in muscle and prevents the abnormal accumulation of FAPs in a Musclin/FILIP1L-dependent manner. The administration of exogenous Musclin exerts a therapeutic effect, demonstrating a potential therapeutic approach for muscle atrophy or acute muscle injury.

Wide-field endoscope accessory for multiplexed fluorescence imaging.

A wide-field endoscope that is sensitive to fluorescence can be used as an adjunct to conventional white light endoscopy by detecting multiple molecular targets concurrently. We aim to demonstrate a flexible fiber-coupled accessory that can pass forward through the instrument channel of standard medical endoscopes for clinical use to collect fluorescence images. A miniature scan mirror with reflector dimensions of 1.30 × 0.45  mm2 was designed, fabricated, and placed distal to collimated excitation beams at λex = 488, 660, and 785 nm. The mirror was driven at resonance for wide angular deflections in the X and Y-axes. A large image field-of-view (FOV) was generated in real time. The optomechanical components were packaged in a rigid distal tip with dimensions of 2.6 mm diameter and 12 mm length. The scan mirror was driven at 27.6 and 9.04 kHz in the fast (X) and slow (Y) axes, respectively, using a square wave with 50% duty cycle at 60 Vpp to collect fluorescence images at 10 frames per sec. Maximum total divergence angles of ± 27.4° and ± 22.8° were generated to achieve a FOV of 10.4 and 8.4 mm, respectively, at a working distance of 10 mm. Multiplexed fluorescence images were collected in vivo from the rectum of live mice using 3 fluorescently-labeled peptides that bind to unique cell surface targets. The fluorescence images collected were separated into 3 channels. Target-to-background ratios of 2.6, 3.1, and 3.9 were measured. This instrument demonstrates potential for broad clinical use to detect heterogeneous diseases in hollow organs.

Prevalence and drug resistance of Escherichia coli among patients with orthopaedic surgical site infections in China: A systematic review and meta-analysis.

To summarize current prevalence and drug resistance rate of Escherichia coli (E. coli) among orthopaedic surgical site infections (SSIs) in China from English and Chinese language sources. Online databases were searched to collect related researches. A meta-analysis was performed to analyse prevalence and 95 % confidence interval (CI) of E. coli among patients with orthopedic surgical site infections. Meta-regression analysis was used to investigate the difference in the prevalence and antimicrobial resistance of E. coli among different subgroups. A total of 52 studies were enrolled into our meta-analysis, with a total of 31,285 strains isolated. The overall E. coli prevalence was 13.4 % (95 % CI 11.6-15.5). Study design (R2 = 8.98) and sample size (R2 = 10.95) might be potential sources of heterogeneity and there were no significant differences in risk of bias (R2 = 0.28), study time (R2 < 0.01), region (R2 = 2.46) and hospital level (R2 = 1.42). E. coli resistance were reported in 43 of the 52 papers. Antimicrobial resistance of E. coli to Ampicillin [87.9 % (95 % CI 83.7-91.1)] before 2015 was higher than that after 2015 [80.3 % (95 % CI 75.0-84.7)] (R2 = 30.93, P = 0.033). While, resistance rate to Cefepime and Amikacin was significantly higher before 2015 (R2 = 17.25 and 6.54, P = 0.043 and 0.048), i.e., 46.4 % (36.3-56.9), 19.9 % (13.8-27.7) and 29.1 % (19.4-41.2), 8.6 % (4.4-16.2) in 2015 and after. It is necessary to carry out long-term monitoring to understand the actual prevalence and antimicrobial resistance of E. coli to develop appropriate health care mechanisms.

The Influence of Surface Processing on the Surface Plasmonic Enhancement of an Al-Nanoparticles-Enhanced ZnO UV Photodectector.

