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1.
Cancer Lett ; 496: 93-103, 2021 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-33038490

RESUMO

Oesophageal cancer is associated with high morbidity and mortality rates because it is highly invasive and prone to recurrence and metastasis, with a five-year survival rate of <20%. Therefore, there is an urgent need for new methods aimed at improving therapeutic intervention. Several studies have shown that targeted therapy may be effective for the treatment of oesophageal cancer. Focal adhesion kinase (FAK), a non-receptor tyrosine kinase with kinase activity and scaffolding function, could be overexpressed in a variety of solid tumours, including oesophageal cancer. FAK participates in survival, proliferation, progression, adhesion, invasion, migration, epithelial-to-mesenchymal transition, angiogenesis, DNA damage repair, and other biological processes through multiple signalling pathways in cancer cells. It plays an important role in the occurrence and development of tumours and has been linked to the prognosis of oesophageal cancer. FAK has been suggested as a potential therapeutic target in oesophageal cancer; thus, the combination of FAK inhibitors with chemotherapy, radiotherapy, and immunotherapy is expected to prolong the survival of patients. This paper presents a brief overview of the structure of FAK and its potential role in oesophageal cancer, providing a rationale for the future application of FAK inhibitors in the treatment of the disease.

2.
Talanta ; 222: 121536, 2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-33167244

RESUMO

The ability to recognize mRNA with high efficiency in cells would greatly facilitate the elucidation of mRNA-mediated cellular cascades and their disease associations. However, most traditional electrochemical strategies targeting nucleotides are always confronted with cumbersome interface operation and washing procedures, as well as the high cost of labeling and the strict reaction conditions of tool enzymes, limiting their potential applications. To address these issues, herein we reported, for the first time, a simple label-free, isothermal, non-enzymatic, and ultrasensitive homogeneous electrochemical biosensor based on autonomous proximity-dependent surface hybridization chain reaction (HCR), for sensitive signal amplification and highly specific detection of target survivin mRNA with a detection limit of 3 fM. The target triggers hybridization chain reaction and mRNA-fueled surface hybridization of ferrocene-tagged metastable DNA hairpin probes on proximity-dependent surface hybridization, resulting in the formation of multiple long-range duplex DNA chains which are immobilized onto the gold electrodes with a substantially stable ferrocene-mediated redox current. Thus, a significant electrochemical signal increase is observed dependent on the concentration of the target RNA, with a very low detection limit. Mo-reover, this molecular biosensor also exhibits excellent specificity to distinguish even single base mismatched, with strong reliability. The developed biosensor provides a novel promising tool for ultra-sensitive and selective detection, and it has great potential to be applied in mRNA-related biochemical research and clinical cancer diagnostics in more detail.

3.
J Atheroscler Thromb ; 2020 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-33191314

RESUMO

AIM: The triglyceride-glucose index (TyG index) is proposed as a surrogate parameter for insulin resistance (IR) and, when elevated, is related to increased cardiovascular risks. Whether the TyG index is of great value in predicting adverse prognosis for individuals diagnosed with non-ST-segment elevation acute coronary syndrome (NSTE-ACS), who received elective percutaneous coronary intervention (PCI), and without recognized diabetes remains unclear. METHODS: Overall, 1,510 subjects diagnosed with NSTE-ACS, who received elective PCI, and without recognized diabetes were enrolled in the current study. All participants received a routine follow-up after discharge. The TyG index was obtained from the following equation: napierian logarithmic (ln) [fasting triglyceride (TG, mg/dL)×fasting blood glucose (FBG, mg/dL)/2]. Adverse cardiovascular events included all-cause death, nonfatal myocardial infarction (MI), nonfatal ischemic stroke, and ischemia-driven revascularization, composite of which was defined as the primary endpoint. RESULTS: Overall, 316 (20.9%) endpoint events were documented during a 48-month follow-up. Despite adjusting for confounding variates, the TyG index remains to be a significant risk predictor for the primary endpoint, with a hazard ratio (HR) [95% confidence interval (CI)] of 2.433 (1.853-3.196) (P<0.001). A significant enhancement on the predictive performance for the primary endpoint emerged when adding the TyG index into a baseline model [area under the receiver-operating characteristic (ROC) curve (AUC), 0.835 for baseline model vs. 0.853 for baseline model+TyG index, P<0.001; net reclassification improvement (NRI), 0.194, P<0.001; integrated discrimination improvement (IDI), 0.023, P=0.007]. CONCLUSIONS: The TyG index is an independent risk predictor for adverse cardiovascular events in nondiabetic subjects diagnosed with NSTE-ACS and who received elective PCI. Further prospective studies are needed to verify these findings.

