Targeting of focal adhesion kinase enhances the immunogenic cell death of PEGylated liposome doxorubicin to optimize therapeutic responses of immune checkpoint blockade.

BACKGROUNDS: Immune checkpoint blockade (ICB) is widely considered to exert long-term treatment benefits by activating antitumor immunity. However, many cancer patients show poor clinical responses to ICB due in part to the lack of an immunogenic niche. Focal adhesion kinase (FAK) is frequently amplified and acts as an immune modulator across cancer types. However, evidence illustrates that targeting FAK is most effective in combination therapy rather than in monotherapy. METHODS: Here, we used drug screening, in vitro and in vivo assays to filter out that doxorubicin and its liposomal form pegylated liposome doxorubicin (PLD) showed synergistic anti-tumor effects in combination with FAK inhibitor IN10018. We hypothesized that anti-tumor immunity and immunogenic cell death (ICD) may be involved in the treatment outcomes through the data analysis of our clinical trial testing the combination of IN10018 and PLD. We then performed cell-based assays and animal studies to detect whether FAK inhibition by IN10018 can boost the ICD of PLD/doxorubicin and further established syngeneic models to test the antitumor effect of triplet combination of PLD, IN10018, and ICB. RESULTS: We demonstrated that the combination of FAK inhibitor IN10018, and PLD/doxorubicin exerted effective antitumor activity. Notably, the doublet combination regimen exhibited response latency and long-lasting treatment effects clinically, outcomes frequently observed in immunotherapy. Our preclinical study confirmed that the 2-drug combination can maximize the ICD of cancer cells. This approach primed the tumor microenvironment, supplementing it with sufficient tumor-infiltrating lymphocytes (TILs) to activate antitumor immunity. Finally, different animal studies confirmed that the antitumor effects of ICB can be significantly enhanced by this doublet regimen. CONCLUSIONS: We confirmed that targeting FAK by IN10018 can enhance the ICD of PLD/doxorubicin, further benefiting the anti-tumor effect of ICB. The animal tests of the triplet regimen warrant further discovery in the real world.

The preventive effects of probiotic Akkermansia muciniphila on D-galactose/AlCl3 mediated Alzheimer's disease-like rats.

AIMS: We induced the AD-like rat models injected by AlCl3 and D-galactose, to explore the effects of an oral treatment of A. muciniphila on AD-like rats with periodontitis and its possible mechanism. MAIN METHODS: We used Morris water maze test and micro-CT to assess the cognitive impairment and bone loss; Aß1-42 deposition was tested by IHC; Serum LPS level and TG, HDL-C and AST/ALT levels were detected by LAL Test and biochemical tests; The gut microbiota was analyzed by 16S rRNA gene sequence. KEY FINDINGS: We found that A. muciniphila could alleviate AD-like rats' cognitive impairment and mitigate ligature-induced periodontitis. Furthermore, A. muciniphila reduced Aß1-42 deposition in the cortex and regions of the rats' brain, and altered TG, HDL-C and AST/ALT levels but had little ability to change circulating LPS level and cross the blood-brain barrier. Notably, A. muciniphila treatment could improve the abundance of some short chain fatty acid (SCFA)-producing or neurotransmitter-producing gut microbiome such as Blautia, Staphylococcus and Lactococcus, while the abundance of pathogenic Aerococcus and Streptococcus, which were associated inflammation, were decreased. SIGNIFICANCE: Our findings suggested that A. muciniphila has a remissive effect on AD-like pathologies, potentially by regulating gut-brain axis through altering composition and function of gut microbial community or moderating peripheral circulation metabolism.

High-Strength and Injectable Supramolecular Hydrogel Self-Assembled by Monomeric Nucleoside for Tooth-Extraction Wound Healing.

Hydrogels with high mechanical strength and injectability have attracted extensive attention in biomedical and tissue engineering. However, endowing a hydrogel with both properties is challenging because they are generally inversely related. In this work, by constructing a multi-hydrogen-bonding system, a high-strength and injectable supramolecular hydrogel is successfully fabricated. It is constructed by the self-assembly of a monomeric nucleoside molecular gelator (2-amino-2'-fluoro-2'-deoxyadenosine (2-FA)) with distilled water/phosphate buffered saline as solvent. Its storage modulus reaches 1 MPa at a concentration of 5.0 wt%, which is the strongest supramolecular hydrogel comprising an ultralow-molecular-weight (MW < 300) gelator. Furthermore, it exhibits excellent shear-thinning injectability, and completes the sol-gel transition in seconds after injection at 37 °C. The multi-hydrogen-bonding system is essentially based on the synergistic interactions between the double NH2 groups, water molecules, and 2'-F atoms. Furthermore, the 2-FA hydrogel exhibits excellent biocompatibility and antibacterial activity. When applied to rat molar extraction sockets, compared to natural healing and the commercial hemorrhage agent gelatin sponge, the 2-FA hydrogel exhibits faster degradation and induces less osteoclastic activity and inflammatory infiltration, resulting in more complete bone healing. In summary, this study provides ideas for proposing a multifunctional, high-strength, and injectable supramolecular hydrogel for various biomedical engineering applications.

