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1.
Surg Endosc ; 2020 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-32277355

RESUMO

OBJECTIVE: The purpose of this study was to explore the role of different undifferentiated components in the lymph node metastasis (LNM) of early mixed gastric cancer. METHODS: A total of 1596 patients with EGC who underwent gastrectomy were divided into four types: pure differentiated (PD), pure poorly differentiated (Poorly D), pure signet ring cell carcinoma (SRC), and mixed. Mixed type was classified into four subtypes: differentiated-predominant type mixed with poorly differentiated component (MD-P), poorly differentiated-predominant type mixed with differentiated component (MP-D), differentiated-predominant type mixed with SRC component (MD-S), and poorly differentiated-predominant type mixed with SRC component (MP-S). We analyzed the clinicopathological differences between all types and the rates of LNM of patients fulfilling endoscopic submucosal dissection (ESD) criteria. RESULTS: LNM was more common in mixed (21.9%) than in PD (7.5%, P < 0.001) or SRC (11.3%, P < 0.001). When analyzed the subgroups of mixed type, LNM was more frequent in MD-P (15.4%) than in PD (7.5%, P = 0.003). LNM in MD-S (7.4%, P = 1.000) was not higher than in PD. MP-S (24.5%) showed a higher rate of LNM than SRC (11.3%, P < 0.001) rather than Poorly-D (22.7%, P = 0.681). For lesions satisfying ESD criteria, MD-S (0%, P = 1.000), and MD-P (5.9%, P = 0.12) did not have higher rates of LNM than PD (1.4%). CONCLUSION: The presence of poorly differentiated component but not SRC increases the LNM rate of mixed type. ESD is recommended for the treatment of MD-S and MD-P consistent with ESD criteria.

2.
Cancer Immunol Immunother ; 69(6): 1057-1069, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32100076

RESUMO

BACKGROUND: Immunotherapy could trigger durable response in advanced gastric cancer, but it only benefits a minority of patients. We aimed to propose a robust molecular classification of gastric cancer microenvironment to identify ideal candidates for tailoring effective immunotherapy. METHODS: A training cohort of 375 gastric cancer samples with RNA sequencing data was analysed. We virtually microdissected tumour, stromal, and immune cell gene expression patterns employing a non-negative matrix factorization algorithm. These expression patterns were annotated using immune- and stromal-related gene signatures. Validation of immunogenomic classification was performed across six microarray datasets of 1406 samples. RESULTS: We found approximately half of gastric cancer samples to have higher immune cell infiltrates, PD-L1 expression, markers of cytolytic activity, and fewer copy number aberrations (all P < 0.05). We termed this group of tumours the Immune Class, which incorporated two components, namely Immune Activation and Immunosuppressive Subtype, according to immunosuppressive or activated microenvironment. Immune Activation Subtype was associated with improved survival in multivariate survival analysis and shared similar genomic characteristics with responders of anti-PD-1 therapy. Immunosuppressive Subtype featured high immune infiltration, stromal enrichment, and transforming growth factor (TGF)-ß signalling pathway activation and correlated with non-responsiveness signature of checkpoint blockade therapy, which might be suitable for anti-PD-L1 and anti-TGF-ß combined therapy. CONCLUSIONS: We proposed and independently validated three reproducible immune molecular subtypes of gastric cancer, which may provide implications for patient selection of immunotherapy.

