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1.
Gene Expr Patterns ; 35: 119096, 2020 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-32027977

RESUMO

Glomerular capillary formation is one of the fundamental mysteries in renal developmental biology. However, there are still debates on this issue, and its detailed formation process has not been clarified. To resolve this problem, we performed antibody staining with ultra-thick section on embryonic and postnatal mouse kidneys. We obtained the expression patterns of several genes that play an important role in the development of glomerular capillaries. We found that blood vessel of the fetal kidneys expanded through proliferation and sprouting. During the comma-stage and S-shaped stage, 3-4 capillaries began to bud and migrate into the glomerular cleft, forming a capillary bed in the Bowman's capsule. Then, the capillary bed expanded into mature glomerular capillary by intussusceptive angiogenesis. The afferent and efferent arterioles were formed through pruning. The distribution of VEGFA in the nephron epithelial cells but not only in podocytes, induced multiple capillaries sprouted into the glomerular cleft. And CXCR4 played an important role in the differentiation and expansion of capillary bed into glomerular capillary. Immunofluorescence performed with ultra-thick section allowed us to investigate the development of complex structure tissues systematically and comprehensively.

2.
Appl Spectrosc ; : 3702820903817, 2020 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-32031012

RESUMO

The aggregation behavior of collagen-based materials plays an important role in their processing because it could affect their physicochemical properties. Based on the intrinsic fluorescence characteristic of tyrosine, fluorescence spectrum technology was used to investigate the aggregation state of the acylated collagen molecules in aqueous solution. The results showed that the aggregate degree of the acylated collagen was higher than that of the native collagen due to the hydrophobic interaction. With the increase of concentrations of the acylated collagen or at NaCl higher than 40 mmol/L, the aggregate degree of the acylated collagen molecules increased. When the pH was close to the isoelectric point of the acylated collagen, the hydrophobic interaction and the hydrogen bond helped to increase the aggregation degree. However, with the increase of temperature (10-70 ℃), the aggregation state of the acylated collagen decreased gradually due to the quenching, the molecular collision, and the broken of hydrogen bonds. Furthermore, two-dimensional correlation spectroscopy (2D-COS) showed that the response order was 360 > 305 nm at various acylated collagen and NaCl (>40 mmol/L) concentrations, while the response order was 305 > 360 nm when the pH value was increased from 5.0 to 9.0. Temperature-dependent 2D-COS showed there were four bands that occurred and the response order was listed as follows: 293 > 305 > 360 > 420 nm. In brief, the results might provide an important guide for molding processes of the acylated collagen.

3.
Int J Biol Sci ; 16(3): 396-407, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32015677

RESUMO

As the most frequent cause of cancer-related death worldwide, lung cancer is closely related to inflammation. The interaction between tumor cells and inflammatory cells promotes tumor development and metastasis. During tumor development, vascular endothelial cells form the most important barrier to prevent tumor cell migration to the blood and tissue. Increased vascular permeability provides favorable conditions for the migration of tumor cells, and endothelial tight junctions are an important component of the vascular barrier. Protein kinase C δ is involved in the occurrence of non-small cell lung cancer and regulates vascular permeability and tight junction protein expression. Src kinase was reported to play an important role in TNF-α-induced endothelial inflammation. Ophiopogon Saponin C1 is a new chemical compound isolated from Liriope muscari, but its pharmacological activities have not been fully elucidated. Therefore, we tested the protective effects of C1 on endothelial permeability in a model of TNF-α-induced endothelial inflammation by transendothelial electrical resistance and sodium fluorescein assays and verified these results in a nude mouse model of experimental pulmonary adenocarcinoma metastasis. We further elucidated the mechanism of C1, which was based on the PKCδ and Src proteins, by Western blotting. C1 can inhibit lung cancer in vivo, regulate the level of plasma inflammation in tumor-bearing mice, and protect the pulmonary vascular barrier against injury induced by cancer. It was investigated the expression and distribution of the TJ index protein ZO-1 in mouse vascular endothelium and HUVECs and found that C1 could inhibit the degradation and breakage of the ZO-1 protein. Related signaling experiments confirmed that C1 can inhibit TNF-α and activation of PKCδ and Src kinase. This study laid the foundation for further analysis of new drugs with clear mechanisms and independent intellectual property rights of traditional Chinese medicines.

