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1.
J Nanobiotechnology ; 19(1): 361, 2021 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-34749740

RESUMO

BACKGROUND: Hepatocellular carcinoma is insensitive to many chemotherapeutic agents. Ferroptosis is a form of programmed cell death with a Fenton reaction mechanism. It converts endogenous hydrogen peroxide into highly toxic hydroxyl radicals, which inhibit hepatocellular carcinoma progression. METHODS: The morphology, elemental composition, and tumour microenvironment responses of various organic/inorganic nanoplatforms were characterised by different analytical methods. Their in vivo and in vitro tumour-targeting efficacy and imaging capability were analysed by magnetic resonance imaging. Confocal microscopy, flow cytometry, and western blotting were used to investigate the therapeutic efficacy and mechanisms of complementary ferroptosis/apoptosis mediated by the nanoplatforms. RESULTS: The nanoplatform consisted of a silica shell doped with iron and disulphide bonds and an etched core loaded with doxorubicin that generates hydrogen peroxide in situ and enhances ferroptosis. It relied upon transferrin for targeted drug delivery and could be activated by the tumour microenvironment. Glutathione-responsive biodegradability could operate synergistically with the therapeutic interaction between doxorubicin and iron and induce tumour cell death through complementary ferroptosis and apoptosis. The nanoplatform also has a superparamagnetic framework that could serve to guide and monitor treatment under T2-weighted magnetic resonance imaging. CONCLUSION: This rationally designed nanoplatform is expected to integrate cancer diagnosis, treatment, and monitoring and provide a novel clinical antitumour therapeutic strategy.

2.
Artigo em Inglês | MEDLINE | ID: mdl-34806809

RESUMO

Plasmonic metals under photoexcitation can generate energetic hot electrons to directly induce chemical reactions. However, the capability and fundamental insights of the transportation of these hot electrons at plasmonic metal-2D material interfaces remain unclear. Herein, hot-electron transfer at Au-graphene interfaces has been in situ studied using surface-enhanced Raman spectroscopy (SERS) with atomic layer accuracy. Combining in situ SERS studies with density functional theory calculations, it is proved that hot electrons can be injected from plasmonic Au nanoparticles to graphene and directly penetrate graphene to trigger photocatalytic reactions. With increasing graphene layers, the transportation of hot electrons decays rapidly and would be completely blocked after five layers of graphene. Moreover, the transfer of hot electrons can be modulated by applying an external electric field, and the hot-electron transfer efficiency under electrochemical conditions is improved by over three times in the presence of a monolayer of graphene. These fundamental understandings about hot-electron transfer provide insightful information to promote the design of more efficient plasmonic materials and devices.

3.
Opt Express ; 29(24): 40274-40285, 2021 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-34809372

RESUMO

A novel approach to generating tunable Costas-coded linear frequency modulation waveforms (LFMWs) from an optoelectronic oscillator (OEO) is proposed and experimentally demonstrated. The OEO works under Fourier domain mode locking, where the oscillation modes are selected by using a fast-scanning microwave bandpass filter based on phase-modulation-to-intensity-modulation conversion via stimulated Brillouin scattering. Costas coding is realized by using an open-loop voltage-controlled oscillator (VCO) with a fast tuning speed to generate an agile fast-scanning probe light via electro-optic frequency shift. The bandwidth of the generated Costas-coded LFMWs can be tuned by varying the voltage range of the low-frequency waveform applied to the VCO, and the center frequency can be finely tuned by varying the electro-optic frequency shift of the pump light. In the experiment, Costas-coded LFMWs with a 12-bit Costas code sequence of [9 5 7 12 6 4 1 8 11 10 2 3], a period of 20.39 µs and tunable frequency range are generated. The cross-correlation result with a time delay of 102.5 µs indicates that the generated Costas-coded LFMWs have excellent pulse-to-pulse coherence. In addition, the bad phase noise performance of the open-loop VCO has a negligible influence on the generated Costas-coded LFMWs. Benefited from employing an open-loop VCO with a fast tuning speed and a broad operation bandwidth, this approach has potential in generating agile broadband multi-format radar waveforms with low phase noise and excellent pulse-to-pulse coherence directly from an OEO.