3.
Curr Eye Res ; : 1-7, 2020 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-32066267

RESUMO

Purpose: To examine the effectiveness of using meibomian gland (MG) dropout and distortion for dry eye disease (DED) diagnosis in a young population with long-term contact lens (CL) wear.Methods: Seventy-three CL-wearers and 68 non-CL-wearers (20-28 years old) participated in the study. The diagnosis of DED was based on an ocular surface disease index ≥ 13, and a noninvasive breakup time < 10 seconds or positive corneal fluorescein staining. The MG dropout and distortion in each subject were quantified with non-invasive meibography. Receiver operating characteristic (ROC) curves were created to evaluate the effectiveness of using MG dropout and distortion to determine the presence of DED in CL-wearers and non-CL-wearers.Results: In non-CL-wearers, the MG distortion was significantly higher in DED subjects than in normal subjects (3.83 ± 1.81 versus 1.59 ± 1.04). In CL-wearers, MG distortion was not significantly different (5.12 ± 4.11 versus 5.51 ± 3.15 in normal and DED subjects respectively). The area under the ROC curve (AUC) for MG distortion was 0.783 in the non-CL-wearers, but 0.507 in CL-wearers. In non-CL-wearers, MG dropout was significantly higher in DED subjects than in normal subjects (0.22 ± 0.08 versus 0.15 ± 0.06). In CL-wearers, MG dropout was also significantly higher in DED subjects than in normal subjects (0.29 ± 0.11 versus 0.22 ± 0.08). The AUC for MG dropout used to classify DED was 0.740 in the non-CL-wearers and 0.715 in CL-wearers.Conclusions: MG dropout was effective in distinguishing subjects with DED from normal subjects in both CL wearers and non-CL wearers. MG distortion can only distinguish DED subjects from normal ones in non-CL wearers, but not in CL wearers.

4.
Int J Pharm ; 578: 119101, 2020 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-32006622

RESUMO

smartPearls technology is one appropriate method to produce anti-psoriatic curcumin (Cur) topical delivery system. To prevent the sedimentation of loaded silica and release changing over the storage, which are disadvantages of smartPearls production, extra glycyrrhizic acid (GA) was added in classical smartPearls ingredients (active and porous material) to get an improved smartPearls production (Cur-GA-silica). The capacity of Cur-GA-silica to remain the gelation state after mixing with water was superior compared to that of the solid cluster without GA and that of the physical mixture of Cur, GA and silica. The Cur-GA-silica practically contained Cur with 1.68% ± 0.12% and showed significant difference with Cur raw drug powder in kinetic solubilities (4.55 ± 0.78 µg/mL vs 0 in 5 min; 3.26 ± 0.17 µg/mL vs 0 in 4 h) which was traceable to the amorphous state of Cur-GA-silica detected by X-ray diffractometer. With the amorphous Cur, two times as much penetrated Cur in Cur-GA-silica as in Cur raw drug powder was achieved on the imiquimod-induced psoriasis-like mice model. The anti-psoriatic efficacy of Cur-GA-silica was confirmed by Psoriasis Area and Severity Index (PASI) evaluation, histological evaluation and decreased IL-17A in the imiquimod-induced psoriasiform mouse skin analyzed by enzyme-linked immunosorbent assay. In conclusion, with the addition of GA, a stable amorphous curcumin topical vehicle fabricated by smartPearls technology without extra dermal matrix is available and facilitates penetration efficacy and anti-psoriatic capacity in imiquimod-induced psoriasiform mice.

5.
Biochim Biophys Acta Mol Cell Res ; 1867(6): 118679, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32061630

RESUMO

Head and neck squamous cell carcinoma (HNSCC) is a highly morbid, genetically unstable disease derived from the mucoepithelium of the upper aerodigestive tract. Recent characterization of this disease has implicated the PI3K-Akt-mTOR pathway as one of the most frequently dysregulated pathways. As such, there are several classes of PI3K inhibitors currently undergoing clinical trials. In this article, we review the PI3K pathway, mutations of this pathway in HNSCC, drugs that target PI3K, the impact of these agents on the PI3K and GSK-3 signaling axes, ongoing clinical trials evaluating PI3K inhibitors, and the challenges of using these drugs in the clinic. This article is part of a Special Issue entitled: GSK-3 and related kinases in cancer, neurological and other disorders edited by James McCubrey, Agnieszka Gizak and Dariusz Rakus.