4.
Medicine (Baltimore) ; 99(6): e19064, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32028428

RESUMO

BACKGROUND: This meta-analysis is to evaluate the efficacy and safety of bivalirudin in patients with ST-elevation myocardial infarction (STEMI). METHODS: PubMed, Cochrane Library, Embase, CNKI, CBMdisc, and VIP database were searched. Randomized controlled trial (RCT) was selected and the meta-analysis was conducted by RevMan 5.1. The primary efficacy endpoint was the incidence of major adverse cardiovascular events (MACE) and the primary safety endpoint was the incidence of major bleeding. Secondary efficacy endpoints were myocardial infarction (MI), target vessel revascularization (TVR), stent thrombosis (ST), stock, mortality, and thrombocytopenia. The pooled risk ratios (RRs) with the corresponding 95% confidence intervals (CI) were used to assess the efficacy and safety of bivalirudin vs heparin. RESULTS: Seven RCTs met the inclusion criteria, and 16,640 patients were included. We found that bivalirudin associated with lower risk of mortality (RR = 1.05; 95% CI = 0.74-1.49; P = .03; I = 2%), major bleeding (RR = 0.64; 95% CI = 0.54-0.75; P < .00001; I = 70%) and thrombocytopenia (RR = 0.39; 95% CI = 0.25-0.61; P < .0001; I = 0) compared with heparin. However, the use of bivalirudin increase the risk of MI(RR = 1.37; 95% CI = 1.10-1.71; P = .004; I = 25%) and ST(RR = 1.61; 95% CI = 1.05-2.47; P = .03; I = 70%) and has similar risk of MACE (RR = 1.00; 95% CI = 0.90-1.11; P = .97; I = 16%), TVR (RR = 1.43; 95% CI = 0.92-2.22; P = .11; I = 46%) and stock (RR = 1.43; 95% CI = 0.92-2.22; P = .11; I = 46%) compared with heparin used in STEMI patients. CONCLUSION: Bivalirudin associated with lower risk of mortality, major bleeding and thrombocytopenia compared with heparin. However, the use of bivalirudin increase the risk of MI and ST and has similar risk of MACE, TVR and stock compared with heparin used in STEMI patients.

5.
Nanotechnology ; 2020 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-32032008

RESUMO

Pyramid SnO/CeO2 nano-heterojunction photocatalysts were successfully synthesized via a facile hydrothermal method. The structural characterizations were investigated by using common characterization tools. The content of SnO affected the morphology and photocatalytic performance of SnO/CeO2 nano-heterojunctions. With the increase of SnO content, the morphology of samples changed from sphere to pyramid. The photocurrent of SnO/CeO2 (1:6) sample was about 36 times than that of pure CeO2. With SnO/CeO2 (1:6) as the photocatalyst, the degradation rate of tetracycline (TC) was 99% within 140 minutes under visible light and after 5 cyclic tests, the photocatalytic efficiency of TC remained 98%, which suggested that SnO/CeO2 (1:6) nano-heterojunction had a high photocatalytic efficiency and stable photocatalytic performance. These results indicated that SnO/CeO2 (1:6) nano-heterojunction possesses broad prospects for industrial application.

6.
Immunity ; 2020 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-32049051

RESUMO

Clearance of apoptotic cells by macrophages prevents excessive inflammation and supports immune tolerance. Here, we examined the effect of blocking apoptotic cell clearance on anti-tumor immune response. We generated an antibody that selectively inhibited efferocytosis by phagocytic receptor MerTK. Blockade of MerTK resulted in accumulation of apoptotic cells within tumors and triggered a type I interferon response. Treatment of tumor-bearing mice with anti-MerTK antibody stimulated T cell activation and synergized with anti-PD-1 or anti-PD-L1 therapy. The anti-tumor effect induced by anti-MerTK treatment was lost in Stinggt/gt mice, but not in Cgas-/- mice. Abolishing cGAMP production in Cgas-/- tumor cells, depletion of extracellular ATP, or inactivation of the ATP-gated P2X7R channel also compromised the effects of MerTK blockade. Mechanistically, extracellular ATP acted via P2X7R to enhance the transport of extracellular cGAMP into macrophages and subsequent STING activation. Thus, MerTK blockade increases tumor immunogenicity and potentiates anti-tumor immunity, which has implications for cancer immunotherapy.