4.
Arch Pathol Lab Med ; 2020 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-33147323

RESUMO

CONTEXT.­: Bone and soft tissue tumors are heterogeneous, diagnostically challenging, and often defined by gene fusions. OBJECTIVE.­: To present our experience using a custom 34-gene targeted sequencing fusion panel. DESIGN.­: Total nucleic acid extracted from formalin-fixed, paraffin-embedded (FFPE) tumor specimens was subjected to open-ended, nested anchored multiplex polymerase chain reaction and enrichment of 34 gene targets, thus enabling detection of known and novel fusion partners. RESULTS.­: During a 12-month period, 145 patients were tested as part of routine clinical care. Tumor percentage ranged from 10% to 100% and turnaround time ranged from 3 to 15 (median, 7.9) days. The most common diagnostic groups were small round blue cell tumors, tumors of uncertain differentiation, fibroblastic/myofibroblastic tumors, and adipocytic tumors. In-frame fusion transcripts were identified in 64 of 140 cases sequenced (46%): in 62 cases, the detection of a disease-defining fusion confirmed the morphologic impression; in 2 cases, a germline TFG-GPR128 polymorphic fusion variant was detected. Several genes in the panel partnered with multiple fusion partners specific for different diagnoses, for example, EWSR1, NR4A3, FUS, NCOA2, and TFE3. Interesting examples are presented to highlight how fusion detection or lack thereof was instrumental in establishing accurate diagnoses. Novel fusion partners were detected for 2 cases of solid aneurysmal bone cysts (PTBP1-USP6, SLC38A2-USP6). CONCLUSIONS.­: Multiplex detection of fusions in total nucleic acid purified from FFPE specimens facilitates diagnosis of bone and soft tissue tumors. This technology is particularly useful for morphologically challenging entities and in the absence of prior knowledge of fusion partners, and has the potential to discover novel fusion partners.

5.
Ann Ital Chir ; 91: 366-371, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33162404

RESUMO

OBJECTIVE: This study aims to evaluate efficacy and safety of mastoscopic skin sparing mastectomy and sentinel lymph node biopsy combined with immediate mammary prosthesis reconstruction for early central breast cancer. MATERIALS AND METHODS: The medical records of patients, who underwent mastoscopic skin sparing mastectomy and sentinel lymph node biopsy combined with immediate mammary prosthesis reconstruction during the period of March 2011 and November 2016, were collected from Fuxing Hospital. Data on clinicopathologic characteristics, operative time, the number of resected sentinel lymph nodes, and complications were analyzed. RESULTS: The procedures were performed in 11 patients with central breast cancer. Among these patients, 10 patients were diagnosed with infiltrating ductal carcinoma, while the remaining patient had Paget's disease with infiltrating ductal carcinoma. The mean operation time was 148.2 minutes with minimal bleeding, and the median number of sentinel lymph nodes dissected from each operation was 4.6. The volume range of implants was 180-245 cc. There were no recurrences and upper limb swelling during the follow-up period. Merely two cases had sporadic axillary pain due to the mastoscopic lymph node dissection performed for the positive sentinel lymph nodes. All patients were satisfied with the reconstructive appearance. CONCLUSION: The present study shows that mastoscopic skin sparing mastectomy and sentinel lymph node biopsy combined with immediate mammary prosthesis reconstruction is a feasible procedure for early central breast cancer. KEY WORDS: Breast cancer, Fat suction, Reconstructive surgery, Sentinel lymph node, Skin sparing mastectomy.