6.
Medicine (Baltimore) ; 99(3): e18896, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32011518

RESUMO

RATIONALE: The dentinogenic ghost cell tumor (DGCT), a locally invasive benign neoplasm, is one of the rarest odontogenic tumors, usually developing in the maxilla or mandible. It can be classified into 2 types: intraosseous (central) and extraosseous (peripheral). Here, we describe the first case of a peripheral DGCT located in the ethmoid sinus. PATIENT CONCERNS: An 8-year-old boy presented to our department with a longer than 7-month history of nasal obstruction, purulent secretion, and reduction in sense of smell in the right nasal cavity. DIAGNOSIS: The patient was diagnosed with peripheral DGCT of the ethmoid sinus based on computed tomography scan and pathology. INTERVENTIONS: Functional endoscopic sinus surgery was performed. OUTCOMES: With 2 years of follow-up, there was no evidence of recurrence. LESSONS: Peripheral DGCT can occur in the paranasal sinus and the need to consider this entity as a possible diagnosis by the clinicians.


Assuntos
Seio Etmoidal , Tumores Odontogênicos/diagnóstico por imagem , Tumores Odontogênicos/cirurgia , Criança , Diagnóstico Diferencial , Humanos , Masculino
7.
Waste Manag ; 103: 305-313, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-31923839

RESUMO

In this paper, three sets of laboratory tests were conducted on high-food-waste-content (HFWC-), no-food-waste-content (NFWC-) and decomposed (D-) MSWs to characterize their compression behaviors. The immediate compression ratios C'c were 0.30, 0.23 and 0.18 for HFWC-MSW, NFWC-MSW and D-MSW respectively, and tended to increase with the increasing food waste content of MSW. The release of intra-particle water contained in food waste contributed over 23.6-29.2% to immediate compression for HFWC-MSW. The mechanical creep ratios C'sc were 0.02, 0.015 and 0.01 for HFWC-MSW, NFWC-MSW and D-MSW respectively. A prediction model for C'sc was proposed which incorporated the effects of moisture content, dry unit weight and organic waste content. The bio-compression ratios C'sbI, C'sbII and C'sbIII in response to degradation stage I, II and III were 0.12, 0.10 and 0.02 for HFWC-MSW, and were 0.01, 0.15 and 0.01 for NFWC-MSW. Bio-compression is dominant in stage I and II and mechanical creep is the major contributor in stage III for HFWC-MSW, but to NFWC-MSW, mechanical creep is dominant in stage I and III, and bio-compression takes the main position in stage II. The bio-compression tended to increase linearly with leachate draining rate for HFWC-MSW, and the release of intra-particle water contributed 61.9-65.6% to bio-compression. A new model was proposed that can well capture the highly non-linear behavior of bio-compression for both HFWC-MSW and NFWC-MSW. Based on the above findings, the settlement behavior of HFWC-MSW and NFWC-MSW landfills was compared, and suggestions for technique-efficient and cost-effective design of a NFWC-MSW landfill were discussed.


Assuntos
Eliminação de Resíduos , China , Alimentos , Pressão , Resíduos Sólidos , Instalações de Eliminação de Resíduos
8.
Spectrochim Acta A Mol Biomol Spectrosc ; 226: 117642, 2020 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-31614273

RESUMO

Tyrosinase is the rate-limiting enzyme for controlling the production of melanin in the human body, and overproduction of melanin can lead to a variety of skin disorders. In this paper, the inhibitory kinetics of phloretin on tyrosinase and their binding mechanism were determined using spectroscopy, molecular docking, antioxidant assays and chromatography. The spectroscopic results indicate that phloretin reversibly inhibits tyrosinase in a mix-type manner through a multiphase kinetic process with the IC50 of 169.36 µmol/L. It is shown that phloretin has a strong ability to quench the intrinsic fluorescence of tyrosinase mainly through a static quenching procedure, suggesting that a stable phloretin-tyrosinase complex is generated. Molecular docking results suggest that the dominant conformation of phloretin binds to the gate of the active site of tyrosinase. Moreover, the antioxidant assays demonstrate that phloretin has powerful antioxidant capacity and has the ability to reduce o-dopaquinone to l-dopa just like ascorbic acid. Interestingly, the results of spectroscopy and chromatography indicate that phloretin is a substrate of tyrosinase but also an inhibitor. The possible inhibitory mechanism is proposed, which will be helpful to design and search for tyrosinase inhibitors.