4.
Signal Transduct Target Ther ; 6(1): 389, 2021 11 10.
Artigo em Inglês | MEDLINE | ID: mdl-34759261

RESUMO

SARS-CoV-2 and SARS-CoV are genetically related coronavirus and share the same cellular receptor ACE2. By replacing the VSV glycoprotein with the spikes (S) of SARS-CoV-2 and SARS-CoV, we generated two replication-competent recombinant viruses, rVSV-SARS-CoV-2 and rVSV-SARS-CoV. Using wild-type and human ACE2 (hACE2) knock-in mouse models, we found a single dose of rVSV-SARS-CoV could elicit strong humoral immune response via both intranasal (i.n.) and intramuscular (i.m.) routes. Despite the high genetic similarity between SARS-CoV-2 and SARS-CoV, no obvious cross-neutralizing activity was observed in the immunized mice sera. In macaques, neutralizing antibody (NAb) titers induced by one i.n. dose of rVSV-SARS-CoV-2 were eight-fold higher than those by a single i.m. dose. Thus, our data indicates that rVSV-SARS-CoV-2 might be suitable for i.n. administration instead of the traditional i.m. immunization in human. Because rVSV-SARS-CoV elicited significantly stronger NAb responses than rVSV-SARS-CoV-2 in a route-independent manner, we generated a chimeric antigen by replacing the receptor binding domain (RBD) of SARS-CoV S with that from the SARS-CoV-2. rVSV expressing the chimera (rVSV-SARS-CoV/2-RBD) induced significantly increased NAbs against SARS-CoV-2 in mice and macaques than rVSV-SARS-CoV-2, with a safe Th1-biased response. Serum immunized with rVSV-SARS-CoV/2-RBD showed no cross-reactivity with SARS-CoV. hACE2 mice receiving a single i.m. dose of either rVSV-SARS-CoV-2 or rVSV-SARS-CoV/2-RBD were fully protected against SARS-CoV-2 challenge without obvious lesions in the lungs. Our results suggest that transplantation of SARS-CoV-2 RBD into the S protein of SARS-CoV might be a promising antigen design for COVID-19 vaccines.


Assuntos
Vacinas contra COVID-19/imunologia , COVID-19/prevenção & controle , Glicoproteína da Espícula de Coronavírus/imunologia , Animais , Anticorpos Neutralizantes/sangue , Anticorpos Antivirais/sangue , Técnicas de Introdução de Genes , Células HEK293 , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Testes de Neutralização , Proteínas Recombinantes de Fusão/imunologia , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus/genética
5.
Front Pharmacol ; 12: 763707, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34776979

RESUMO

Introduction : Targeted medication, including mostly biologics and small-molecule chemical drugs, is an important therapy for ankylosing spondylitis (AS). There are still limited data on the preference of different targeted drugs in Chinese AS patients. Methods : A questionnaire-based cross-sectional study was performed on AS patients from six hospitals in three provinces in South China. Anti-rheumatic diseases' medication history includes the recent and previous usage of biologics or Janus kinase inhibitors (JAKi) in the last complete course of treatment, disease severity, and reasons for targeted-treatment change or preference. Results : 354 of 366 participants responded to the online survey. The participants' median age was 32 years, with a median of 7.3 years of disease duration; 79.7% were male. 63.6% of them were in the course of biologics or JAKi. Generic ETN is the most widely used and willing-to-use biologic though the proportion of its usage shrunk in the present compared with the past. The choice of original-branded ADA demonstrated an increase in usage. The preference of secukinumab and tofacitinib depicted a quick ascending trend. Conclusion : TNF-α inhibitors (TNFi) are still the most popular targeted medication for AS in China. Their price influences patients' preferences mostly. The doctor's recommendation is also part of the equation. Rheumatologists should pay more attention to patients' education to formulate targeted therapeutic plans.