6.
Artigo em Inglês | MEDLINE | ID: mdl-33156910

RESUMO

OBJECTIVES: The aim of this study was to compare the outcomes of tricuspid valve (TV) repair versus replacement for patients with infective endocarditis (IE). METHODS: In this nationwide population-based cohort study, we identified 704 patients from Taiwan National Health Insurance Research Database who underwent TV surgery due to IE between 2000 and 2013. Of them, 412 (58.5%) underwent TV repair and 292 (41.5%) underwent TV replacement, and their perioperative and late outcomes were analysed. Confounding was reduced using the inverse probability of treatment weighting on propensity score. RESULTS: After inverse probability of treatment weighting, the in-hospital mortality rate between the 2 groups was not significantly different. However, patients who received TV repair had lower rates of perioperative complications, including massive blood transfusion, de novo dialysis and deep wound infection; longer ICU and hospital stays; and higher hospital cost. Regarding late outcomes, TV repair was associated with lower risks of all-cause readmission [subdistribution hazard ratio (HR) 0.68, 95% confidence interval (CI) 0.60-0.78; P < 0.001], readmission for adverse liver outcomes (subdistribution HR 0.75, 95% CI 0.58-0.97; P = 0.025), new permanent pacemaker implantation (subdistribution HR 0.27, 95% CI 0.15-0.48; P < 0.001) and all-cause mortality (HR 0.60, 95% CI 0.51-0.71; P < 0.001) than TV replacement. CONCLUSIONS: For IE, TV repair is associated with better early and late outcomes than TV replacement. A repair-first strategy is recommended for patients with IE for whom TV surgery is indicated.

7.
Biomed Pharmacother ; 131: 110769, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33152931

RESUMO

OBJECTIVES: Pomegranate flower is a kind of uygur medicine with anti - type 2 diabetes, anti - lipid, anti - inflammation, anti - oxidation. We investigated the effect of pomegranate flower extract (PFE) on the proliferation, differentiation and apoptosis of 3T3-L1 preadipocytes, as well as the effects of five compounds in PF on cell differentiation. METHODS: 3T3-L1 preadipocytes were treated with PFE (0.5, 1, 2, 5, 10, 20, 50, 100 µg/mL), quercetin, luteolin, ursolic acid, apigenin and kaempferol (5, 10, 20, 40, 80 µM), and cell viability was measured at 24, 48 and 72 h by Cell Counting Kit-8. The modified cocktail induction method induced the differentiation of 3T3-L1 preadipocytes, and treated them with PFE and the compounds. The lipid accumulation was determined by oil red O staining, and the intracellular triglyceride content was determined by commercial kit. The expressions of PPARγ, C/EBP, LPL, DGAT and aP2 mRNA in mature adipocyte were determined by q-PCR, and the expressions of PPARγ, Akt, p-akt and PI3K protein were determined by western blot. 3T3-L1 preadipocytes were treated with PFE (5, 10, 20 µg/mL) while induced apoptosis by palmitate (300 µM), Hoechst staining to observe apoptosis morphology, Annexin Ⅴ- FITC/PI staining with flow cytometry instrument to detect the number of early and late apoptosis cells, the q-PCR and western blot for determining the Bcl-2, Bax, caspase 3 mRNA and protein expression. RESULTS: PFE (5, 10, 20 µg/mL) promoted or did not affect the proliferation and differentiation of 3T3-L1 preadipocytes, and reduced the number of early and late apoptotic cells, increased the expression of Bcl-2 mRNA and protein, and inhibited the expression of Bax and caspase-3 mRNA and protein. Furthermore, PFE (40, 60 µg/mL), quercetin (10, 20, 40 µM), luteolin (5, 10, 20 µM), apigenin(20,40 µM), kaempferol (20, 40 µM) significantly restrain the 3T3-L1 different extent proliferation and differentiation of preadipocyte, reduce the accumulation of lipids in adipocyte, reduce expression of adipogenesis factor, PFE(40, 60 µg/mL) inhibited the activation of the PI3K-Akt pathway by inhibiting the expression of PI3K and p-Akt proteins, and inhibited preadipocyte differentiation by reduce the expression of PPARγ protein. CONCLUSION: PFE has a concentration-related bidirectional effect on the proliferation, differentiation and apoptosis of 3T3-L1 preadipocytes, which depends on the regulation of PI3K-Akt pathway, which is of guiding role for PFE in the treatment of type 2 diabetes, hyperlipidemia, obesity and other diseases.