7.
Br J Pharmacol ; 2020 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-32022249

RESUMO

BACKGROUND AND PURPOSE: Regulating macrophage-hepatocyte crosstalk through P2X7 receptor (P2X7R) has led to the emergence of new pharmacologic strategies to reverse alcoholic hepatosteatosis. We investigated how tetrahydroxystilbene glucoside (2354glu) purified from Polygonum multiflorum modulates macrophage-hepatocyte crosstalk during alcoholic hepatosteatosis. EXPERIMENTAL APPROACH: Alcoholic hepatosteatosis was established by intragastrically administering ethanol to C57BL/6 mice. HepG2 cells were incubated in conditioned medium from LPS/ATP-activated THP-1 human macrophages with silenced or overexpressed P2X7R. THP-1 macrophages or mouse peritoneal macrophages were pretreated with 2354glu for 1 h prior to LPS/ATP stimulation. HepG2 cells were cultured with the conditioned medium from the LPS/ATP-activated THP-1 macrophages. KEY RESULTS: Knockdown or overexpression of P2X7R in THP-1 macrophages altered the release of mature IL-1ß. P2X7R gene expression in the THP-1 macrophages modulated lipid metabolism in the HepG2 cells via LKB-AMPK axis. 2354glu significantly ameliorated hepatosteatosis in mice after alcohol expose by regulating LKB1-AMPK-SREBP1 axis and its target genes. The suppression of P2X7R activation by 2354glu administration inhibited IL-1ß release, and reduced macrophage and neutrophil infiltration. The expression of P2X7R, caspase-1 and NF-κB, the release of IL-1ß, calcium influx and PI uptake were reduced by 2354glu in macrophages stimulated with LPS/ATP. SIRT1-LKB1-AMPK-SREBP1 axis-mediated lipid accumulation in HepG2 cells was reduced, when HepG2 cells were cultured with conditioned medium from LPS/ATP-activated THP-1 macrophages pretreated with 2354glu. CONCLUSIONS AND IMPLICATIONS: Alteration of P2X7R in macrophages might regulate lipid accumulation in hepatocytes during alcoholic hepatosteatosis, and 2354glu might be a promising candidate that targets P2X7R in macrophages interacting with hepatocytes during alcoholic hepatosteatosis.

8.
J Cell Sci ; 2020 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-32005701

RESUMO

Macrophages are tissue-resident immune cells crucial for the initiation and maintenance of immune responses. Purinergic signaling modulates macrophage activity and impacts cellular plasticity. The ATP-activated purinergic receptor P2X7 has pro-inflammatory properties, which contribute to macrophage activation. P2X7 receptor signaling is in turn modulated by ectonucleotidases such as CD39/E-NTPDase1, expressed in caveolae and lipid rafts. Here, we examined P2X7 receptor activity and determined impacts on ectonucleotidase localization and function in LPS-primed macrophages. First, we verified that ATP boosted CD39 activity and caveolin-1 expression in LPS-primed macrophages. Drugs that disrupt cholesterol-enriched domains - such as nystatin and methyl-ß-cyclodextrin - decreased CD39 enzymatic activity in all circumstances. We noted that CD39 colocalized with lipid raft markers (flotillin-2 and caveolin-1) in LPS-primed macrophages treated with ATP. P2X7 receptor inhibition blocked these ATP-mediated increases in caveolin-1 expression and inhibited the colocalization with CD39. Further, we found that STAT3 activation is significantly attenuated in LPS and LPS+BzATP-treated caveolin-1 deficient macrophages. Taken together, our data suggest that P2X7 receptor triggers the initiation of lipid raft-dependent mechanisms that upregulates CD39 activity and could contribute to limit macrophage responses restoring homeostasis.

9.
J Control Release ; 320: 293-303, 2020 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-32004584

RESUMO

Treatment of solid tumors by chemotherapy is usually failed in clinical because of its low effectiveness and side effects. Stimulation of immune system in vivo to fight cancer has been proved to be a pleasant complementary to systemic chemotherapy. Herein, we have developed a combination cancer therapy strategy by using polymer nanoparticles to deliver Gd-metallofullerenol and doxorubicin simultaneously. The Gd-metallofullerenol provoked the Th1 immune response by regulating the M1 macrophage polarization and the doxorubicin realized direct tumor cells killing by its cytotoxic effect. Also, the Gd-metallofullerenol as part of component in delivery system enhances the encapsulation efficiency of doxorubicin in polymer cargo for potential passive tumor target. The biocompatible and reliable method by combining nanoparticle-induced immune modulation and chemotherapy triggers systemic antitumor immune responses for the synergistic inhibition of tumor growth in vivo. The integration of Gd-metallofullerenol and doxorubicin with potentially complementary functions in one nanoplatform may provide new opportunities to improve cancer treatments.