6.
J Cancer ; 12(21): 6473-6483, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34659538

RESUMO

To quickly locate cancer lesions, especially suspected metastatic lesions after gastrectomy, AI algorithms of object detection and semantic segmentation were established. A total of 509 macroscopic images from 381 patients were collected. The RFB-SSD object detection algorithm and ResNet50-PSPNet semantic segmentation algorithm were used. Another 57 macroscopic images from 48 patients were collected for prospective verification. We used mAP as the metrics of object detection. The best mAP was 95.90% with an average of 89.89% in the test set. The mAP reached 92.60% in validation set. We used mIoU for evaluation of semantic segmentation. The best mIoU was 80.97% with an average of 79.26% in the test set. In addition, 81 out of 92 (88.04%) gastric specimens were accurately predicted for the cancer lesion located at the serosa by ResNet50-PSPNet semantic segmentation model. The positive rate and accuracy of AI prediction were different based on cancer invasive depth. The metastatic lymph nodes were predicted in 24 cases by semantic segmentation model. Among them, 18 cases were confirmed by pathology. The predictive accuracy was 75.00%. Our well-trained AI algorithms effectively identified the subtle features of gastric cancer in resected specimens that may be missed by naked eyes. Taken together, AI algorithms could assist clinical doctors quickly locating cancer lesions and improve their work efficiency.

7.
Immunity ; 54(10): 2218-2230.e5, 2021 10 12.
Artigo em Inglês | MEDLINE | ID: mdl-34644557

RESUMO

The RNA sensor MDA5 recruits the signaling adaptor MAVS to initiate type I interferon signaling and downstream antiviral responses, a process that requires K63-linked polyubiquitin chains. Here, we examined the mechanisms whereby K63-polyUb chain regulate MDA5 activation. Only long unanchored K63-polyUbn (n ≥ 8) could mediate tetramerization of the caspase activation and recruitment domains of MDA5 (MDA5CARDs). Cryoelectron microscopy structures of a polyUb13-bound MDA5CARDs tetramer and a polyUb11-bound MDA5CARDs-MAVSCARD assembly revealed a tower-like formation, wherein eight Ubs tethered along the outer rim of the helical shell, bridging MDA5CARDs and MAVSCARD tetramers into proximity. ATP binding and hydrolysis promoted the stabilization of RNA-bound MDA5 prior to MAVS activation via allosteric effects on CARDs-polyUb complex. Abundant ATP prevented basal activation of apo MDA5. Our findings reveal the ordered assembly of a MDA5 signaling complex competent to recruit and activate MAVS and highlight differences with RIG-I in terms of CARD orientation and Ub sensing that suggest different abilities to induce antiviral responses.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Helicase IFIH1 Induzida por Interferon/metabolismo , Transdução de Sinais/fisiologia , Proteínas Adaptadoras de Transdução de Sinal/química , Microscopia Crioeletrônica , Células HEK293 , Humanos , Imunidade Inata/fisiologia , Helicase IFIH1 Induzida por Interferon/química , Helicase IFIH1 Induzida por Interferon/ultraestrutura , Poliubiquitina/química , Poliubiquitina/metabolismo , Ligação Proteica
8.
Front Med (Lausanne) ; 8: 719236, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34712676

RESUMO

Background: Immune checkpoint inhibitors have provided significant clinical benefits to many patients with advanced cancer; however, severe immune-related adverse events (irAEs) have occurred. Detecting and treating irAEs early could improve patient prognoses. Therefore, clinicians and patients should understand that these irAEs exist, especially those that are rare and serious. Case Presentation: In this report, an 86-year-old male patient, diagnosed with metastatic gastric cancer involving the peritoneum and retroperitoneal lymph nodes was treated with 5-cycle pembrolizumab therapy (100 mg q 2 weeks), achieving a partial response. However, the patient developed Grade 3 cholestatic hepatitis and delayed pneumonia 10 days and 2 months after the final pembrolizumab dose, respectively. After discontinuing the pembrolizumab therapy and excluding obstructive jaundice with imaging studies, the patient received steroid therapy, with a gradual symptom improvement. However, the patient developed delayed pneumonia with type 1 respiratory failure 1-month post-discharge. Several microbiologic tests were negative, and immune-associated pneumonia was suspected, but we could not exclude an opportunistic infection. The patient recovered with steroids and antibiotics and remained in partial remission 5 months after pembrolizumab withdrawal. Conclusions: Cholestatic hepatitis is a rarely reported toxicity of immune checkpoint inhibitors, which should be suspected and addressed once obstructive jaundice is ruled out. In addition, clinicians should be aware that irAEs can occur at any time in patients treated with immune checkpoint inhibitors and that a timely diagnosis should be made.