8.
Mol Imaging Biol ; 2020 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-33185840

RESUMO

PURPOSE: To evaluate the utility of three-dimensional (3D) amide proton transfer-weighted (APTw) imaging for differentiation of endometrial adenocarcinoma and uterine benign lesions. PROCEDURES: This prospective study enrolled 22 normal volunteers and 113 patients with suspicious uterine lesions, including endometrial adenocarcinoma, leiomyoma, and adenomyosis. Pelvic APTw MRI was performed on a 3-T MRI scanner with default APTw parameters. Two radiologists blindly evaluated uterine lesion APTw image quality by a 3-point Likert scale and independently measured APTw values on images with excellent to good image quality. Inter-reader agreement was evaluated. The Mann-Whitney U test with Bonferroni correction was used to compare the differences among different types of uterine lesions. A receiver operating characteristic analysis was performed. RESULTS: A total of 111 lesions (33 endometrial adenocarcinoma, 26 leiomyoma, and 52 adenomyosis lesions) from 99 patients revealing a majority of good quality with excellent inter-reader agreement were included for the image quality evaluation. APTw values of endometrial adenocarcinoma were 2.9 ± 0.1 %, significantly higher than those of leiomyoma (1.9 ± 0.1 %), adenomyosis (2.2 ± 0.1 %), and normal uterine myometrium (1.9 ± 0.1 %) (all p < 0.0001). The area under the receiver operating characteristic curve for differentiating endometrial adenocarcinoma from leiomyoma, adenomyosis, and myometrium was 0.87, 0.85, and 0.91, respectively. Feasible threshold APTw values of each group were determined as 2.4 %, 2.7 %, and 2.4 % with a sensitivity of 83.3 %, 76.7 %, and 83.3 % and a specificity of 83.3 %, 81.6 %, and 86.4 %, respectively. CONCLUSIONS: Malignant endometrial adenocarcinoma had significantly higher APTw values than leiomyoma, adenomyosis, and normal uterine myometrium. Our study adds to the growing body of validation on 3D APTw imaging and uterine lesions.

9.
Zhongguo Zhong Yao Za Zhi ; 45(17): 4089-4098, 2020 Sep.
Artigo em Chinês | MEDLINE | ID: mdl-33164393

RESUMO

To investigate the potential mechanism of Puerariae Lobatae Radix in the treatment of hepatocellular carcinoma by network pharmacology and in vitro cell experiment. The main active components of Puerariae Lobatae Radix and their predicted targets were obtained from TCMSP, and the disease targets were obtained from GeneCards database. The disease and drug prediction targets were intersected to select the common potential therapeutic targets. The "compound-target-disease" network diagram was constructed in Cytoscape 3.7.1, and the common targets were input into the STRING database to build the PPI network of proteins interaction. GO function and KEGG pathway enrichment analysis on effective targets were performed by using R software. Autodock vina 1.1.2 was used for molecular docking. Finally, the core targets and pathways were preliminarily verified by in vitro experiments. The proliferation of human hepatocellular carcinoma cells was detected by CCK-8 and EDU enzyme staining, and the expressions of PTEN, PDK1, Akt and GSK3 were detected by Western blot. In this study, 10 components of Puerariae Lobatae Radix(9 components involved in hepatocellular carcinoma-related targets and signaling pathways), and 149 hepatocellular carcinoma-related targets and 156 signaling pathways were screened out. The results of network analysis indicated that Puerariae Lobatae Radix may play an anti-hepatocellular carcinoma effect on key targets, such as Akt, IL6, MAPK3, EGFR, and key pathways, such as PI3 K-Akt. The results of molecular docking indicated that puerarin, genistein and daidzein had a good binding ability with the key targets such as AKT1, MAPK3, MAPK1 and CASP3, and puerarin had the lowest Vina score with AKT1 and MAPK3 and also similar to them. In vitro cell experiments confirmed that puerarin has a significantly inhibitory effect on the proliferation of human hepatocellular carcinoma cells. Western blot results showed that puerarin could increase the phosphorylation of PTEN in human hepatocellular carcinoma cells through the PTEN/Akt/GSK3ß signaling pathway, and the phosphorylation level of its downstream Akt decreased. This series of studies confirm that puerarin can treat hepatocellular carcinoma by blocking PTEN/Akt/GSK3ß cellular signaling pathway, so as to provide ideas for subsequent studies for the molecular mechanism of puerarin in the treatment of liver cancer.


