Potential of semen coicis in enhancing the anti-tumor effects of PD-1 inhibitor on A549 cell lines by blocking the PI3K-AKT-mTOR pathway.

BACKGROUND: The objective of this research was to investigate how the combination of semen coicis extract and PD-1 inhibitors can potentially work together to enhance the anti-tumor effects, with a focus on understanding the underlying mechanism. METHODS: We obtained the active components and specific targets of semen coicis in the treatment of NSCLC from various databases, namely TCMSP, GeneCard, and OMIM. By utilizing the STRING database and Cytoscape software, we established a protein interaction network (PPI) for the active ingredient of semen coicis and the target genes related to NSCLC. To explore the potential pathways involved, we conducted gene ontology (GO) and biological pathway (KEGG) enrichment analyses, which were further supported by molecular docking technology. Additionally, we conducted cyto-inhibition experiments to verify the inhibitory effects of semen coicis alone or in combination with a PD-1 inhibitor on A549 cells, along with examining the associated pathways. Furthermore, we investigated the synergistic mechanism of these two drugs through cytokine release experiments and the PD-L1 expression study on A549 cells. RESULTS: Semen coicis contains two main active components, Omaine and (S)-4-Nonanolide. Its primary targets include PIK3R1, PIK3CD, PIK3CA, AKT2, and mTOR. Molecular docking experiments confirmed that these ingredients and targets form stable bonds. In vitro experiments showed that semen coicis demonstrates inhibitory effects against A549 cells, and this effect was further enhanced when combined with PD-1 inhibitors. PCR and WB analysis confirmed that the inhibition of the PI3K-AKT-mTOR pathway may contribute to this effect. Additionally, semen coicis was observed to decrease the levels of IFN-γ, IL-6, and TNF-α, promoting the recovery of the human anti-tumor immune response. And semen coicis could inhibit the induced expression of PD­L1 of A549 cells stimulated by IFN­Î³ as well. CONCLUSION: Semen coicis not only has the ability to kill tumor cells directly but also alleviates the immunosuppression found in the tumor microenvironment. Additionally, it collaboratively enhances the effectiveness of PD-1 inhibitors against tumors by blocking the activation of PI3K-AKT-mTOR.

Quantitative systems pharmacology modeling of HER2-positive metastatic breast cancer for translational efficacy evaluation and combination assessment across therapeutic modalities.

HER2-positive (HER2+) metastatic breast cancer (mBC) is highly aggressive and a major threat to human health. Despite the significant improvement in patients' prognosis given the drug development efforts during the past several decades, many clinical questions still remain to be addressed such as efficacy when combining different therapeutic modalities, best treatment sequences, interindividual variability as well as resistance and potential coping strategies. To better answer these questions, we developed a mechanistic quantitative systems pharmacology model of the pathophysiology of HER2+ mBC that was extensively calibrated and validated against multiscale data to quantitatively predict and characterize the signal transduction and preclinical tumor growth kinetics under different therapeutic interventions. Focusing on the second-line treatment for HER2+ mBC, e.g., antibody-drug conjugates (ADC), small molecule inhibitors/TKI and chemotherapy, the model accurately predicted the efficacy of various drug combinations and dosing regimens at the in vitro and in vivo levels. Sensitivity analyses and subsequent heterogeneous phenotype simulations revealed important insights into the design of new drug combinations to effectively overcome various resistance scenarios in HER2+ mBC treatments. In addition, the model predicted a better efficacy of the new TKI plus ADC combination which can potentially reduce drug dosage and toxicity, while it also shed light on the optimal treatment ordering of ADC versus TKI plus capecitabine regimens, and these findings were validated by new in vivo experiments. Our model is the first that mechanistically integrates multiple key drug modalities in HER2+ mBC research and it can serve as a high-throughput computational platform to guide future model-informed drug development and clinical translation.

Injectable Nano-Micro Composites with Anti-bacterial and Osteogenic Capabilities for Minimally Invasive Treatment of Osteomyelitis.