10.
BMC Genomics ; 21(1): 144, 2020 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-32041548

RESUMO

BACKGROUND: The brown planthopper (BPH, Nilaparvata lugens Stål) is a kind of phloem-feeding pest that adversely affects rice yield. Recently, the BPH-resistance gene, BPH6, was cloned and applied in rice breeding to effectively control BPH. However, the molecular mechanisms underlying BPH6 are poorly understood. RESULTS: Here, an integrated miRNA and mRNA expression profiling analysis was performed on BPH6-transgenic (BPH6G) and Nipponbare (wild type, WT) plants after BPH infestation, and a total of 217 differentially expressed miRNAs (DEMs) and 7874 differentially expressed mRNAs (DEGs) were identified. 29 miRNAs, including members of miR160, miR166 and miR169 family were opposite expressed during early or late feeding stages between the two varieties, whilst 9 miRNAs were specifically expressed in BPH6G plants, suggesting involvement of these miRNAs in BPH6-mediated resistance to BPH. In the transcriptome analysis, 949 DEGs were opposite expressed during early or late feeding stages of the two genotypes, which were enriched in metabolic processes, cellular development, cell wall organization, cellular component movement and hormone transport, and certain primary and secondary metabolite synthesis. 24 genes were further selected as candidates for BPH resistance. Integrated analysis of the DEMs and DEGs showed that 34 miRNAs corresponding to 42 target genes were candidate miRNA-mRNA pairs for BPH resistance, 18 pairs were verified by qRT-PCR, and two pairs were confirmed by in vivo analysis. CONCLUSIONS: For the first time, we reported integrated small RNA and transcriptome sequencing to illustrate resistance mechanisms against BPH in rice. Our results provide a valuable resource to ascertain changes in BPH-induced miRNA and mRNA expression profiles and enable to comprehend plant-insect interactions and find a way for efficient insect control.

11.
Food Chem ; 315: 126273, 2020 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-32032832

RESUMO

Sea cucumber (Stichopus japonicus) is a high-protein food with the potential to release certain peptides through enzymolysis. This work is to explore the characteristics of peptides released from Stichopus japonicus protein in the process of digestion. Hydrolysates were obtained by gastrointestinal digestion and fractioned to <3, 3-10, 10-30 and >30 kDa fractions. Fifty-eight peptides from <3 kDa fraction were characterized using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Hydrolysates could improve glucose uptake of 3 T3-L1 cells and high insulin-induced insulin-resistant Hep G2 cells. Molecular docking showed that the released peptides had similar binding mode with anagliptin, a dipeptidyl peptidase IV (DPP-IV) inhibitor. The <3 kDa fraction in gastro and intestinal digestion showed the greatest DPP-IV inhibitory potency (IC50 0.51 and 0.52 mg/mL, respectively). The results indicated that sea cucumber could be used as a functional food to release antidiabetic peptides through gastrointestinal digestion.

12.
J Cell Physiol ; 2020 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-31970783

RESUMO

Follicle development is a key factor that determines the reproductive performance of poultry. The existing evidence suggests that circular RNAs (circRNAs) play an important role in a variety of biological processes, especially in posttranscriptional regulation, but the regulatory mechanism of circRNAs in duck follicle development has rarely been reported. To better explore the molecular mechanism of follicle development in ducks, we sequenced and analyzed the follicular circRNAs; 4,204 circRNAs were predicted in the duck follicles. Fourteen circRNAs were differentially expressed between the white follicles and yellow follicles. The results of our studies showed that aplacirc_013267 promoted cell apoptosis in duck GCs. Moreover, a bioinformatics prediction analysis demonstrated that aplacirc_013267 was involved in a circRNA-miRNA-mRNA coexpression network and was observed to sponge two follicle-related miRNAs by a luciferase activity assay. Furthermore, we found that overexpression of aplacirc_013267 significantly increased thrombospondin-1 (THBS1) expression and downregulated granulosa cell apoptosis. The mechanistic study showed that aplacirc_013267 directly binds to and inhibits apla-mir-1-13; then, aplacirc_013267 increases the expression of THBS1 and upregulates granulosa cell apoptosis. Taken together, our findings demonstrate that circRNAs have potential effects in duck ovarian follicles and that circRNAs may represent a new avenue to understand follicular development.