Assuntos
Carcinoma Hepatocelular , Medicamentos de Ervas Chinesas , Neoplasias Hepáticas , Pueraria , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/genética , Medicamentos de Ervas Chinesas/farmacologia , Quinase 3 da Glicogênio Sintase , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Simulação de Acoplamento Molecular
10.
Anal Chem ; 92(22): 14892-14897, 2020 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-33151059

RESUMO

Short-chain fatty acids (SCFAs) are small molecules ubiquitous in nature. In mammalian guts, SCFAs are mostly produced by anaerobic intestinal microbiota through the fermentation of dietary fiber. Levels of microbe-derived SCFAs are closely relevant to human health status and indicative to gut microbiota dysbiosis. However, the quantification of SCFA using conventional chromatographic approaches is often time consuming, thus limiting high-throughput screening tests. Herein, we established a novel method to quantify SCFAs by coupling amidation derivatization of SCFAs with paper-loaded direct analysis in real time mass spectrometry (pDART-MS). Remarkably, SCFAs of a biological sample were quantitatively determined within a minute using the pDART-MS platform, which showed a limit of detection at the µM level. This platform was applied to quantify SCFAs in various biological samples, including feces from stressed rats, sera of patients with kidney disease, and fermentation products of metabolically engineered cyanobacteria. Significant differences in SCFA levels between different groups of biological practices were promptly revealed and evaluated. As there is a burgeoning demand for the analysis of SCFAs due to an increasing academic interest of gut microbiota and its metabolism, this newly developed platform will be of great potential in biological and clinical sciences as well as in industrial quality control.

11.
Sci Rep ; 10(1): 19530, 2020 11 11.
Artigo em Inglês | MEDLINE | ID: mdl-33177547

RESUMO

Over the past decades, one main issue that has emerged in ecological and environmental research is how losses in biodiversity influence ecosystem dynamics and functioning, and consequently human society. Although biodiversity is a common indicator of ecosystem functioning, it is difficult to measure biodiversity in microbial communities exposed to subtle or chronic environmental perturbations. Consequently, there is a need for alternative bioindicators to detect, measure, and monitor gradual changes in microbial communities against these slight, chronic, and continuous perturbations. In this study, microbial networks before and after subtle perturbations by adding S. acidaminiphila showed diverse topological niches and 4-node motifs in which microbes with co-occurrence patterns played the central roles in regulating and adjusting the intertwined relationships among microorganisms in response to the subtle environmental changes. This study demonstrates that microbial networks are a good bioindicator for chronic perturbation and should be applied in a variety of ecological investigations.

12.
Aging (Albany NY) ; 122020 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-33196458

RESUMO

Malignant cancer may contain highly heterogeneous populations of cells, including stem-like cells which were resistant to chemotherapy agents, radiation, mechanical stress, and immune surveillance. The characterization of these specific subpopulations might be critical to develop novel strategy to remove malignant tumors. We selected and enriched small population of human melanoma A2058 cells by repetitive selection cycles (selection, restoration, and amplification). These subpopulation of melanoma cells persisted the characteristics of slower cell proliferation, enhanced drug-resistance, elevated percentage of side population as analyzed by Hoechst33342 exclusion, in vitro sphere formation, and in vivo xenograft tumor formation by small amount of tumor cells. The selected populations would be melanoma stem-like cells with high expression of stem cell markers and altered kinase activation. Microarray and bioinformatics analysis highlighted the high expression of angiopoietin-like 4 protein in drug-selected melanoma stem-like cells. Further validation by specific shRNA demonstrated the role of angiopoietin-like 4 protein in drug-selected subpopulation associated with enhanced drug-resistance, sphere formation, reduced kinase activation, in vitro tube-forming ability correlated with heparan-sulfate proteoglycans. Our finding would be applicable to explore the mechanism of melanoma stemness and use angiopoietin-like 4 as potential biomarkers to identify melanoma stem-like cells.