The effective management of osteomyelitis remains extremely challenging due to the difficulty associated with treating bone defects, the high probability of recurrence, the requirement of secondary surgery or multiple surgeries, and the difficulty in eradicating infections caused by methicillin-resistant Staphylococcus aureus (MRSA). Hence, smart biodegradable biomaterials that provide effective and precise local anti-infection effects and can promote the repair of bone defects are actively being developed. Here, a novel nano-micro composite is fabricated by combining calcium phosphate (CaP) nanosheets with drug-loaded GelMA microspheres via microfluidic technology. The microspheres are covalently linked with vancomycin (Van) through an oligonucleotide (oligo) linker using an EDC/NHS carboxyl activator. Accordingly, a smart nano-micro composite called "CaP@MS-Oligo-Van" is synthesized. The porous CaP@MS-Oligo-Van composites can target and capture bacteria. They can also release Van in response to the presence of bacterial micrococcal nuclease and Ca2+, exerting additional antibacterial effects and inhibiting the inflammatory response. Finally, the released CaP nanosheets can promote bone tissue repair. Overall, the findings show that a rapid, targeted drug release system based on CaP@MS-Oligo-Van can effectively target bone tissue infections. Hence, this agent holds potential in the clinical treatment of osteomyelitis caused by MRSA.

The role of radiotherapy in tumor immunity and the potential of PET/CT in detecting the expression of PD-1/PD-L1.

Upregulation of PD-1/PD-L1 allows cancer cells to escape from host immune systems by functionally inactivating T-cell immune surveillance. Clinical blockade strategies have resulted in an increased prevalence of patients with late-stage cancers. However, many cancer patients had limited or no response to current immunotherapeutic strategies. Therefore, how to improve the sensitivity of immunotherapy has become the focus of attention of many scholars. Radiotherapy plays a role in the recruitment of T cells in the tumor microenvironment, increases CD4 + and CD8 + T cells, and increases PD-L1 expression, resulting in the synergistically enhanced antitumor effect of irradiation and PD-L1 blockade. Radiotherapy can cause changes in tumor metabolism, especially glucose metabolism. Tumor glycolysis and tumor immune evasion are interdependent, glycolytic activity enhances PD-L1 expression on tumor cells and thus promotes anti-PD-L1 immunotherapy response. Therefore, the mechanism of radiotherapy affecting tumor immunity may be partly through intervention of tumor glucose metabolism. Furthermore, some authors had found that the uptake of 2'-deoxy-2'-[18F]fluoro-D-glucose(18F-FDG) was correlated with PD-1/PD-L1 expression. Positron emission tomography/computed tomography (PET/CT) is a non-invasive detection method for PD-1/PD-L1 expression and has several potential advantages over immunohistochemical (IHC), PET/CT can dynamically reflect the expression of PD-1/PD-L1 inside the tumor and further guide clinical treatment.

Surgical treatment of mixed cervical spondylosis with spontaneous cerebrospinal fluid leakage: A case report.

BACKGROUND: Spontaneous cerebrospinal fluid (CSF) leaks associated with cervical spondylosis are rare. To our knowledge, only a few cases have been reported in which treatment is challenging and varies from case to case. Here, we review the literature and describe the surgical treatment of a 70-year-old woman who presented with a CSF leak due to a cervical spine spur. CASE SUMMARY: A 70-year-old female patient who was treated for a cerebral infarction, presented with complains of weakness in the right lower extremity and a feeling of stepping on cotton. The patient underwent regular neck massage and presented with neck and right shoulder pain radiating to the right upper extremity one-month ago. Magnetic resonance imaging showed a strip of leaking cerebrospinal fluid posterior to the C1-4 vertebrae, and computed tomography showed a "sickle-shaped" disc prolapse with calcification in C4/5. We chose to perform an anterior cervical discectomy. When the prolapsed C4/5 disc was scraped, clear fluid leakage was observed, and exploration revealed a 1 mm diameter rupture in the anterior aspect of the dura mater, which was compressed continuously with cotton patties, with no significant cerebrospinal fluid leakage after 1 h. CONCLUSION: Three months after surgery, the patient was asymptomatic and follow-up imaging demonstrated complete resolution.