9.
Nat Hum Behav ; 2021 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-34711977

RESUMO

Urbanicity is a growing environmental challenge for mental health. Here, we investigate correlations of urbanicity with brain structure and function, neuropsychology and mental illness symptoms in young people from China and Europe (total n = 3,867). We developed a remote-sensing satellite measure (UrbanSat) to quantify population density at any point on Earth. UrbanSat estimates of urbanicity were correlated with brain volume, cortical surface area and brain network connectivity in the medial prefrontal cortex and cerebellum. UrbanSat was also associated with perspective-taking and depression symptoms, and this was mediated by neural variables. Urbanicity effects were greatest when urban exposure occurred in childhood for the cerebellum, and from childhood to adolescence for the prefrontal cortex. As UrbanSat can be generalized to different geographies, it may enable assessments of correlations of urbanicity with mental illness and resilience globally.

10.
Front Vet Sci ; 8: 693755, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34660751

RESUMO

Background: Japanese quail (Coturnix japonica) are important and widely distributed poultry in China. Researchers continue to pursue genetic selection for heavier quail. The intestinal microbiota plays a substantial role in growth promotion; however, the mechanisms involved in growth promotion remain unclear. Results: We generated 107.3 Gb of cecal microbiome data from ten Japanese quail, providing a series of quail gut microbial gene catalogs (1.25 million genes). We identified a total of 606 main microbial species from 1,033,311 annotated genes distributed among the ten quail. Seventeen microbial species from the genera Anaerobiospirillum, Alistipes, Barnesiella, and Butyricimonas differed significantly in their abundances between the female and male gut microbiotas. Most of the functional gut microbial genes were involved in metabolism, primarily in carbohydrate transport and metabolism, as well as some active carbohydrate-degrading enzymes. We also identified 308 antibiotic-resistance genes (ARGs) from the phyla Bacteroidetes, Firmicutes and Euryarchaeota. Studies of the differential gene functions between sexes indicated that abundances of the gut microbes that produce carbohydrate-active enzymes varied between female and male quail. Bacteroidetes was the predominant ARG-containing phylum in female quail; Euryarchaeota was the predominant ARG-containing phylum in male quail. Conclusion: This article provides the first description of the gene catalog of the cecal bacteria in Japanese quail as well as insights into the bacterial taxa and predictive metagenomic functions between male and female quail to provide a better understanding of the microbial genes in the quail ceca.

11.
Artigo em Inglês | MEDLINE | ID: mdl-34518488

RESUMO

INTRODUCTION: The anterosuperior portion of the bulla lamella can extend into the frontal sinus and form the supra bulla frontal cell (SBFC) and supraorbital ethmoid cell (SOEC). This can affect the frontal drainage pathway and make surgery more challenging. OBJECTIVES: The aim of the study was to compare the anatomical characteristics of SBFC and SOEC in Chinese chronic rhinosinusitis (CRS) patients and explore the relationship between the cells and frontal sinusitis (FS). The surgical skills in dealing with these cells were also studied. METHODS: We prospectively identified SBFC and SOEC in 114 patients with CRS by computed tomography (CT). The sides of the patients were divided into groups A (with FS) and B (without FS). CT scans were analyzed to distinguish the SBFC, SOEC, and the drainage pathway. Statistical analysis was conducted to determine whether the cells were associated with the occurrence of FS. RESULTS: The prevalence of frontal cells was as follows: SBFC: 9.65%, SOEC: 21.93%. There was an association between the presence of SBFC and FS (p < 0.05). The anterior drainage pathway was present in patients with SBFC and SOEC, anterolateral pathway in those with SBFC/SOEC coexisting with the frontal septal cell, and anteromedial pathway in those with SBFC/SOEC coexisting with the supra agger frontal cell. CONCLUSIONS: There was an association between the presence of SBFC and the occurrence of FS. Extension of the anterosuperior portion of the bulla lamella into the frontal sinus obstructed the drainage pathway posteriorly. Understanding the anatomy may help surgeons thoroughly dissect the bulla lamella.