13.
Ophthalmol Ther ; 2020 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-33068267

RESUMO

Immunoglobulin G4-related optic neuropathy caused by optic perineuritis is a rare complication of immunoglobulin G4-related disease (IgG4-RD). Herein, we report a 38-year-old Asian man with history of sinusitis who presented with painless blurred vision and proptosis for over 6 months. Examination with the Hertel exophthalmometer revealed 21.5 mm on both eyes. Magnetic resonance imaging revealed a doughnut sign encircling the right optic nerve, bilateral tram-track signs on both optic nerves, enlarged bilateral maxillary nerves with perineural spreading to the infraorbital nerves, hypertrophy of extraocular muscles, and pansinusitis. Visual evoked potentials displayed bilateral delayed P100 latency, indicating bilateral optic neuropathy. Biopsy with functional endoscopic sinus surgery demonstrated diffuse dense lymphoplasmacytic infiltrate and fibrosis. IgG4-positive plasma cells exceeded 50 cells per high-power field while the overall IgG4/IgG ratio was above 40%. Serological studies unveiled extremely high serum concentrations of IgG4 (2650 mg/dL), and the calculated serum IgG4/IgG ratio was 100%. These comprehensive features supported the diagnosis of IgG4-RD with bilateral optic perineuritis, branches of trigeminal nerve involvement, and pansinusitis. The visual acuity improved slightly following the initiation of treatment with corticosteroids, but it became worse again during the tapering course. Following another course of corticosteroids followed by subsequent immunosuppressant treatment with azathioprine, vision in both eyes ultimately improved during the 2-year follow-up period.

14.
Artigo em Inglês | MEDLINE | ID: mdl-33077179

RESUMO

OBJECTIVES: The effect of previous coronary stenting on subsequent coronary artery bypass graft is inconclusive. METHODS: We used Taiwan's National Health Insurance Database to retrospectively evaluate patients with multivessel coronary artery bypass graft between January 2000 and December 2013. Overall, 32,335 patients who received coronary artery bypass graft were included, of whom 3028 had previous coronary stenting. Propensity-score matching yielded 2977 cases each for evaluation under the previous stenting and no stenting groups. The 30-day mortality and major adverse cardiac events, including all-cause mortality, acute myocardial infarction, and revascularization, were considered primary outcomes. RESULTS: The number of coronary artery bypass grafts decreased per year. However, the percentage of patients who had previous coronary stent implantation before coronary artery bypass graft increased steadily (P for trend <.001), and the average number of stents implanted in a patient also increased per year (P for trend <.001). The previous stent group had a significantly greater 30-day mortality rate than did the no-stent group (7.2% vs 5.0%; odds ratio, 1.47; 95% confidence interval, 1.19-1.82). The previous stent group had a greater rate of revascularization (14.4% and 10.0%; subdistribution hazard ratio, 1.50; 95% confidence interval, 1.30-1.74) in the last follow-up at year 13. CONCLUSIONS: Previous coronary stenting before coronary artery bypass graft for multivessel coronary artery disease significantly increased 30-day mortality but did not affect late survival. However, patients who had coronary stenting before coronary artery bypass graft experienced more revascularization events during late follow-up.

15.
J Exp Clin Cancer Res ; 39(1): 221, 2020 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-33081836

RESUMO

BACKGROUND: Peritoneal metastasis (PM) is an important pathological process in the progression of gastric cancer (GC). The metastatic potential of tumor and stromal cells is governed by hypoxia, which is a key molecular feature of the tumor microenvironment. Mesothelial cells also participate in this complex and dynamic process. However, the molecular mechanisms underlying the hypoxia-driven mesothelial-tumor interactions that promote peritoneal metastasis of GC remain unclear. METHODS: We determined the hypoxic microenvironment in PM of nude mice by immunohistochemical analysis and screened VEGFA by human growth factor array kit. The crosstalk mediated by VEGFA between peritoneal mesothelial cells (PMCs) and GC cells was determined in GC cells incubated with conditioned medium prepared from hypoxia-treated PMCs. The association between VEGFR1 and integrin α5 and fibronectin in GC cells was enriched using Gene Set Enrichment Analysis and KEGG pathway enrichment analysis. In vitro and xenograft mouse models were used to evaluate the impact of VEGFA/VEGFR1 on gastric cancer peritoneal metastasis. Confocal microscopy and immunoprecipitation were performed to determine the effect of hypoxia-induced autophagy. RESULTS: Here we report that in the PMCs of the hypoxic microenvironment, SIRT1 is degraded via the autophagic lysosomal pathway, leading to increased acetylation of HIF-1α and secretion of VEGFA. Under hypoxic conditions, VEGFA derived from PMCs acts on VEGFR1 of GC cells, resulting in p-ERK/p-JNK pathway activation, increased integrin α5 and fibronectin expression, and promotion of PM. CONCLUSIONS: Our findings have elucidated the mechanisms by which PMCs promote PM in GC in hypoxic environments. This study also provides a theoretical basis for considering autophagic pathways or VEGFA as potential therapeutic targets to treat PM in GC.