Effectiveness of the recurrent laryngeal nerve monitoring during endoscopic thyroid surgery: systematic review and meta-analysis.

BACKGROUND: Thyroid disease is a common endocrine disorder, and thyroid surgeries and postoperative complications have increased recently. This study aimed to explore the effectiveness of intraoperative nerve monitoring (IONM) in endoscopic thyroid surgery using subgroup analysis and determine confounding factors. MATERIALS AND METHODS: Two researchers individually searched for relevant studies published till November 2022 in the PubMed, Embase, Web of Science and Cochrane Library databases. Eventually, eight studies met the inclusion criteria. Heterogeneity was assessed using the Cochran's Q test, and a funnel plot was implemented to evaluate publication bias. The odds ratio or risk difference were calculated using fixed-effects models. The weighted mean difference of continuous variables was calculated. Subgroup analysis was performed according to the disease type. RESULTS: Eight eligible papers included 915 patients and 1242 exposed nerves. The frequencies of transient, permanent and total recurrent laryngeal nerve (RLN) palsy were 2.64, 0.19 and 2.83%, respectively, in the IONM group and 6.15, 0.75 and 6.90%, respectively, in the conventional exposure group. In addition, analysis of the secondary outcome indicators for the average total length of surgery, localisation time of the RLN, recognition rate of the superior laryngeal nerve and length of incision revealed that IONM reduced the localisation time of the RLN and increased the identification rate of the superior laryngeal nerve. Subgroup analysis showed that IONM significantly reduced the incidence of RLN palsy in patients with malignancies. CONCLUSIONS: The use of IONM significantly reduced the incidence of transient RLN palsy during endoscopic thyroid surgery, but it did not significantly reduce the incidence of permanent RLN palsy. However, the reduction in the total RLN palsy was statistically significant. In addition, IONM can effectively reduce the location time of the RLN and increase the recognition rate of the superior laryngeal nerve. Therefore, the application of IONM for malignant tumours is recommended.

Pepsin Increases the Proliferation of Vocal Cord Leukoplakia Epithelial Cells by Inducing Autophagy.

OBJECTIVE: To investigate the role of H+ /K+ ATPase in the proliferation of pepsin-induced vocal cord leukoplakia (VCL) cells. STUDY DESIGN: Translation research. SETTING: Affiliated Hospital of University. METHODS: Immunohistochemistry was used to detect pepsin, H+ /K+ ATPase (ATP4A and ATP4B subunits) in VCL cells with varying degrees of dysplasia. After primary cultures of VCL cells had been established, the effects of acidified pepsin on the proliferation, autophagy, and H+ /K+ -ATPase distribution of VCL cells were investigated. RESULTS: The levels of pepsin, ATP4A, and ATP4B were significantly higher in VCL tissue with moderate-to-severe dysplasia than in normal tissue (p < .05); these levels gradually increased according to dysplasia severity. The expression levels of ATP4A and ATP4B were significantly correlated with the amount of pepsin in VCL cells (p < .01). Acidified pepsin enhanced the levels of proliferation and autophagy in human VCL epithelial cells. The cloning- and autophagy-promoting effects of acidified pepsin on VCL cells were partially reversed by pantoprazole; these effects were completely blocked by the autophagy inhibitor chloroquine. Finally, acidified pepsin promoted the colocalization of H+ /K+ -ATPase and lysosomes in VCL cells; it also mediated lysosome acidification. CONCLUSION: Pepsin and H+ /K+ -ATPase may contribute to the progression of VCL. Specifically, acidified pepsin may regulate lysosome acidification by promoting lysosomal localization of H+ /K+ -ATPase.

Spectral computed tomography-guided radiotherapy of osteosarcoma utilizing BiOI nanosheets.