9.
J Exp Bot ; 71(4): 1503-1513, 2020 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-31665748

RESUMO

In plants, a large root system improves the uptake of water and nutrients, and is important for responding to drought stress. The poplar WUSCHEL-related homeobox (WOX) transcription factor promotes adventitious rooting, but its regulation of root growth in response to drought stress remains elusive. In this study, we found that PagWOX11/12a from hybrid poplar 84K (Populus alba×Populus glandulosa) is expressed predominantly in the roots and is strongly induced by drought stress. Compared with non-transgenic 84K plants, transgenic poplar plants overexpressing PagWOX11/12a displayed increased root biomass and enhanced drought tolerance, while opposite phenotypes were observed for PagWOX11/12a dominant repression plants. PagWOX11/12a functions as a nuclear transcriptional activator with a transactivation domain at the C-terminus. In addition, PagERF35 was found to specifically bind to a dehydration-responsive element (DRE) within the PagWOX11/12a promoter and activate PagWOX11/12a gene expression. These results indicate that PagERF35 may activate PagWOX11/12a expression in response to drought stress by promoting root elongation and biomass, thereby increasing drought tolerance of poplar.

10.
Respir Res ; 20(1): 285, 2019 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-31852500

RESUMO

BACKGROUND: ß2 receptor agonists induce airway smooth muscle relaxation by increasing intracellular cAMP production. PKA is the traditional downstream signaling pathway of cAMP. Exchange protein directly activated by cAMP (Epac) was identified as another important signaling molecule of cAMP recently. The role of Epac in asthmatic airway inflammation and airway remodeling is unclear. METHODS: We established OVA-sensitized and -challenged acute and chronic asthma mice models to explore the expression of Epac at first. Then, airway inflammation and airway hyperresponsiveness in acute asthma mice model and airway remodeling in chronic asthma mice model were observed respectively after treatment with Epac-selective cAMP analogue 8-pCPT-2'-O-Me-cAMP (8pCPT) and Epac inhibitor ESI-09. Next, the effects of 8pCPT and ESI-09 on the proliferation and apoptosis of in vitro cultured mouse airway smooth muscle cells (ASMCs) were detected with CCK-8 assays and Annexin-V staining. Lastly, the effects of 8pCPT and ESI-09 on store-operated Ca2+ entry (SOCE) of ASMCs were examined by confocal Ca2+ fluorescence measurement. RESULTS: We found that in lung tissues of acute and chronic asthma mice models, both mRNA and protein expression of Epac1 and Epac2, two isoforms of Epac, were lower than that of control mice. In acute asthma mice model, the airway inflammatory cell infiltration, Th2 cytokines secretion and airway hyperresponsiveness were significantly attenuated by 8pCPT and aggravated by ESI-09. In chronic asthma mice model, 8pCPT decreased airway inflammatory cell infiltration and airway remodeling indexes such as collagen deposition and airway smooth muscle cell proliferation, while ESI-09 increased airway inflammation and airway remodeling. In vitro cultured mice ASMCs, 8pCPT dose-dependently inhibited, whereas ESI-09 promoted ASMCs proliferation. Interestingly, 8pCPT promoted the apoptosis of ASMCs, whereas ESI-09 had no effect on ASMCs apoptosis. Lastly, confocal Ca2+ fluorescence examination found that 8pCPT could inhibit SOCE in ASMCs at 100 µM, and ESI-09 promoted SOCE of ASMCs at 10 µM and 100 µM. In addition, the promoting effect of ESI-09 on ASMCs proliferation was inhibited by store-operated Ca2+ channel blocker, SKF-96365. CONCLUSIONS: Our results suggest that Epac has a protecting effect on asthmatic airway inflammation and airway remodeling, and Epac reduces ASMCs proliferation by inhibiting SOCE in part.