16.
J Vasc Surg ; 2020 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-33080324

RESUMO

BACKGROUND: The Superficial Femoral Artery-Popliteal EvidencE Development (SPEED) Study Group developed contemporary objective performance goals (OPG) for peripheral vascular interventions (PVI) for superficial femoral (SFA)-popliteal artery disease utilizing the Registry Assessment of Peripheral Interventional Devices (RAPID). METHODS: The Society for Vascular Surgery (SVS) Vascular Quality Initiative (VQI) PVI Registry from January 2010-October 2016 was used to develop OPGs based on SFA-popliteal procedures (N= 21, 377) for claudication (IC) and critical limb ischemia (CLI). OPGs included one-year rates for target lesion revascularization (TLR), major amputation, and one and four-year survival. OPGs were calculated for the SFA and popliteal arteries and stratified by four treatments: angioplasty alone (PTA), self-expanding stenting, atherectomy, and any treatment type.. Outcomes were illustrated by unadjusted Kaplan-Meier analyses. RESULTS: Cohorts included PTA (N= 7,505), stenting (N= 9,217), atherectomy (N= 2,510) and any treatment (N= 21,377). The mean age was 69 years, 58% were male, 79% were white and 52% had CLI. The freedom from TLR OPGs at one year in the SFA were 80.3% (PTA), 83.2% (stenting), 83.9% (atherectomy), and 81.9% (any treatments). The freedom from TLR OPGs at one year in the popliteal were 81.3% (PTA), 81.3% (stenting), 80.2% (atherectomy), and 81.1% (any treatments). The freedom from major amputation OPGs at one year after SFA PVI were 93.4% (PTA), 95.7% (stenting), 95.1% (atherectomy), and 94.8%, (any treatments). The freedom from major amputation OPG at one year after popliteal PVI were 90.5% (PTA), 93.7% (stenting), 91.8% (atherectomy), and 91.8%, (any treatments). Four-year survival OPGs after SFA PVI were 76% (PTA), 80% (stenting), 82% (atherectomy), and 79% (any treatments) and for the popliteal artery were 72% (PTA), 77% (stenting), 82% (atherectomy), and 75% (any treatment). In multivariable analysis, which included patient level, leg level and lesion level covariates, CLI was the single independent factor associated with increased TLR, amputation and mortality. CONCLUSIONS: The SPEED OPGs define a new, contemporary benchmark for SFA-popliteal interventions utilizing a large subset of real-world evidence to inform more efficient peripheral device clinical trial designs to support regulatory and clinical decision making. It is appropriate to discuss proposals intended for regulatory approval with the FDA to refine the OPG to match the specific trial population. The OPGs may be updated using coordinated registry networks to assess long-term real-world device performance.

17.
Laryngoscope ; 2020 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-33085091

RESUMO

OBJECTIVES/HYPOTHESIS: To investigate the lingual artery (LA) position in the tongue base through intraoperative ultrasound (IOU) imaging during transoral robotic surgery (TORS) and evaluate bleeding complications with or without the assistance of IOU. STUDY DESIGN: Cohort study with historical control. METHODS: Patients with obstructive sleep apnea (OSA) who underwent TORS for tongue base resection were recruited since 2016. During surgery, ultrasound imaging was employed to identify anatomic parameters of the LA in the tongue base, including distance to the midline and arterial depth and diameter. RESULTS: Ninety-three OSA patients (82 men, 88.2%) were analyzed. Mean age was 42.2 ± 10.0 years and body mass index was 29.2 ± 4.5 kg/m2 . Average apnea-hypopnea index (AHI) was 58.1 ± 21.4 events/hour. Overall, 70 patients who underwent TORS with IOU had a shorter operation time (191.7 ± 3.8 vs. 220.1 ± 6.6 minutes), lower total blood loss (11.3 ± 10.8 vs. 19.6 ± 26.7 mL), and higher tongue base reduction volume (7.1 ± 2.5 vs. 3.9 ± 1.6 mL) than 23 patients who underwent TORS without IOU. Significant predictors of arterial depth included higher AHI level during the rapid eye movement sleep (P = .038), larger tonsil size (P = .034), and more elevated Friedman tongue position (P = .012). Postoperative complications associated with LA injury were not found in patients subjected to IOU. CONCLUSIONS: With the assistance of IOU, surgeons can confidently determine LA position. The use of IOU can maximize efficiency and minimize catastrophic bleeding complications when OSA patients undergo TORS for tongue base resection. LEVEL OF EVIDENCE: 4 Laryngoscope, 2020.