As an aggressive malignant bone tumor, osteosarcoma (OS) is usually found in children and adolescents. Computed tomography (CT) is an important tool for the clinical evaluation of osteosarcoma, but limits to low diagnostic specificity due to single parameters of traditional CT and modest signal-to-noise ratio of clinical iodinated contrast agents. As one kind of spectral CT, dual-energy CT (DECT), with the advantage of a provision of multi-parameter information, makes it possible to acquire the best signal-to-noise ratio image, accurate detection, as well as imaging-guided therapy of bone tumors. Hereby, we synthesized BiOI nanosheets (BiOI NSs) as a DECT contrast agent with superior imaging capability compared to iodine agents for clinical detection of OS. Meanwhile, the synthesized BiOI NSs with great biocompatibility is able to achieve effective radiotherapy (RT) by enhancing X-ray dose deposition at the tumor site, leading to DNA damage, which in turn inhibits tumor growth. This study offers a promising new avenue for DECT imaging-guided treatment of OS. STATEMENT OF SIGNIFICANCE: Osteosarcoma (OS) is a common primary malignant bone tumor. Traditional surgical procedures and conventional CT scans are often used for the treatment and monitoring of OS, but the effects are generally unsatisfactory. In this work, BiOI nanosheets (NSs) was reported for dual-energy CT (DECT) imaging-guided OS radiotherapy. The powerful and constant X-ray absorption of BiOI NSs at any energy guarantees excellent enhanced DECT imaging performance, allowing detailed visualization of OS through images with a better signal-to-noise ratio and guiding radiotherapy process. The deposition of X-rays could be greatly enhanced by Bi atoms to induce serious DNA damage in radiotherapy. Taken together, the BiOI NSs for DECT-guided radiotherapy will greatly improve the current treatment status of OS.

Multiple Thyroglossal Duct Cysts: Clinical Experience and Literature Review.

Thyroglossal duct cysts (TDCs) are generally single cyst, multiple TDCs are rare. We describe a case of multiple TDCs, discuss its characteristic features and management, and provide a review of the literature, to improve clinical diagnosis and treatment. We report an extremely rare case of multiple TDCs containing five cysts, together with a review of the relevant English medical literature. To the best of our knowledge, this is the first reported case of TDCs containing more than three cysts in the anterior cervical region. The five cysts were completely excised in a Sistrunk operation. Histological examination of the cystic lesions revealed TDCs. The patient recovered well and no recurrence was found during the 6-year of follow-up. Multiple TDCs are extremely rare, and may be misdiagnosed as a single cyst. Clinicians should be aware of the possibility of multiple thyroglossal duct cysts. Adequate preoperative radiological examinations should be performed, and careful interpretation of the CT or MRI scans is important to diagnosis and surgery.

Interfering biosynthesis by nanoscale metal-organic frameworks for enhanced radiation therapy.

Radiation therapy (RT) is one of the most widely used cancer treatments. However, the vigorous biosynthesis of cancer cells plays an important role for RT resistance. Herein, we develop a hafnium-based nanoscale metal-organic frameworks (Hf-nMOFs) loaded with 3-bromopyruvate (3-BrPA) to overcome RT resistance and achieve favorable RT efficacy. The deposition of X-rays is greatly enhanced by Hf-nMOFs to induce stronger damage to DNA in RT. Simultaneously, as an inhibitor of glycolysis, the loaded 3-BrPA can reduce the supply of energy and interfere with the biosynthesis of proteins to decrease the DNA damage repair. As a result, the 3-BrPA@Hf-nMOFs (BHT) will overcome the RT resistance and enhance the curative effect of RT. Up and down-regulated genes as well as the related pathways in cellular metabolism and biosynthesis are well investigated to reveal the radiosensitization mechanism of BHT. In addition, the Hf element endows BHT with CT imaging capability to real-timely monitor the therapeutic process. Hence, the designed strategy of biosynthesis-targeted radiosensitization could decrease the doses of ionizing radiations and provide fresh perspectives on cancer treatment.

Paracoccus marinaquae sp. nov., isolated from coastal water of the Yellow Sea.