11.
Sichuan Da Xue Xue Bao Yi Xue Ban ; 50(6): 919-924, 2019 Dec.
Artigo em Chinês | MEDLINE | ID: mdl-31880125

RESUMO

OBJECTIVE: To explore the relationships of BRAF V600E and TERT promoter mutations with the clinicopathological features in papillary thyroid carcinoma (PTC). METHODS: The mutations of BRAF V600E and TERT promoters were examined by PCR-direct sequencing in tumor tissues from 326 PTC patients, while the relationships between the gene mutations and clinicopathological features were analyzed. RESULTS: BRAF V600E mutation was found in 269/326 (82.52%), and TERT promoter mutation in 11/326 (3.37%) of PTC patients. In site mutations of TERT promoter, 9 cases were C228T and 2 cases were C250T. Single factor analysis showed that BRAF V600E mutations were significantly associated with age and recurrence/distant metastasis of tumor (P < 0.05), while TERT promoter mutations were significantly associated with age, tumor size, extrathyroidal extension, T stage, AJCC stage and recurrence/distant metastasis of tumor (P < 0.05). Coexistence of BRAF V600E and TERT promoter mutations (BRAF+/TERT+) were particularly associated with age, tumor size, extrathyroidal extension, T stage and AJCC stage (P < 0.05). CONCLUSION: Coexistence of BRAF V600E and TERT promoter mutations in PTC shows more aggressive tumor behavior.


Assuntos
Proteínas Proto-Oncogênicas B-raf/genética , Telomerase/genética , Câncer Papilífero da Tireoide , Neoplasias da Glândula Tireoide , Humanos , Mutação , Recidiva Local de Neoplasia , Prognóstico , Câncer Papilífero da Tireoide/genética , Neoplasias da Glândula Tireoide/genética
12.
Int J Biol Macromol ; 2019 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-31756479

RESUMO

The cell adhesion and proliferation of zein-based biomaterials in cell culture application are limited by the strong hydrophobic surface with low surface energy. In this study, atmospheric cold plasma (ACP) was developed as a modification approach in enhancing the surface hydrophilic and cytocompatibility of zein films. The results indicated that water contact angles decreased from 72.85° (untreated) to 47.43° under the voltage of 100 V. The improvement of the surface free energy (SFE) was mainly attributed to the polar component rather than dispersive component. X-ray photoelectron spectroscopy (XPS) results indicated the change of surface physicochemical properties was mainly due to the partially transformation of long-chain aliphatic hydrocarbons (CH and/or CC) to oxygen- and nitrogen-containing bonds (CO, CO and CN). Furthermore, the content of secondary structure demonstrated ß-turn and α-helix were transformed into ß-sheet and random coil after ACP treatment. Combining with the cell experiment results, plasma treatment could significantly improve the adhesion rate and proliferation activity of C2C12 cells on zein films. With better cytocompatibility, the potentials of zein in tissue engineering scaffold could be readily exploited.

13.
DNA Cell Biol ; 38(11): 1207-1222, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31483163

RESUMO

Multiple studies have shown that cancer-specific alternative splicing (AS) alterations are associated with clinical outcome. In this study, we aimed to profile prognostic AS signatures for pancreatic ductal adenocarcinoma (PDAC). We integrated the percent-spliced-in (PSI) data of AS in 140 PDAC patients based on the Cancer Genome Atlas (TCGA) dataset. We identified overall survival (OS)-associated AS events using univariate Cox regression analysis. Then, prognostic AS signatures were constructed for OS and chemoresistance prediction using the least absolute shrinkage and selection operator (LASSO) method. We also analyzed splicing factors (SFs) regulatory networks by Pearson's correlation. We detected 677 OS-related AS events in 485 genes by profiling 10,354 AS events obtained from 140 PDAC patients. Gene functional enrichment analysis demonstrated the pathways enriched by survival-associated AS. The AS signatures constructed with significant survival-associated AS events revealed high performance in predicting PDAC survival and gemcitabine chemoresistance. The area under the receiver operator characteristic curve was 0.937 in training cohort and 0.748 in validation cohort at 2000 days of OS. Furthermore, we identified prognostic SFs (e.g., ESRP1 and HNRNPC) to build the AS regulatory network. We constructed AS signatures for OS and gemcitabine chemoresistance in PDAC patients, which may provide clues for further experiment-based mechanism study.