Orthodontic maximum anchorages in malocclusion treatment: A systematic review and network meta-analysis.

OBJECTIVE: We did a network meta-analysis and systematic review among patients seeking for maximum anchorage and provided a guidance of selecting certain systems in clinical practice. METHODS: Seven databases were searched, and randomized controlled trials (RCTs) published with no language restrictions from January 1994 to February 2021 comparing any of the following seven anchorage systems for maximum anchorage orthodontic treatment were selected(PROSPERO: CRD42019117995). A network meta-analysis (NMA) was then conducted to integrate direct evidence with indirect evidence based on logical inference to compare and rank treatments for maximum anchorages in the capacity of maintaining anchorage and duration of total treatment time. RESULTS: Nine publications with 522 participants were considered eligible and were taken into evaluation. According to the capacity of anchorage reinforcement, three skeleton anchorages including miniscrew implants, midpalate implants and Onplant midpalate implants were significantly more effective than conventional anchorages including headgears, TPAs and Nance buttons respectively. According to conventional anchorages, headgears and Nance buttons were significantly more effective than TPA. The strategy ranking reflected the same results as above. However, miniscrew implants required the longest total treatment time. CONCLUSIONS: In general, miniscrew impants are most effective in reserving anchorage. Nance buttons require the least total treatment time. Total evidence is graded as moderate. Midpalatal implants might be the best choice when doing treatment planning because it has the most favorable balance between effectiveness and treatment time. But data analysis of the acceptability and acquisition cost of those anchorage systems must be done to make final decisions.

Interactions Between Neutrophils and Periodontal Pathogens in Late-Onset Periodontitis.

Late-onset periodontitis is associated with a series of inflammatory reactions induced by periodontal pathogens, such as Porphyromonas gingivalis, a keystone pathogen involved in periodontitis. Neutrophils are the most abundant leukocytes in the periodontal pocket/gingival crevice and inflamed periodontal tissues. They form a "wall" between the dental plaque and the junctional epithelium, preventing microbial invasion. The balance between neutrophils and the microbial community is essential to periodontal homeostasis. Excessive activation of neutrophils in response to periodontal pathogens can induce tissue damage and lead to periodontitis persistence. Therefore, illuminating the interactions between neutrophils and periodontal pathogens is critical for progress in the field of periodontitis. The present review aimed to summarize the interactions between neutrophils and periodontal pathogens in late-onset periodontitis, including neutrophil recruitment, neutrophil mechanisms to clear the pathogens, and pathogen strategies to evade neutrophil-mediated elimination of bacteria. The recruitment is a multi-step process, including tethering and rolling, adhesion, crawling, and transmigration. Neutrophils clear the pathogens mainly by phagocytosis, respiratory burst responses, degranulation, and neutrophil extracellular trap (NET) formation. The mechanisms that pathogens activate to evade neutrophil-mediated killing include impairing neutrophil recruitment, preventing phagocytosis, uncoupling killing from inflammation, and resistance to ROS, degranulation products, and NETs.

Comparative proteomic analysis of fluoride treated rat bone provides new insights into the molecular mechanisms of fluoride toxicity.

Long-term excessive intake of fluoride (F) could lead to chronic fluorosis. To explore the underlying molecular mechanisms, present study is designed to elucidate the effect of fluoride on proteome expression of bone in sodium fluoride (NaF)-treated SD rats. Hematoxylin and eosin (H&E) staining was used to determine the severity of osteofluorosis, and bone samples were submitted for iTRAQ analysis. The results showed that the cortical thickness and trabecular area of femur bone in medium- and high-dose groups were higher than in control group. Contrary to this, trabecular area was reduced in the low-dose group, indicating that the bone mass was increased in medium- and high-dose groups, and decreased in the low-dose group. Thirteen (13), 35, and 34 differentially expressed proteins were identified in low-, medium-, and high-dose group, respectively. The medium- and high-dose groups shared a more similar protein expression pattern. These proteins were mainly associated with collagen metabolism, proteoglycans (PGs), matrix metalloproteinases (MMPs), etc. The results suggested that the effect of NaF on SD rats is in a dose-dependent manner. Some key proteins found here may be involved in affecting the bone tissues and bone marrow or muscle, and account for the complex pathology and clinical symptoms of fluorosis.