A Gram-stain-negative, non-motile and coccoid bacterial strain, designated XHP0099T, was isolated from the coastal water of the Yellow Sea, China. Growth occurred at 20-37 â„ƒ (optimum, 28 â„ƒ), pH 5.0-9.0 (optimum, pH 7.0-8.0), and with 0-7.0% NaCl (optimum, 2.0-3.0%). Phylogenetic analysis based on 16S rRNA gene sequences showed that strain XHP0099T was related to members of the genus Paracoccus and shared the highest sequence similarity with "P. siganidrum" M26 (98.2%), followed by P. alkanivorans 4-2 T (97.6%) and P. alkenifer DSM 11593 T (97.4%). The average nucleotide identity, amino acid identity, and digital DNA-DNA hybridization values of strain XHP0099T against related members in the genus Paracoccus were below the cut-off points proposed for the delineation of a novel species. The major cellular fatty acids (> 10%) were summed feature 8 (C18:1 ω7c/C18:1 ω6c), and C18:0. The major isoprenoid quinone was Q-10 and the polar lipids contained diphosphatidylglycerol (DPG), phosphatidylglycerol (PG), phosphatidylethanolamine (PE), phosphatidylcholine (PC), aminolipid (AL) and unidentified polar lipids (L). The G + C content of the genomic DNA of strain XHP0099T was 66.0%. Genomic analysis suggested that strain XHP0099T harbored gene clusters for formaldehyde and the XoxF-type methanol oxidation and type 1 Calvin cycle, which could confer the methylotrophy pathway. Based on the phenotypic, phylogenetic, biochemical and chemotaxonomic analysis, strain XHP0099T represents a novel species of the genus Paracoccus, for which the name Paracoccus marinaquae sp. nov. is proposed. The type strain is XHP0099T (= JCM 34661 T = GDMCC 1.2414 T = MCCC 1K05846T).

Screening of cellulose-degrading yeast and evaluation of its potential for degradation of coconut oil cake.

Coconut oil cake (COC), a byproduct of oil extraction, contains high levels of cellulose. The aim of this study was to isolate a cellulose-degrading yeast from rotten dahlia that can effectively use COC as the only carbon source for cellulase secretion. Based on screening, Meyerozyma guillermondii CBS 2030 (M. guillermondii) was identified as a potential candidate, with the highest cellulolytic activity among the yeast strains isolated, with the carboxymethyl cellulase (CMCase) activity reaching 102.96 U/mL on day 5. The cellulose in COC samples was evaluated before and after degradation by M. guillermondii. Analysis based on field emission scanning electron microscopy (FESEM) revealed that the COC structure was changed significantly during the treatment, indicating effective hydrolysis. Fourier transform infrared spectroscopy (FTIR) of the modified functional groups indicated successful depolymerization of coconut cake. X-ray diffraction (XRD) and analysis of color differences established effective degradation of COC by M. guillermondii. The results demonstrate that M. guillermondii effectively secretes CMCase and degrades cellulose, which has important practical significance in COC degradation.

Characterization of Marinilongibacter aquaticus gen. nov., sp. nov., a unique marine bacterium harboring four CRISPR-Cas systems in the phylum Bacteroidota.

A novel bacterium, designated YYF0007T, was isolated from an agar-degrading co-culture. The strain was found harboring four CRISPR-Cas systems of two classes in the chromosome and subsequently subjected to a study on polyphasic taxonomy. Pairwise analyses of the 16S rRNA gene sequences indicated that strain YYF0007T had highest 16S rRNA gene sequence similarity (92.2%) to Jiulongibacter sediminis JN-14-9T. The phylogenomic trees based on the 16S rRNA gene and 269 single-copy orthologous gene clusters (OCs) indicated that strain YYF0007T should be recognized as a novel genus of the family Spirosomaceae. The cells were Gramstain-negative, nonmotile, strictly aerobic, and straight long rods with no flagellum. Optimum growth occurred at 28°C and pH 7.0 with the presence of NaCl concentration 1.0-3.0% (w/v). The strain showed oxidase and catalase activities. The major fatty acids were C16:1ω5c, iso-C15:0 and summed feature 3 (C16:1ω7c and/or C16:1ω6c). The predominant isoprenoid quinone was MK-7. The complete genome size was 4.64 Mb with a DNA G + C content of 44.4%. Further typing of CRISPR-Cas systems in the family Spirosomaceae and the phylum Bacteroidota indicated that it was remarkable for strain YYF0007T featured by such a set of CRISPR-Cas systems. This trait highlights the applications of strain YYF-0007T in studies on the evolutionary dynamics and bacterial autoimmunity of CRISPR-Cas system as a potential model. The name Marinilongibacter aquaticus gen. nov., sp. nov. is proposed, and the type strain is YYF0007T (= MCCC 1K06017T = GDMCC 1.2428T = JCM 34683T).