Assuntos
Processamento Alternativo/genética , Biomarcadores Tumorais/genética , Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Transcriptoma , Carcinoma Ductal Pancreático/diagnóstico , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/mortalidade , Estudos de Coortes , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Humanos , Masculino , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/mortalidade , Prognóstico , Análise de Sequência de RNA , Análise de Sobrevida
14.
Biomed Microdevices ; 21(3): 63, 2019 07 04.
Artigo em Inglês | MEDLINE | ID: mdl-31273475

RESUMO

Microneedle (MN) patch has been used for collecting dermal interstitial fluid (ISF) containing biomarkers from patients with safety, pain-free and easy-to-use manner. However, long sampling time for biomarkers analysis still poses a significant challenge. Here, we describe a new sponge-forming MN patch consisting of polyvinyl formal (PVF) for rapidly extracting ISF from skin. Owing to the supreme water affinity of PVF, this MN patch can extract 1.6 mg ISF in 1 min without the assistance of extra devices, which remarkably facilitates timely analysis. The MN patch had preserved structural integrity in the swelling hydrated state without leaving residues in skin after usage, and the treated skin recovered within 8 h. More importantly, the extracted ISF can be efficiently recovered from the MN patch by simple centrifugation for the subsequent offline analysis of biomarkers such as glucose and cholesterol. Our results reveal that the new sponge-forming MN patch holds considerable promise for minimally invasive sampling ISF for biomarkers detection in real-life situations.


Assuntos
Líquido Extracelular/metabolismo , Microtecnologia/instrumentação , Agulhas , Animais , Colesterol/metabolismo , Glucose/metabolismo , Hidrogéis , Masculino , Fenômenos Mecânicos , Ratos , Ratos Sprague-Dawley , Pele/metabolismo , Fatores de Tempo
15.
MethodsX ; 6: 1036-1043, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31193181

RESUMO

This paper presents a method to solidify/stabilize the municipal solid waste incineration (MSWI) fly ash by originally employing the microbial induced carbonate precipitation (MICP) technique. In this method, the rich endogenous calcium in the MSWI fly ash was utilized to induce calcite precipitation, which is different from the operation of adding extra calcium source in previous researches. The fly ash sample had a CaO content of 44.5%, and its leaching concentrations of Zn, Cr and Pb exceed the limits of the identification standard for hazardous wastes in China. The optical density at 600 nm (OD600) of the bacterial solution was about 1.0 after the processes of bacterial activation and reproduction. The prepared fly ash sample was well mixed with bacterial solution at an ash-liquid ratio of 1 kg: 0.3 L and cured at a temperature of 20 °C and a humidity of ≥95% for 7 days. After treatment, the heavy metal leachability significantly reduced to meet the standard for pollution control of landfill site, and the unconfined compressive strength increased approximately 40%. The precipitated carbonates were verified by SEM-EDS analysis and quantified by measurement of carbonate content via acid-dissolving method. The results shone a light on the possibility of using MICP technique as a useful and efficient tool to stabilize the MSWI fly ash before being reused or properly stored in landfills. •The MICP method is efficient to reduce the heavy metal leachability and increase the compressive strength of MSWI fly ash.•The endogenous calcium in MSWI fly ash was utilized to induce calcite precipitation.•The heavy metals in MSWI fly ash were well immobilized by the formation of carbonates.