13.
J Ethnopharmacol ; 251: 112550, 2020 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-31918015

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Isatidis Radix, the sun-dried roots of Isatis indigotica Fortune ex Lindl., is one of the most usually used traditional Chinese medicines. For centuries, the herb has been employed in clinical practice for treatment of virus infection and inflammation. However, its active ingredients remain unclear. AIM OF THE STUDY: In the present study, the anti-influenza virus activity of epiprogoitrin, progoitrin, epigoitrin and goitrin, the Isatidis Radix derived glucosinolate isomers and their breakdown products, was firstly evaluated in vitro and in ovo and their mechanism of action was investigated. MATERIALS AND METHODS: Epiprogoitrin, progoitrin, epigoitrin and goitrin were isolated from Isatidis Radix by chiral separation. In vitro and in ovo evaluations were performed on Madin-Darby canine kidney (MDCK) cells and embryonated eggs respectively, both using protocols including prevention, treatment and virus neutralization. Hemagglutination (HA) and neuraminidase (NA) inhibition assays were performed for further understanding of the antiviral mechanism. RESULTS: Isatidis Radix derived glucosinolate isomers and their breakdown products all exhibited dose-dependent inhibition effect against influenza A virus (H1N1) without toxicity. The antiviral potency of the components was in the order of progoitrin > goitrin > epigoitrin > epiprogoitrin. The attachment of the constituents to the viral envelope conduced to the mechanism of their antiviral action without disturbing viral adsorption or budding. CONCLUSION: Taken together, these results are promising for further development of Isatidis Radix and may contribute an adjunct to pharmacotherapy for influenza virus infection.

14.
J Ethnopharmacol ; 251: 112554, 2020 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-31923541

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Ulcerative colitis (UC) is tightly associated with inflammation response and oxidative stress. As a folk medicine applied in treatment of diarrhea, Bruguiera gymnorrhiza also possesses anti-inflammatory and anti-oxidative activities, which indicated that B. gymnorrhiza may exert anti-colitis effect. AIM OF THE STUDY: To investigate effect and mechanism of B. gymnorrhiza on experimental UC. MATERIALS AND METHODS: Aqueous extract of B. gymnorrhiza leaves (ABL) was used for investigation in the present study. Murine UC was established through access to 3% dextran sulfate sodium (DSS) for 7 days. Meanwhile, mice accepted treatment with ABL (25, 50, 100 mg/kg) or sulfasalazine (200 mg/kg) once daily. On the last day, disease activity index (DAI) including body weight loss, fecal character and degree of bloody diarrhea was evaluated, colon segments were obtained for length measurement and further analysis and feces were collected for intestinal microbiota analysis. RESULTS: ABL ameliorated DAI scores, colon length shortening and histopathological damage in DSS-induced colitis mice obviously. SOD activity, levels of MDA and GSH altered by colitis were restored remarkably after ABL treatment. ABL inhibited increases in levels of colonic COX-2, iNOS, TNF-α, IL-6, IL-1ß, IL-4, IL-10 and IL-11 in colitis mice. Moreover, ABL prominently suppressed NF-κB p65 and IκB phosphorylation and down-regulated mRNA levels of COX-2, iNOS, TNF-α, IL-6 and IL-1ß elevated by colitis. As shown in microbiota analysis, ABL modulated composition of intestinal microbiota of colitis mice. CONCLUSION: ABL exhibited protective effect against DSS-induced ulcerative colitis through suppressing NF-κB activation and modulating intestinal microbiota.