12.
J Geriatr Cardiol ; 18(8): 623-630, 2021 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-34527028

RESUMO

OBJECTIVE: To compare the morphological and compositional characteristics of carotid plaques in two cohorts (2002-2005 and 2012-2015) of Chinese patients using magnetic resonance vessel wall imaging. METHODS: Symptomatic patients with carotid atherosclerotic plaques who underwent carotid vessel wall magnetic resonance imaging between 2002-2005 and 2012-2015 were retrospectively recruited. Plaque morphology [including mean wall area, wall thickness, and maximum normalized wall index (NWI)] and composition [including calcification, intraplaque hemorrhage, and lipid-rich necrotic core (LRNC)] in symptomatic carotid arteries were evaluated and compared between patients in these two time periods. RESULTS: A total of 258 patients, including 129 patients in the 2002-2005 cohort and 129 patients in the 2012-2015 cohort, were recruited. Statin use (49.6%vs. 32.6%, P = 0.004) and hypertension (76.0% vs. 62.8%, P = 0.015) were significantly more common in the 2012-2015 cohort than in the 2002-2005 cohort. Patients in the 2012-2015 cohort also exhibited significantly low plaque burden parameters (allP < 0.05), as well as a lower prevalence (68.2% vs. 89.9%, P < 0.001) and volume percentages of LRNC (11.2% ± 14.2% vs. 25.7% ± 17.7%, P < 0.001). These differences remained significant after adjustment for clinical factors. The differences in the volume percentages of LRNC also remained significant after an additional adjustment for maximum NWI ( P < 0.001). CONCLUSIONS: Patients in the 2012-2015 cohort had a lower plaque burden and volume percentages of LRNC in symptomatic carotid arteries than those in the 2002-2005 cohort. These findings indicate that carotid plaques in the recent cohort had a lower severity and vulnerability.

13.
Mol Oncol ; 2021 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-34543520

RESUMO

We studied the value of circulating tumor DNA (ctDNA) in predicting early postoperative tumor recurrence and monitoring tumor burden in patients with hepatocellular carcinoma (HCC). Plasma-free DNA, germline DNA, and tissue DNA were isolated from 41 patients with HCC. Serial ctDNAs were analyzed by next-generation sequencing before and after operation. Whole-exome sequencing was used to detect the DNA of HCC and adjacent tissues. In total, 47 gene mutations were identified in the ctDNA of the 41 patients analyzed before surgery. ctDNA was detected in 63.4% and 46% of the patient plasma pre- and postoperation, respectively. The preoperative ctDNA positivity rate was significantly lower in the nonrecurrence group than in the recurrence group. With a median follow-up of 17.7 months, nine patients (22%) experienced tumor recurrence. ctDNA positivity at two time-points was associated with significantly shorter recurrence-free survival (RFS). Tumors with NRAS, NEF2L2, and MET mutations had significantly shorter times to recurrence than those without mutations and showed high recurrence prediction performance by machine learning. Multivariate analyses showed that the median variant allele frequency (VAF) of mutations in preoperative ctDNA was a strong independent predictor of RFS. ctDNA is a real-time monitoring indicator that can accurately reflect tumor burden. The median VAF of baseline ctDNA is a strong independent predictor of RFS in individuals with HCC.

14.
J Am Chem Soc ; 143(38): 15635-15643, 2021 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-34541841

RESUMO

Understanding the fundamental insights of oxygen activation and reaction at metal-oxide interfaces is of significant importance yet remains a major challenge due to the difficulty in in situ characterization of active oxygen species. Herein, the activation and reaction of molecular oxygen during CO oxidation at platinum-ceria interfaces has been in situ explored using surface-enhanced Raman spectroscopy (SERS) via a borrowing strategy, and different active oxygen species and their evolution during CO oxidation at platinum-ceria interfaces have been directly observed. In situ Raman spectroscopic evidence with isotopic exchange experiments demonstrate that oxygen is efficiently dissociated to chemisorbed O on Pt and lattice Ce-O species simultaneously at interfacial Ce3+ defect sites under CO oxidation, leading to a much higher activity at platinum-ceria interfaces compared to that at Pt alone. Further in situ time-resolved SERS studies and density functional theory simulations reveal a more efficient molecular pathway through the reaction between adsorbed CO and chemisorbed Pt-O species transferred from the interfaces. This work deepens the fundamental understandings on oxygen activation and CO oxidation at metal-oxide interfaces and offers a sensitive technique for the in situ characterization of oxygen species under working conditions.