Synthesis of 4-Tetrazolyl-Substituted 3,4-Dihydroquinazoline Derivatives with Anticancer Activity via a One-Pot Sequential Ugi-Azide/Palladium-Catalyzed Azide-Isocyanide Cross-Coupling/Cyclization Reaction.

A new one-pot preparation of 4-tetrazolyl-3,4-dihydroquinazolines has been reported. The Ugi-azide reactions of 2-azidobenzaldehydes, amines, trimethylsilyl azide, and isocyanides produced azide intermediates without separation, which were treated with isocyanides to give 4-tetrazolyl-3,4-dihydroquinazoline derivatives through a sequential Palladium-catalyzed azide-isocyanide cross-coupling/cyclization reaction in moderate to good yields. The biological evaluation demonstrated that compound 6c inhibited breast cancer cells well and displayed broad applications for synthesis and medicinal chemistry.

Open-Shell Nanosensitizers for Glutathione Responsive Cancer Sonodynamic Therapy.

Deleterious effects to normal tissues and short biological half-life of sonosensitizers limit the applications of sonodynamic therapy (SDT). Herein, a new sonosensitizer (Cu(II)NS) is synthesized that consists of porphyrins, chelated Cu2+ , and poly(ethylene glycol) (PEG) to overcome the challenges of SDT. As Cu2+ contains 27 electrons, Cu(II)NS has an unpaired electron (open shell), resulting in a doublet ground state and little sonosensitivity. Overexpressed glutathione in the tumor can reduce Cu2+ to generate Cu(I)NS, leading to a singlet ground state and recuperative sonosensitivity. Additionally, PEG endows Cu(II)NS with increased blood biological half-life and enhanced tumor accumulation, further increasing the effect of SDT. Through regulating the valence state of Cu, cancer SDT with enhanced therapeutic index is achieved.

Endotoxin tolerance induced by Porphyromonas gingivalis lipopolysaccharide alters macrophage polarization.

Endotoxin tolerance refers to a state refractory to subsequent lipopolysaccharide (LPS) stimulations following a primary LPS exposure. To study the relationship between endotoxin tolerance and macrophage polarization, endotoxin tolerance was induced by 1 µg/mL LPS from the periodontal pathogen, Porphyromonas gingivalis (P. gingivalis), in peritoneal macrophages (PMs) and bone marrow-derived macrophages (BMDMs). Repeated P. gingivalis LPS challenges increased the quantities of CD206+ PMs, while the number of CD86+CD206+ PMs was reduced compared with the non-tolerant group (p < 0.05). However, there were no changes in BMDMs (p > 0.05). Down regulations of TNF-α, IL-12, nitric oxide and MMP-2 production, and upregulated IL-10, MMP-9 levels and arginase-1 activities occurred in tolerant PMs and BMDMs (p < 0.05). P. gingivalis LPS-tolerant PMs and BMDMs also enhanced scrape-wound healing abilities of 15p-1 cells (p < 0.05). Expressions of phospho-signal transducer and activator of transcription 6 (p-STAT6) and protein tyrosine phosphatase 1B (PTP1B) were increased, while p-MEK1/2 levels were downregulated in tolerant PMs and BMDMs (p < 0.05). IL-10 production in tolerant Stat6 knockdown RAW264.7 cells was lower than tolerant control cells (p < 0.05). P. gingivalis LPS-tolerant macrophages represented an intermediate state between M1/M2 polarization, which functioned as M2-like cells, and led to limited inflammatory responses and enhanced wound healing activities. The PTP1B-MEK1/2-STAT6 signaling pathway might be involved in the polarization of tolerant macrophages.