Surface Plasmonic Resonance (SPR) induced by metallic nanoparticles can be exploited to enhance the response of photodetectors (PD) to a large degree. Since the interface between metallic nanoparticles and semiconductors plays an important role in SPR, the magnitude of the enhancement is highly dependent on the morphology and roughness of the surface where the nanoparticles are distributed. In this work, we used mechanical polishing to produce different surface roughnesses for the ZnO film. Then, we exploited sputtering to fabricate Al nanoparticles on the ZnO film. The size and spacing of the Al nanoparticles were adjusted by sputtering power and time. Finally, we made a comparison among the PD with surface processing only, the Al-nanoparticles-enhanced PD, and the Al-nanoparticles-enhanced PD with surface processing. The results showed that increasing the surface roughness could enhance the photo response due to the augmentation of light scattering. More interestingly, the SPR induced by the Al nanoparticles could be strengthened by increasing the roughness. The responsivity could be enlarged by three orders of magnitude after we introduced surface roughness to boost the SPR. This work revealed the mechanism behind how surface roughness influences SPR enhancement. This provides new means for improving the photo responses of SPR-enhanced photodetectors.

Ultrasound-enhanced theranostics of orthotopic breast cancer through a multifunctional core-shell tecto dendrimer-based nanomedicine platform.

Design of multifunctional nanoplatforms combined with ultrasound-targeted microbubble destruction (UTMD) technology for enhanced tumor accumulation is feasible to solve the bottleneck of theranostics. Herein, we present the development of zwitterion-modified gadolinium (Gd)-chelated core-shell tecto dendrimers (CSTDs) as a nanomedicine platform (PCSTD-Gd) for enhanced magnetic resonance (MR) imaging-guided chemo-gene therapy of orthotopic breast cancer with the assistance of UTMD. In our design, CSTDs synthesized via supramolecular recognition of ß-cyclodextrin and adamantane were covalently linked with tetraazacyclododecane tetraacetic acid-Gd(III) chelators, modified with 1,3-propane sultone to achieve good protein-resistance property, and used for co-delivery of an microRNA 21 inhibitor (miR 21i) and an anticancer drug doxorubicin (DOX). The overall design is quite advantageous and cooperative. The CSTDs with a greater size than single-generation core dendrimers have amplified the enhanced permeability and retention effect for better passive tumor targeting, with a larger r1 relaxivity for sensitive MR imaging and serum-enhanced gene delivery efficiency due to the better compaction ability as well as the protein resistance ability, and with larger interior space for improved drug loading. Through the unique design and the assistance of UTMD, the obtained PCSTD-Gd/DOX/miR 21i polyplexes enable enhanced MR imaging-guided combined chemo-gene therapy of an orthotopic breast cancer model in vivo.

A tumor microenvironment-responsive core-shell tecto dendrimer nanoplatform for magnetic resonance imaging-guided and cuproptosis-promoted chemo-chemodynamic therapy.

Theranostic nanoplatforms for combination tumor therapy have gained lots of attention recently due to the optimized therapeutic efficiency and simultaneous diagnosis performance. Herein, a novel tumor microenvironment (TME)-responsive core-shell tecto dendrimer (CSTD) was assembled by phenylboronic acid- and mannose-modified poly(amidoamine) dendrimers via the phenylboronic ester bonds that are responsive to low pH and reactive oxygen species (ROS), and efficiently loaded with copper ions and chemotherapeutic drug disulfiram (DSF) for tumor-targeted magnetic resonance (MR) imaging and cuproptosis-promoted chemo-chemodynamic therapy. The formed CSTD-Cu(II)@DSF could be specifically taken up by MCF-7 breast cancer cells, accumulated to the tumor model after circulation, and released drugs in response to the weakly acidic TME with overexpressed ROS. The enriched intracellular Cu(II) ions could induce the oligomerization of lipoylated proteins and proteotoxic stress for cuproptosis, and lipid peroxidation for chemodynamic therapy as well. Moreover, the CSTD-Cu(II)@DSF could cause the dysfunction of mitochondria and arrest the cell cycle at the G2/M phase, leading to enhanced DSF-mediated cell apoptosis. As a result, CSTD-Cu(II)@DSF could effectively inhibit the growth of MCF-7 tumors by a combination therapy strategy integrating chemotherapy with cuproptosis and chemodynamic therapy. Lastly, the CSTD-Cu(II)@DSF also displays Cu(II)-associated r1 relaxivity, allowing for T1-weighted real-time MR imaging of tumors in vivo. The developed tumor-targeted and TME-responsive CSTD-based nanomedicine formulation may be developed for accurate diagnosis and synergistic treatment of other cancer types. STATEMENT OF SIGNIFICANCE: Constructing an effective nanoplatform for the combination of therapeutic effects and real-time tumor imaging remains a challenge. In this study, we reported for the first time an all-in-one tumor-targeted and tumor microenvironment (TME) responsive nanoplatform based on core-shell tecto dendrimer (CSTD) for the cuproptosis-promoted chemo-chemodynamic therapy and enhanced MR imaging. The efficient loading, selective tumor-targeting, and TME-responsive release of Cu(II) and disulfiram could enhance the intracellular accumulation of drugs, induce cuproptosis of cancer cells, and amplify the synergistic chemo-chemodynamic therapeutic effect, resulting in enhanced MR imaging and accelerated tumor eradication. This study sheds new light on the development of theranostic nanoplatforms for early accurate diagnosis and effective treatment of cancers.