16.
Nat Commun ; 10(1): 2701, 2019 06 20.
Artigo em Inglês | MEDLINE | ID: mdl-31221965

RESUMO

One of the biggest hurdles for the development of metabolism-targeted therapies is to identify the responsive tumor subsets. However, the metabolic vulnerabilities for most human cancers remain unclear. Establishing the link between metabolic signatures and the oncogenic alterations of receptor tyrosine kinases (RTK), the most well-defined cancer genotypes, may precisely direct metabolic intervention to a broad patient population. By integrating metabolomics and transcriptomics, we herein show that oncogenic RTK activation causes distinct metabolic preference. Specifically, EGFR activation branches glycolysis to the serine synthesis for nucleotide biosynthesis and redox homeostasis, whereas FGFR activation recycles lactate to fuel oxidative phosphorylation for energy generation. Genetic alterations of EGFR and FGFR stratify the responsive tumors to pharmacological inhibitors that target serine synthesis and lactate fluxes, respectively. Together, this study provides the molecular link between cancer genotypes and metabolic dependency, providing basis for patient stratification in metabolism-targeted therapies.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias/metabolismo , Inibidores de Proteínas Quinases/uso terapêutico , Receptores Proteína Tirosina Quinases/metabolismo , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Conjuntos de Dados como Assunto , Mutação com Ganho de Função , Perfilação da Expressão Gênica/métodos , Glicólise/efeitos dos fármacos , Glicólise/genética , Homeostase/efeitos dos fármacos , Homeostase/genética , Humanos , Redes e Vias Metabólicas/efeitos dos fármacos , Redes e Vias Metabólicas/genética , Metabolômica/métodos , Camundongos , Neoplasias/tratamento farmacológico , Neoplasias/genética , Neoplasias/patologia , Seleção de Pacientes , Inibidores de Proteínas Quinases/farmacologia , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Receptores Proteína Tirosina Quinases/genética , Serina/biossíntese , Transdução de Sinais/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
17.
World J Clin Cases ; 7(8): 961-971, 2019 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-31119141

RESUMO

BACKGROUND: Adrenocorticotropic hormone (ACTH)-independent Cushing's syndrome (CS) is mostly due to unilateral tumors, with bilateral tumors rarely reported. Its common causes include primary pigmented nodular adrenocortical disease, ACTH-independent macronodular adrenal hyperplasia, and bilateral adrenocortical adenomas (BAAs) or carcinomas. BAAs causing ACTH-independent CS are rare; up to now, fewer than 40 BAA cases have been reported. The accurate diagnosis and evaluation of BAAs are critical for determining optimal treatment options. Adrenal vein sampling (AVS) is a good way to diagnose ACTH-independent CS. CASE SUMMARY: A 31-year-old woman had a typical appearance of CS. The oral glucose tolerance test showed impaired glucose tolerance and obviously increased insulin and C-peptide levels. Her baseline serum cortisol and urine free cortisol were elevated and did not show either a circadian rhythm or suppression with dexamethasone administration. The peripheral 1-deamino-8-D-arginine-vasopressin (DDVAP) stimulation test showed a delay of the peak level, which was 1.05 times as high as the baseline level. Bilateral AVS results suggested the possibility of BAAs. Abdominal computed tomography showed bilateral adrenal adenomas with atrophic adrenal glands (right: 3.1 cm × 2.0 cm × 1.9 cm; left: 2.2 cm × 1.9 cm × 2.1 cm). Magnetic resonance imaging of the pituitary gland demonstrated normal findings. A left adenomectomy by retroperitoneoscopy was performed first, followed by resection of the right-side adrenal mass 3 mo later. Biopsy results of both adenomas showed cortical tumors. Evaluations of ACTH and cortisol showed a significant decrease after left adenomectomy but could still not be suppressed, and the circadian rhythm was absent. Following bilateral adenomectomy, this patient has been administered with prednisone until now, all of her symptoms were alleviated, and she had normal blood pressure without edema in either of her lower extremities. CONCLUSION: BAAs causing ACTH-independent CS are rare. AVS is of great significance for obtaining information on the functional state of BAAs before surgery.