16.
J Mol Cell Cardiol ; 139: 75-86, 2020 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-31982429

RESUMO

AIMS: The antimicrobial peptide cathelicidin (Camp) has multifunctional immunomodulatory activities. However, its roles in inflammation-related myocardial ischemia/reperfusion (MI/R) injury remain unclear. METHODS AND RESULTS: In this study, adult male C57BL/6 wild-type (WT) mice were subjected to MI/R injury by left anterior descending coronary artery ligation for 45 min followed by 3 or 24 h of reperfusion. An abundant cardiac expression of cathelicidin was observed during ischemia and reperfusion, which was mainly derived from heart-infiltrating neutrophils. Knockout of Camp in mice reduced MI/R-induced myocardial inflammation, infarct size, and circulating cTnI levels (an indicator of heart damage). CRAMP (the mature form of murine cathelicidin) administration of WT mice immediately before MI/R exerted detrimental effects on the reperfused heart. CRAMP exacerbates MI/R injury via a TLR4 and P2X7R/NLRP3 inflammasome-dependent mechanism, since I/R-induced myocardial infarction was reserved by inhibition of TLR4, P2X7R, or NLRP3 inflammasome in CRAMP-treated WT mice. Depletion of neutrophils before MI/R abrogated the amplification of infarct size in CRAMP-treated WT mice. Heart-infiltrating neutrophils were found to be one of major cellular sources of myocardial IL-1ß (a "first line" pro-inflammatory cytokine) at the early stage of MI/R. At this stage, CRAMP administration just before MI/R induced pro-IL-1ß protein expression in heart-infiltrating neutrophils, but not in non-neutrophils. In vitro experiments showed that LL-37 (the mature form of human cathelicidin) treatment promotes the processing and secretion of IL-1ß from human neutrophils via stimulating TLR4 signaling and P2X7R/NLRP3 inflammasome. CONCLUSIONS: Our findings reveal that, at the early stage of MI/R, neutrophil-derived cathelicidin plays an injurious role in the heart. Cathelicidin aggravates MI/R injury by over-activating TLR4 signaling and P2X7R/NLRP3 inflammasome in heart-infiltrating neutrophils, which leads to the excessive secretion of IL-1ß and subsequent inflammatory injury.

17.
BMC Cancer ; 20(1): 26, 2020 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-31914948

RESUMO

BACKGROUND: Combining anti-cancer therapies with orthogonal modes of action, such as direct cytotoxicity and immunostimulatory, hold promise for expanding clinical benefit to patients with metastatic disease. For instance, a chemotherapy agent Oxaliplatin (OXP) in combination with Interleukin-12 (IL-12) can eliminate pre-existing liver metastatic colorectal cancer and protect from relapse in a murine model. However, the underlying dynamics associated with the targeted biology and the combinatorial space consisting of possible dosage and timing of each therapy present challenges for optimizing treatment regimens. To address some of these challenges, we developed a predictive simulation platform for optimizing dose and timing of the combination therapy involving Mifepristone-induced IL-12 and chemotherapy agent OXP. METHODS: A multi-scale mathematical model comprised of impulsive ordinary differential equations was developed to describe the interaction between the immune system and tumor cells in response to the combined IL-12 and OXP therapy. An ensemble of model parameters were calibrated to published experimental data using a genetic algorithm and used to represent three different phenotypes: responders, partial-responders, and non-responders. RESULTS: The multi-scale model captures tumor growth patterns of the three phenotypic responses observed in mice in response to the combination therapy against a tumor re-challenge and was used to explore the impacts of changing the dose and timing of the mixed immune-chemotherapy on tumor growth subjected to a tumor re-challenge in mice. An increased ratio of CD8 + T effectors to regulatory T cells during and after treatment was key to improve tumor control in the responder cohort. Sensitivity analysis indicates that combined OXP and IL-12 therapy worked more efficiently in responders by increased priming of T cells, enhanced CD8 + T cell-mediated killing, and functional inhibition of regulatory T cells. In a virtual cohort that mimics non-responders and partial-responders, simulations show that an increased dose of OXP alone would improve the response. In addition, enhanced IL-12 expression alone or an increased number of treatment cycles of the mixed immune-chemotherapy can barely improve tumor control for non-responders and partial responders. CONCLUSIONS: Overall, this study illustrates how mechanistic models can be used for in silico screening of the optimal therapeutic dose and timing in combined cancer treatment strategies.