Enhanced Responsive Formation of Extracellular Traps in Macrophages Previously Exposed to Porphyromonas gingivalis.

Tolerance is defined to be a hyporesponsive state following repeated stimulations with bacteria or their virulence factors and has potential impacts on the development of periodontitis. Recently, macrophages have been reported to release chromatin and antimicrobial peptides to form extracellular traps upon bacterial or chemical stimulations. Thus, we explored the roles and mechanisms of tolerance induced by Porphyromonas gingivalis (P. gingivalis) in macrophage extracellular traps (METs). Tolerance in peritoneal macrophages from mice was triggered by repeated P. gingivalis stimulation. METs were observed using fluorescence microscopy, and the levels of extracellular DNA were determined by microplate reader assays. The expression of p-RAF, p-MEK, and p-ERK was examined by Western blot, and reactive oxygen species (ROS) production was explored using flow cytometry. Moreover, the levels of intracellular Ca2+ were also determined by confocal microscopy to identify the possible mechanisms related to the changes in METs in P. gingivalis-pretreated macrophages. Repeated P. gingivalis stimulation contributed to the formation of METs and increased levels of extracellular DNA (p < 0.05). ROS generation and RAF/MEK/ERK phosphorylation were decreased in P. gingivalis-pretreated macrophages compared with non-pretreated cells (p < 0.05), which was inconsistent with the changes in METs. However, in P. gingivalis-pretreated macrophages, the levels of intracellular Ca2+ were significantly increased compared with the single stimulation group. Additionally, inhibition of intracellular Ca2+ resulted in a decrease in the levels of extracellular DNA in P. gingivalis-pretreated cells (p < 0.05). Taken together, P. gingivalis-pretreated macrophages released more METs, possibly related to the increased levels of intracellular Ca2+.

Cerebellar Stroke in a COVID-19 Infected Patient. a Case Report.

BACKGROUND: Recent studies have reported that COVID-19 infected patients with stroke, who were often in the older age group, had a higher incidence of vascular risk factors, and more severe infection related respiratory symptoms. These observations provided little evidence to suggest that COVID-19 infection is a potential causative factor for stroke. This report describes a young patient with a cerebellar stroke secondary to COVID-19 infection. CASE PRESENTATION: A 45-year old male presented at a hospital, reporting a two-day history of headache, vertigo, persistent vomiting, and unsteady gait. Physical examination revealed gaze-evoked nystagmus on extraocular movement testing, left-sided dysmetria and dysdiadochokinesia. He was diagnosed with a left cerebellar stroke. An external ventricular drain was inserted, and sub-occipital craniectomy was performed to manage the effects of elevated intracranial pressure due to the extent of oedema secondary to the infarct. He also underwent screening for the COVID-19 infection, which was positive on SARS-COV-2 polymerase chain reaction testing of his endotracheal aspirate. Blood and cerebrospinal fluid samples were negative. After the surgery, the patient developed atrial fibrillation and had prolonged vomiting symptoms, but these resolved eventually with symptomatic treatment. He was started on aspirin and statin therapy, but anticoagulation was withheld due to bleeding concerns. The external ventricular drain was removed nine days after the surgery. He continued with active rehabilitation. CONCLUSIONS: Young patients with COVID-19 infection may be more susceptible to stroke, even in the absence of risk factors. Standard treatment with aspirin and statins remains essential in the management of COVID-19 related stroke. Anticoagulation for secondary prevention in those with atrial fibrillation should not be routine and has to be carefully evaluated for its benefits compared to the potential harms of increased bleeding associated with COVID-19 infection.

Hollow Mesoporous Silica Nanoparticles Gated by Chitosan-Copper Sulfide Composites as Theranostic Agents for the Treatment of Breast Cancer.