18.
Pharmazie ; 74(6): 345-349, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-31138371

RESUMO

Azithromycin was loaded onto the µm-sized mesoporous silica Davisil® SP53D-11920 using the wetness impregnation method with fractional steps (WIFS) and further incorporated into a 5 % hydroxypropyl cellulose gel to prevent Lyme disease. Maximum loadings (32.0 % w/w and 33.2 % w/w) were produced by different concentrated loading solutions and determined by X-ray diffraction (XRD). A total of 24 months stability of the amorphous azithromycin state in the silica (33.2 % loading) and 18 months stability in the gel (33.2 % loading) at 4 °C were also confirmed by XRD. The higher kinetic solubility at 40 min (1,300 µg/mL versus 93 µg/mL) and higher porcine ear skin penetration compared to the raw drug powder indicated higher dermal bioavailability of the azithromycin-loaded silica (32.0 % loading), even when compared to the "gold standard" nanocrystals and another clinical effective azithromycin formulation with ethanol. In summary, maximum loaded silicas with azithromycin by WIFS is a promising dermal formulation for prophylaxis against Lyme disease.

19.
Pharmazie ; 74(5): 277-285, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-31109397

RESUMO

Azithromycin was optimized as nanocrystals with a drug content of 10.0 % (w/w) and a surfactant D-α -tocopheryl polyethylenglycol 1000 succinate (TPGS) content of 1.0 % (w/w) using bead milling for 10 min. The photon correlation spectroscopy (PCS) diameter of the bulk population was 189 nm, laser diffraction (LD) diameter 90 % was 370 nm. Spherical morphology of the optimal nanocrystals was observed by transmission electron microscope (TEM). They were stable over 1 year of storage at 4 °C with the particle size within the nanometer range which was confirmed by PCS, LD and light microscope. An acceptable physical stability of 2 years was also obtained when stored at 4 °C. No microbial attack to the nanocrystals was observed before 3 years storage at 4 °C. The saturation solubility of the nanocrystals was up to triple compared to the raw drug powder (RDP) in water. When incorporated into the gel base, highest penetration efficacy was achieved by the optimal nanocrystals compared to 1) the clinically effective ethanol-solution-gel, 2) the gel with propylene glycol and 3) the gel with RDP in the ex vivo porcine ear penetration study. Even though propylene glycol improved saturation solubility of nanocrystals, it could not bring benefit to nanocrystals in the penetration study. Based on these optimized azithromycin nanocrystals, topical administration for enhanced dermal bioavailability of azithromycin seems to be feasible.

20.
Kaohsiung J Med Sci ; 35(7): 401-407, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31001918

RESUMO

Ubiquitin specific peptidase 49 (USP49) has been reported as a tumor suppressor in several tumors, but its function and molecular mechanism in non-small cell lung cancer (NSCLC) are still unknown. In this study, USP49 was found downregulated in NSCLC primary tissues and cell lines, and high USP49 predicted a positive index for the overall survival of NSCLC patients. Overexpression of USP49 downregulated the expression levels of Cyclin D1, and upregulated p53 expression. Further flow cytometry analysis showed that overexpressed USP49 induced cell cycle arrest at G0/G1 phase. As a result, overexpression of USP49 significantly inhibited cell growth of NSCLC cells. In mechanism, overexpression of USP49 inhibited PI3K/AKT signaling, but knockdown of USP49 enhanced this signaling. Further studies indicated that USP49 deubiquitinated PTEN and stabilized PTEN protein, which suggested that USP49 inhibited PI3K/AKT signaling by stabilizing PTEN in NSCLC cells. In conclusion, we demonstrated that USP49 was functional in NSCLC cells, and inhibited NSCLC cell growth by suppressing PI3K/AKT signaling, suggesting that USP49 could be as a novel target for NSCLC therapy.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias Pulmonares/genética , Fosfatidilinositol 3-Quinases/genética , Proteínas Proto-Oncogênicas c-akt/genética , Ubiquitina Tiolesterase/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Pontos de Checagem do Ciclo Celular/genética , Linhagem Celular Tumoral , Proliferação de Células , Ciclina D1/genética , Ciclina D1/metabolismo , Células HEK293 , Humanos , Pulmão/metabolismo , Pulmão/patologia , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , PTEN Fosfo-Hidrolase/genética , PTEN Fosfo-Hidrolase/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Fase de Repouso do Ciclo Celular , Transdução de Sinais , Análise de Sobrevida , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Ubiquitina Tiolesterase/antagonistas & inibidores , Ubiquitina Tiolesterase/metabolismo
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