Alterations of commensal microbiota are associated with pancreatic cancer.

BACKGROUND: Dysbiosis commonly occurs in pancreatic cancer, but its specific characteristics and interactions with pancreatic cancer remain obscure. MATERIALS AND METHODS: The 16S rRNA sequencing method was used to analyze multisite (oral and gut) microbiota characteristics of pancreatic cancer, chronic pancreatitis, and healthy controls. Differential analysis was used to identify the pancreatic cancer-associated genera and pathways. A random forest algorithm was adopted to establish the diagnostic models for pancreatic cancer. RESULTS: The chronic pancreatitis group exhibited the lowest microbial diversity, while no significant difference was found between the pancreatic cancer group and healthy controls group. Diagnostic models based on the characteristics of the oral (area under the curve (AUC) 0.916, 95% confidence interval (CI) 0.832-1) or gut (AUC 0.856; 95% CI 0.74, 0.972) microbiota effectively discriminate the pancreatic cancer samples in this study, suggesting saliva as a superior sample type in terms of detection efficiency and clinical compliance. Oral pathogenic genera (Granulicatella, Peptostreptococcus, Alloprevotella, Veillonella, etc.) and gut opportunistic genera (Prevotella, Bifidobacterium, Escherichia/Shigella, Peptostreptococcus, Actinomyces, etc.), were significantly enriched in pancreatic cancer. The 16S function prediction analysis revealed that inflammation, immune suppression, and barrier damage pathways were involved in the course of pancreatic cancer. CONCLUSION: This study comprehensively described the microbiota characteristics of pancreatic cancer and suggested potential microbial markers as non-invasive tools for pancreatic cancer diagnosis.

Phase separation of the nuclear pore complex facilitates selective nuclear transport to regulate plant defense against pathogen and pest invasion.

The nuclear pore complex (NPC), the sole exchange channel between the nucleus and cytoplasm, is composed of several subcomplexes, among which the central barrier determines the permeability/selectivity of the NPC to dominate the nucleocytoplasmic trafficking essential for many important signaling events in yeast and mammals. How plant NPC central barrier controls selective transport is a crucial question remaining to be elucidated. In this study, we uncovered that phase separation of the central barrier is critical for the permeability and selectivity of plant NPC in the regulation of various biotic stresses. Phenotypic assays of nup62 mutants and complementary lines showed that NUP62 positively regulates plant defense against Botrytis cinerea, one of the world's most disastrous plant pathogens. Furthermore, in vivo imaging and in vitro biochemical evidence revealed that plant NPC central barrier undergoes phase separation to regulate selective nucleocytoplasmic transport of immune regulators, as exemplified by MPK3, essential for plant resistance to B. cinerea. Moreover, genetic analysis demonstrated that NPC phase separation plays an important role in plant defense against fungal and bacterial infection as well as insect attack. These findings reveal that phase separation of the NPC central barrier serves as an important mechanism to mediate nucleocytoplasmic transport of immune regulators and activate plant defense against a broad range of biotic stresses.

Dual-Responsive Core-Shell Tecto Dendrimers Enable Efficient Gene Editing of Cancer Cells to Boost Immune Checkpoint Blockade Therapy.