18.
J Phys Chem Lett ; : 9468-9475, 2020 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-33108192

RESUMO

The two liquid-water states, which lead to some anomalies when temperature crosses over 50 ± 10 °C at the atmospheric pressure, have been continuously catching popular attention. In this study, using the excited-state proton transfer (ESPT) catalyzed by water molecules as a prototypical reaction, we demonstrate that the kinetics of ESPT indeed is influenced by the two liquid-water states. In the water-catalyzed ESPT of 3-cyano-7-azaindole (3CAI), a repetitive and comprehensive temperature-dependent study of ESPT in H2O from 0 to 90 °C shows anomalous behavior. The plot of the logarithm of ESPT rate constant as a function of inverse of absolute temperature deviates from a straight line. The convex-Arrhenius behavior manifests the activation free energy for water-assisted ESPT being dependent on temperature and hence the liquid water structure. To simplify the discussion, the plot is well fitted by using two straight lines that are crossed over in the vicinity of 40 °C. The free energy difference between water-solvated 3CAI and the 1:1 H2O:3CAI complex is deduced to be 2.29 ± 0.04 and 1.96 ± 0.04 kcal·mol-1 in the regions of 0-40 and 40-90 °C water, respectively, which also results in different frequency factors, i.e., the proton transfer/tunneling rates of (5.83 ± 0.36) × 1010 and (3.48 ± 0.27) × 1010 s-1, respectively. In a qualitative manner, the results are then rationalized by the different types of H-bonding configuration as proposed for two liquid-water phases, rendering experimental evidence to support the different water phases in ambient temperatures at 1 bar.

19.
Future Med Chem ; 12(19): 1709-1727, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33028090

RESUMO

Aim: With the increasing emergence of drug-resistant bacteria, the need for new antimicrobial agents has become extremely urgent. This work was to develop sulfonyl thiazoles as potential antibacterial agents. Results & methodology: Novel hybrids of sulfonyl thiazoles were developed from commercial acetanilide and acetylthiazole. Hybrids 6e and 6f displayed excellent inhibitory efficacy against clinical methicillin-resistant Staphylococcus aureus (MRSA) (minimum inhibitory concentration = 1 µg/ml) without obvious toxicity toward normal mammalian cells (RAW 264.7). The combination uses were found to improve the antimicrobial ability. Further preliminary antibacterial mechanism experiments showed that the active molecule 6f could effectively interfere with MRSA membrane and insert into MRSA DNA. Conclusion: Compounds 6e and 6f could serve as potential DNA-targeting templates toward the development of promising antimicrobial agents.

20.
PLoS Pathog ; 16(10): e1008990, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33035275

RESUMO

Positive-stranded (+)RNA viruses greatly exploit host cells to support viral replication. However, unlike many other pathogens, (+)RNA viruses code for only a limited number of genes, making them highly dependent on numerous co-opted host factors for supporting viral replication and other viral processes during their infections. This excessive dependence on subverted host factors, however, renders (+)RNA viruses vulnerable to host restriction factors that could block virus replication. Interestingly, cellular ATP-dependent DEAD-box RNA helicases could promote or inhibit the replication of Tomato bushy stunt virus (TBSV) replication. However, it is currently unknown what features make a particular DEAD-box helicase either pro-viral or antiviral. In this work, we succeeded in reversing the viral function of the antiviral DDX17-like RH30 DEAD-box helicase by converting it to a pro-viral helicase. We also turned the pro-viral DDX3-like RH20 helicase into an antiviral helicase through deletion of a unique N-terminal domain. We demonstrate that in the absence of the N-terminal domain, the core helicase domain becomes unhinged, showing altered specificity in unwinding viral RNA duplexes containing cis-acting replication elements. The discovery of the sequence plasticity of DEAD-box helicases that can alter recognition of different cis-acting RNA elements in the viral genome illustrates the evolutionary potential of RNA helicases in the arms race between viruses and their hosts, including key roles of RNA helicases in plant innate immunity. Overall, these findings open up the possibility to turn the pro-viral host factors into antiviral factors, thus increasing the potential antiviral arsenal of the host for the benefit of agriculture and health science.

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