15.
Eur J Surg Oncol ; 2021 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-34304951

RESUMO

BACKGROUND: To investigate the prognostic value of dual-energy CT (DECT) based radiomics to predict disease-free survival (DFS) and overall survival (OS) for patients with advanced gastric cancer (AGC) after neoadjuvant chemotherapy (NAC). METHODS: From January 2014 to December 2018, a total of 156 AGC patients were enrolled and randomly allocated into a training cohort and a testing cohort at a ratio of 2:1. Volume of interest of primary tumor was delineated on eight image series. Four feature sets derived from pre-NAC and delta radiomics were generated for each survival arm. Random survival forest was used for generating the optimal radiomics signature (RS). Statistical metrics for model evaluation included Harrell's concordance index (C-index) and the average cumulative/dynamic AUC throughout follow-up. A clinical model and a combined Rad-clinical model were built for comparison. RESULTS: The pre-IU (derived from iodine uptake images before NAC) RS performed best for DFS and OS in the testing cohort (C-indices, 0.784 and 0.698; the average cumulative/dynamic AUCs, 0.80 and 0.77). When compared with the clinical model, the radiomics model had significantly higher C-index to predict DFS in the testing cohort (0.784 vs. 0.635, p < 0.001), but no statistical difference was found for OS (0.698 vs. 0.680, p = 0.473). The combined Rad-clinical models showed improved performance in the testing cohort, with C-indices of 0.810 and 0.710 for DFS and OS, respectively. CONCLUSION: DECT-derived radiomics serves as a promising non-invasive biomarker to predict survival for AGC patients after NAC, providing an opportunity for transforming proper treatment.

16.
Front Pharmacol ; 12: 684869, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34305597

RESUMO

Objective: Hypopituitarism (Hypo-Pit) is partial or complete insufficiency of anterior pituitary hormones. Besides hormone metabolism, the global metabolomics in Hypo-Pit are largely unknown. We aimed to explore potential biomarkers to aid in diagnosis and personalized treatment. Methods: Using both univariate and multivariate statistical methods, we identified 72 differentially abundant features through liquid chromatography coupled to high-resolution mass spectrometry, obtained in 134 males with Hypo-Pit and 90 age matched healthy controls. Results: Hypopituitarism exhibits an increased abundance of metabolites involved in amino acid degradation and glycerophospholipid synthesis, but decreased content of metabolites in steroid hormone synthesis and fatty acid beta-oxidation. Significantly changed metabolites included creatine, creatinine, L-alanine, phosphocholines, androstenedione, hydroprenenolone, and acylcarnitines. In Hypo-Pit patients, the increased ratio of creatine/creatinine suggested reduced creatine uptake and impaired creatine utilization, whereas the decreased level of beta-hydroxybutyrate, acetylcarnitine (C2) and a significantly decreased ratio of decanoylcarnitine (C10) to free carnitine suggested an impaired beta-oxidation. Furthermore, the creatine/creatinine and decanoylcarnitine/carnitine ratio were identified as diagnostic biomarkers for Hypo-Pit with AUCs of 0.976 and 0.988, respectively. Finally, we found that the creatinine and decanoylcarnitine/carnitine ratio could distinguish cases that were sensitive vs. resistant to human chorionic gonadotropin therapy. Conclusion: We provided a global picture of altered metabolic pathways in Hypo-Pit, and the identified biomarkers in creatine metabolism and beta-oxidation might be useful for the preliminary screening and diagnosis of Hypo-Pit.

17.
Artigo em Inglês | MEDLINE | ID: mdl-34255132

RESUMO

OBJECTIVE: To investigate the molecular characteristics in tumor immune microenvironment that affect long-term survival of patients with pancreatic adenocarcinoma (PAAD). METHODS: The tumor related genetic features of a female PAAD patient (over 13-year survival) who suffered from multiple recurrences and metastases, and six operations over one decade were investigated deeply. Genomic features and immune microenvironment signatures of her primary lesion as well as six metastatic tumors at different time-points were characterized. RESULTS: High-frequency clonal neoantigenic mutations identified in these specimens revealed the significant associations between clonal neoantigens with her prognosis after each surgery. Meanwhile, the TCGA and ICGC databases were employed to analyse the function of KRAS G12V in pancreatic cancer. CONCLUSIONS: The genomic analysis of clonal neoantigens combined with tumor immune microenvironment could promote the understandings of personalized prognostic evaluation and the stratification of resected PAAD individuals with better outcome.