Immune checkpoint blockade (ICB) therapy has become a promising strategy in treating multiple tumor types, but the therapeutic efficacy is still unsatisfactory due to the temporary and inefficient blocking and the poor immune responsiveness. Herein, we report the development of dual reactive oxygen species (ROS)- and pH-responsive core-shell tecto dendrimers loaded with gold nanoparticles (for short, Au CSTDs) to deliver a plasmid-clustered regularly interspersed short palindromic repeats (CRISPR)/Cas9 system for the permanent disruption of the programmed death ligand 1 (PD-L1) gene in cancer cells to boost cancer immunotherapy. In our work, Au CSTDs were constructed using lactobionic acid (LA)-modified generation 5 poly(amidoamine) dendrimers entrapped with gold nanoparticles as cores and phenylboronic acid (PBA)-conjugated generation 3 dendrimers as shells via the formation of responsive phenylborate ester bonds between PBA and LA. The plasmid-CRISPR/Cas9 system can be efficiently compacted and specifically taken up by cancer cells overexpressing sialic acids due to the PBA-mediated targeting and be responsively released in cancer cells by the responsive dissociation of the Au CSTDs, leading to the successful endosomal escape and the efficient knockout of the PD-L1 gene. Further in vivo delivery in a mouse melanoma model reveals that the developed Au CSTDs/plasmid-CRISPR/Cas9 complexes can be specifically accumulated at the tumor site for enhanced computed tomography (CT) imaging of tumors, owing to the X-ray attenuation effect of Au, and disrupt the PD-L1 expression in tumor cells, thus promoting the ICB-based antitumor immunity. The designed dual-responsive Au CSTDs may be developed as a versatile tool for genetic engineering of other cell types to achieve different therapeutic effects for expanded space of biomedical applications.

Multifunctional Low-Generation Dendrimer Nanogels as an Emerging Probe for Tumor-Specific CT/MR Dual-Modal Imaging.

The development of nanoprobes that have amplified enhanced permeability and retention (EPR) effect is crucial for their precise cancer diagnosis performance. Here, we present the development of functional dendrimer-based nanogels (DNGs) with the generation three primary amine-terminated poly(amidoamine) (PAMAM) dendrimers (G3·NH2) cross-linked by N,N'-bis(acryloyl) cystamine (BAC). The DNGs were prepared through a Michael addition reaction between G3·NH2 dendrimers and BAC via an inverse microemulsion method and entrapped with gold nanoparticles (Au NPs) to form Au-DNGs. The Au-DNGs were sequentially modified with diethylenetriamine penta-acetic acid (DTPA)-gadolinium (Gd) complex, poly(ethylene glycol) (PEG)-linked arginine-glycine-aspartic (RGD) peptide, and 1,3-propanesultone (1,3-PS). The formed multifunctional RGD-Gd@Au-DNGs-PS (R-G@ADP) possessing an average diameter of 122 nm are colloidally stable and display a high X-ray attenuation coefficient, excellent r1 relaxivity (9.13 mM-1 s-1), desired protein resistance rendered by the zwitterionic modification, and cytocompatibility. With the targeting specificity mediated by RGD and the much better tumor penetration capability than the counterpart material of single dendrimer-entrapped Au NPs, the developed multifunctional R-G@ADP enable targeted and enhanced computed tomography (CT)/magnetic resonance (MR) dual-modal imaging of a pancreatic tumor model in vivo. The current work demonstrates a unique design of targeted and zwitterionic DNGs with prolonged blood circulation time as an emerging nanoprobe for specific tumor CT/MR imaging through amplified passive EPR effect.

Confocal laser endomicroscope with distal MEMS scanner for real-time histopathology.

Confocal laser endomicroscopy is an emerging methodology to perform real time optical biopsy. Fluorescence images with histology-like quality can be collected instantaneously from the epithelium of hollow organs. Currently, scanning is performed at the proximal end of probe-based instruments used routinely in the clinic, and flexibility to control the focus is limited. We demonstrate use of a parametric resonance scanner packaged in the distal end of the endomicroscope to perform high speed lateral deflections. An aperture was etched in the center of the reflector to fold the optical path. This design reduced the dimensions of the instrument to 2.4 mm diameter and 10 mm length, allowing for forward passage through the working channel of a standard medical endoscope. A compact lens assembly provides lateral and axial resolution of 1.1 and 13.6 µm, respectively. A working distance of 0 µm and field-of-view of 250 µm × 250 µm was achieved at frame rates up to 20 Hz. Excitation at 488 nm was delivered to excite fluorescein, an FDA-approved dye, to generate high tissue contrast. The endomicroscope was reprocessed using a clinically-approved sterilization method for 18 cycles without failure. Fluorescence images were collected during routine colonoscopy from normal colonic mucosa, tubular adenomas, hyperplastic polyps, ulcerative colitis, and Crohn's colitis. Individual cells, including colonocytes, goblet cells, and inflammatory cells, could be identified. Mucosal features, such as crypt structures, crypt lumens, and lamina propria, could be distinguished. This instrument has potential to be used as an accessory during routine medical endoscopy.