18.
J Mater Chem B ; 8(6): 1223-1234, 2020 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-31950968

RESUMO

Based on the concept of starving tumor therapy, in this study we put forward a new idea that the pH-sensitive Ca2+ delivery of calcium carbonate nanoparticles (CaCO3 NPs) induced blood coagulation of tumor vessels, and first explored the effect of CaCO3 NPs on the in vitro and in vivo blood coagulation by acid stimulus. CaCO3 NPs with a size of about 100 nm and a porous structure of several nanometers were synthesized in an emulsion system, which showed a high loading capacity (49%) of doxorubicin hydrochloride (DOX) with an encapsulation efficiency of 98% and a pH-sensitive drug delivery. The hemolysis test showed that CaCO3 NPs were blood compatible. The in vitro Ca2+ delivery and blood clotting tests indicated that CaCO3 NPs pH-sensitively released Ca2+, and caused rapid blood coagulation at pH 5.0 but no thrombus at pH 7.4. Confocal laser scanning microscopy showed that after uptake by MCF-7 or MDA-MB-231 breast cancer cells, CaCO3 NPs mainly distributed in endosomes/lysosomes within the initial 2 h and then decomposed by acid stimulus, leading to the intracellular delivery of Ca2+ that subsequently migrated outside the cells. CaCO3 NPs were nontoxic to NIH3T3 mouse fibroblasts, but highly toxic to both MCF-7 and MDA-MB-231 cells after loading DOX. After topical administration into the breast tumors of mice, CaCO3 NPs evoked significant thrombosis and hemorrhage of tumor vasculature by hematoxylin-eosin and Masson's trichrome staining. These results indicated that CaCO3 NPs could induce blood coagulation via acid stimulus, showing potential applications in blocking tumor vessels for starving tumor therapy.

19.
Cancer Imaging ; 20(1): 7, 2020 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-31937372

RESUMO

BACKGROUND: The difficulty of assessment of neoadjuvant chemotherapeutic response preoperatively may hinder personalized-medicine strategies that depend on the results from pathological examination. METHODS: A total of 191 patients with high-grade osteosarcoma (HOS) were enrolled retrospectively from November 2013 to November 2017 and received neoadjuvant chemotherapy (NCT). A cutoff time of November 2016 was used to divide the training set and validation set. All patients underwent diagnostic CTs before and after chemotherapy. By quantifying the tumor regions on the CT images before and after NCT, 540 delta-radiomic features were calculated. The interclass correlation coefficients for segmentations of inter/intra-observers and feature pair-wise correlation coefficients (Pearson) were used for robust feature selection. A delta-radiomics signature was constructed using the lasso algorithm based on the training set. Radiomics signatures built from single-phase CT were constructed for comparison purpose. A radiomics nomogram was then developed from the multivariate logistic regression model by combining independent clinical factors and the delta-radiomics signature. The prediction performance was assessed using area under the ROC curve (AUC), calibration curves and decision curve analysis (DCA). RESULTS: The delta-radiomics signature showed higher AUC than single-CT based radiomics signatures in both training and validation cohorts. The delta-radiomics signature, consisting of 8 selected features, showed significant differences between the pathologic good response (pGR) (necrosis fraction ≥90%) group and the non-pGR (necrosis fraction < 90%) group (P < 0.0001, in both training and validation sets). The delta-radiomics nomogram, which consisted of the delta-radiomics signature and new pulmonary metastasis during chemotherapy showed good calibration and great discrimination capacity with AUC 0.871 (95% CI, 0.804 to 0.923) in the training cohort, and 0.843 (95% CI, 0.718 to 0.927) in the validation cohort. The DCA confirmed the clinical utility of the radiomics model. CONCLUSION: The delta-radiomics nomogram incorporating the radiomics signature and clinical factors in this study could be used for individualized pathologic response evaluation after chemotherapy preoperatively and help tailor appropriate chemotherapy and further treatment plans.

20.
J Cell Mol Med ; 2020 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-31957265

RESUMO

This study sought to find more exon mutation sites and lncRNA candidates associated with type 2 diabetes mellitus (T2DM) patients with obesity (O-T2DM). We used O-T2DM patients and healthy individuals to detect mutations in their peripheral blood by whole-exon sequencing. And changes in lncRNA expression caused by mutation sites were studied at the RNA level. Then, we performed GO analysis and KEGG pathway analysis. We found a total of 277 377 mutation sites between O-T2DM and healthy individuals. Then, we performed a DNA-RNA joint analysis. Based on the screening of harmful sites, 30 mutant genes shared in O-T2DM patients were screened. At the RNA level, mutations of 106 differentially expressed genes were displayed. Finally, a consensus mutation site and differential expression consensus gene screening were performed. In the current study, the results revealed significant differences in exon sites in peripheral blood between O-T2DM and healthy individuals, which may play an important role in the pathogenesis of O-T2DM by affecting the expression of the corresponding lncRNA. This study provides clues to the molecular mechanisms of metabolic disorders in O-T2DM patients at the DNA and RNA levels, as well as biomarkers of the risk of these disorders.

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