18.
Avicenna J Phytomed ; 11(4): 353-366, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34290967

RESUMO

Objective: A fraction from Khaya grandifoliola has recently been shown to inhibit hepatitis C virus (HCV) infection and three limonoids (17-epi-methyl-6-hydroxylangolensate, 7-deacetoxy-7-oxogedunin and 7-deacetoxy-7R-hydroxygedunin) were purified from this fraction. The present study aimed at assessing the inhibitory effect of these limonoids on HCV using cell-culture derived HCV (HCVcc) system. Materials and Methods: Cytotoxic effects of the limonoids on Huh7.5 cells were assessed by MTT assay. Huh7.5 cells were transfected with RNA transcripts of the plasmid Jc1/GLuc2a, carrying a Gaussia luciferase reporter gene to rescue the HCVcc particles which were used to infect naïve cells in the presence or absence of the studied limonoids during 72 hr. Infection and replication rates were monitored by luciferase reporter assay and immunofluorescence assay (IFA) while cellular gene expression was analyzed by western blot, respectively. Results: The limonoids inhibited HCV infection mostly by targeting entry and replication stage. Their inhibitory effect on entry step, comparable to that of anti-CD81 antibody, was related to the blocking of CD81 receptor. In the replication step, the limonoids decreased the expression of NS5B similar to danoprevir. These compounds also significantly decreased but up-regulated the expression of Class-III phosphatidylinositol 4-kinase alpha and 2',5'-oligoadenylate synthase-3, respectively. Conclusion: The present findings suggest that limonoids from K. grandifoliola are potential anti-HCV agents and may offer an advantage in the treatment of HCV infection.

19.
Artigo em Inglês | MEDLINE | ID: mdl-34255938

RESUMO

Acarbose and metformin have been recommended both as monotherapy and add-on therapy in type 2 diabetes mellitus. A novel fixed-dose combination (FDC) of acarbose and metformin has been developed to improve compliance and patient adherence to therapy. The current study investigated the bioequivalence (BE) between acarbose/metformin FDC (50 mg/500 mg) with corresponding loose combination of individual components under fasting conditions in healthy Chinese male and female subjects, using a randomized, 2-period, 2-way crossover study design. Pharmacodynamic parameters of serum glucose ratio between treatment day and baseline (ratio of maximum concentration [Cmax ], day 1/Cmax , day -1 and ratio of area under the concentration-time curve [AUC] from time 0 to 4 hours, day 1/AUC from time 0 to 4 hours, day -1) were used as the primary variables to evaluate BE of acarbose. Pharmacokinetic parameters Cmax , AUC from time 0 to the last data point greater than the lower limit of quantification, and AUC were used to evaluate BE of metformin. The results showed that the 90% confidence intervals of the ratios of all primary target variables including ratio of Cmax , day 1/Cmax , day -1 and ratio of AUC from time 0 to 4 hours, day 1/AUC from time 0 to 4 hours, day -1 for acarbose, and Cmax , AUC from time 0 to the last data point greater than the lower limit of quantification, and AUC for metformin all fell within the acceptance limits of 0.8 to 1.25. Thus, BE between 50-mg acarbose and 500-mg metformin as an FDC and loose combination was established. Furthermore, different kinds of exploratory pharmacodynamic parameters (based on either serum glucose or insulin) including several newly proposed parameters were also investigated for acarbose BE evaluation in this study, and inconsistent results were observed.

20.
Inorg Chem ; 60(13): 9282-9286, 2021 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-34165286

RESUMO

Energetic metal-organic frameworks (EMOFs) are very promising as heat-resistant explosives, affording both thermal stability and energy properties. In this work, the self-assembly of high-energy nitrogen-rich linkers with nontoxic alkali-metal lithium/sodium leads to four new solvent-free EMOFs. Because of unparalleled decomposition temperature (Tdec = 403 °C) and heats of detonation (3.475 kcal·g-1), a 3D Li(I)-EMOF can be considered to be a superheat-resistant explosive candidate.

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