The combination of chemotherapy and photothermal therapy (PTT) into a single formulation has attracted increasing attention as a strategy for enhancing cancer treatment. Here, hollow mesoporous silica nanoparticles (HMSNs) were used as a base carrier material, loaded with the anti-cancer drug doxorubicin (DOX), and surface functionalized with chitosan (CS) and copper sulfide (CuS) nanodots to give HMSNs-CS-DOX@CuS. In this formulation, the CuS dots act as gatekeepers to seal the surface pores of the HMSNs, preventing a burst release of DOX into the systemic circulation. S-S bonds connect the CuS dots to the HMSNs; these are selectively cleaved under the reducing microenvironment of the tumor, permitting targeted drug release. This, coupled with the PTT properties of CuS, results in a potent chemo/PTT platform. The HMSNs-CS-DOX@CuS nanoparticles have a uniform size (150 ± 13 nm), potent photothermal properties (η = 36.4 %), and tumor-targeted and near infrared (NIR) laser irradiation-triggered DOX release. In vitro and in vivo experimental results confirmed that the material has good biocompatibility, but is effectively taken up by cancer cells. Moreover, the CuS nanodots permit simultaneous thermal/photoacoustic dual-modality imaging. Treatment with HMSNs-CS-DOX@CuS and NIR irradiation caused extensive apoptosis in cancer cells both in vitro and in vivo, and could dramatically extend the lifetimes of animals in a murine breast cancer model. The system developed in this work therefore merits further investigation as a potential nanotheranostic platform for cancer treatment. STATEMENT OF SIGNIFICANCE: Conventional cancer chemotherapy is accompanied by unavoidable off-target toxicity. Combination therapies, which can ameliorate these issues, are attracting significant attention. Here, the anticancer drug doxorubicin (DOX) was encapsulated in the central cavity of chitosan (CS)-modified hollow mesoporous silica nanoparticles (HMSNs). The prepared system can target drug release to the tumor microenvironment. When exposed to near infrared laser (NIR) irradiation, CuS nanodots located at the surface pores of the HMSNs generate energy, accelerating drug release. In addition, a systematic in vitro and in vivo evaluation confirmed the HMSNs-CS-DOX@CuS platform to give highly effective synergistic chemotherapeutic-photothermal therapy and have effective thermal/photoacoustic dual-imaging properties. This work may open up a new avenue for NIR-enhanced synergistic therapy with simultaneous thermal/photoacoustic dual imaging.

Decreased Absolute Number of Circulating Regulatory T Cells in Patients With Takayasu's Arteritis.

Background: Takayasu's arteritis (TA) is a type of primary large vessel vasculitis. Th1, Th17, and Tfh cells have been reported to be associated with TA relapse. However, the relationship between regulatory T cells (Tregs) and TA remains unclear. Objective: To analyze the levels of circulating lymphocytes, especially Treg cells (CD4+CD25+FOXP3+ T cells) and serum cytokines in TA patients and explore their relationship with their changes and TA disease activity. Methods: A total of 57 TA patients and 43 sex- and age-matched healthy controls (HCs) were enrolled. According to NIH standards, 36 patients had active disease status. Flow cytometry combined with counting was used to detect the absolute numbers and ratios of Th1, Th2, Th17, and Treg cells in the peripheral blood of all the subjects. Magnetic bead-based multiplex immunoassay was used to detect cytokines. Results: Compared to HCs, the absolute number and proportion of peripheral Treg cells in TA patients was significantly decreased, while Th17 cells were significantly increased. Furthermore, compared to the inactive group, the TA active group had significantly increased levels of interleukin (IL)-6, IL-10, and tumor necrosis factor (TNF)-α, but lower IL-10 levels. The absolute number of Th2 cells was negatively associated with platelet (PLT) and NIS scores in TA patients. The proportion of Th2 cells was negatively associated with the erythrocyte sedimentation rate in TA patients. After treatment, Treg cells were markedly increased. Conclusion: There was a Th17-Treg cell imbalance with a significant reduction in peripheral Treg cells and an increase in Th17 cells in TA patients compared to the HCs. The levels of IL-6, IL-10, IL-17, and TNF-α appeared to be related to disease activity.