New insights into ruthenium(II) metallodendrimers as anticancer drug nanocarriers: from synthesis to preclinic behaviour.

Dendrimers have been studied as promising materials for the delivery of anticancer drugs. In this work, low-generation (0-2) nitrile poly(alkylidenamine)-based dendrimers were explored as nanocarriers for the organometallic complex [Ru(η5-C5H5)(PPh3)2]+ (RuCp+) and investigated for their anticancer action and involved mechanisms, which were evaluated both in vitro and in vivo. It was observed that their biological behaviour is generation dependent, where the highest generation metallodendrimer (G2Ru) was overall more effective than the other metallodendrimers. G2Ru was active against a set of six cancer cell lines, revealing its important selectivity for these cells (the IC50 values were about 4-fold lower than that for non-cancer cells). Importantly, the in vivo studies with G2Ru in an MCF-7 xenograft mouse model showed that it exhibited low systemic toxicity, low accumulation in the main organs of the mice, preferential accumulation in the tumour, and remarkable capacity to limit tumour growth. The in vitro and in vivo studies revealed that G2Ru caused high levels of cell necrosis and apoptosis. The in vitro cell death mechanism studies showed the capacity of G2Ru to induce mitochondrial depolarization and ROS production. Altogether, pre-clinical results indicated G2Ru as a promising anticancer drug and the potential of low-generation poly(alkylidenamine)-based dendrimers as drug nanocarriers.

Chemotherapy Mediated by Biomimetic Polymeric Nanoparticles Potentiates Enhanced Tumor Immunotherapy via Amplification of Endoplasmic Reticulum Stress and Mitochondrial Dysfunction.

Construction of multifunctional nanoplatforms to elevate chemotherapeutic efficacy and induce long-term antitumor immunity still remains to be an extreme challenge. Herein, the design of an advanced redox-responsive nanomedicine formulation based on phosphorus dendrimer-copper(II) complexes (1G3 -Cu)- and toyocamycin (Toy)-loaded polymeric nanoparticles (GCT NPs) coated with cancer cell membranes (CM) are reported. The designed GCT@CM NPs with a size of 210 nm are stable under physiological conditions but are rapidly dissociated in the reductive tumor microenvironment to deplete glutathione and release drugs. The co-loading of 1G3 -Cu and Toy within the NPs causes significant tumor cell apoptosis and immunogenic cell death through 1G3 -Cu-induced mitochondrial dysfunction and Toy-mediated amplification of endoplasmic reticulum stress, respectively, thus effectively suppressing tumor growth, promoting dendritic cell maturation, and increasing tumor-infiltrating cytotoxic T lymphocytes. Likewise, the coated CM and the loaded 1G3 -Cu render the GCT@CM NPs with homotypic targeting and T1 -weighted magnetic resonance imaging of tumors, respectively. With the assistance of programmed cell death ligand 1 antibody, the GCT@CM NP-mediated chemotherapy can significantly potentiate tumor immunotherapy for effective inhibition of tumor recurrence and metastasis. The developed GCT@CM NPs hold a great potential for chemotherapy-potentiated immunotherapy of different tumor types through different mechanisms or synergies.

Surgical and oncological outcomes of distal gastrectomy compared to total gastrectomy for middle-third gastric cancer: A systematic review and meta-analysis.

Distal gastrectomy (DG) and total gastrectomy (TG) are the most common types of radical surgery for patients with middle-third gastric cancer (MTGC). However, the indications and benefits of the two procedures still remain controversial. The present meta-analysis aimed to compare the surgical and oncological outcomes of DG and TG in the treatment of MTGC. A rigorous literature review was performed in the databases of PubMed, Embase, Web of Science, China National Knowledge Infrastructure and Chinese BioMedical Literature to retrieve studies published up to February 2022. The Newcastle-Ottawa Scale was used to assess the quality of included studies and a meta-analysis was performed using RevMan 5.3 software. A total of 12 retrospective studies performing comparisons of DG and TG were included in the present meta-analysis. For patients who underwent DG, a lower rate of overall post-operative complications, anastomosis leakage and intro-abdominal infection was determined. No significant difference was observed between DG and TG in the 5-year overall survival when the proximal resection margin ranged from 3 to 5 cm. Although DG was associated with a higher 5-year overall survival rate when compared to TG, there was no significant difference in the stratified analyses by TNM stage. In conclusion, the prognosis of MTGC did not depend on the extent of gastrectomy. With lower complications and acceptable oncological outcomes, DG was a safe and feasible surgical procedure for MTGC when a negative proximal margin was confirmed.

The associations between interleukin-17 single-nucleotide polymorphism and colorectal cancer susceptibility: a systematic review and meta-analysis.

BACKGROUND: Numerous case-control studies have reported associations between interleukin-17 (IL-17) polymorphisms and colorectal cancer; however, the results were inconsistent. The aim of this meta-analysis was to further clarify the effects of IL-17 polymorphisms on colorectal cancer susceptibility. MATERIALS AND METHOD: Relevant studies were extracted from the electronic databases PubMed, Embase, Web of Science, China National Knowledge Infrastructure (CNKI), and the Chinese Biomedical Literature Database (CMB) up to April 2021. The odds ratio and 95% confidence interval were used to estimate the strength of the associations. RESULTS: Ten articles including 2599 cases and 2845 controls were enrolled in our research after strict literature screening. Highly significant associations between the IL-17A rs2275913 polymorphism and increased colorectal cancer susceptibility were observed in all five gene models (allelic, dominant, recessive, homozygous, and heterozygous models), and subgroup analysis based on ethnicity revealed that these associations existed not only in the Asian population but also in the Caucasian population. However, the results showed no significantly elevated colorectal cancer risk correlated with the IL-17F rs763780 polymorphism, and a slightly lower colorectal cancer susceptibility for the Caucasian population was discovered in the recessive and homozygous models of this mutation. CONCLUSION: The IL-17A rs2275913 polymorphism may be an independent risk factor contributing to colorectal cancer susceptibility, while the IL-17F rs763780 polymorphism may decrease susceptibility to colorectal cancer. Future studies with large-scale samples are warranted to identify these associations.

Intelligent design of iron-doped LDH nanosheets for cooperative chemo-chemodynamic therapy of tumors.

Chemodynamic therapy (CDT) has received increasing attention due to its unique tumor microenvironment (TME) responsiveness and minimal adverse side effects, but the therapeutic effect of CDT alone is always limited due to the low Fenton or Fenton-like reaction efficiency at tumor sites. Herein, Fe-doped layered double hydroxide (LDH) nanosheets were synthesized to load the anticancer drug epigallocatechin-3-O-gallate (EGCG) and then conjugated with boronic acid-modified hyaluronic acid for targeted and cooperative chemo-chemodynamic therapy of tumors. The formed LDH-EGCG-HA nanoplatforms could specifically target tumor cells overexpressing CD44 receptors, quickly release iron ions and EGCG in the TME, and efficiently generate toxic hydroxyl radicals with the acceleration of Fe3+/Fe2+ cycling in the Fenton reaction by EGCG. The cooperative cancer cell inhibition effect through chemotherapy and chemodynamic therapy was achieved by the significant upregulation of caspase-3 and p53 expression to induce cell apoptosis, and the deactivation of xCT and GPX-4 to inhibit GSH synthesis and reduce lipid peroxides for reinforced ferroptosis. In vivo experiments further verified that the intelligently designed LDH-EGCG-HA nanoplatforms had a superior biocompatibility with normal organs with an excellent inhibition efficacy towards tumors overexpressing CD44 receptors by targeted chemo-chemodynamic therapy.