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2.
Front Immunol ; 12: 642528, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33868277

RESUMO

The adoptive transfer of chimeric antigen receptor T (CAR T) cells have been recognized as a promising therapeutic strategy for the treatment of hematological malignancies; however, clinical success using CAR T cells for the treatment of solid tumors are still limited since the T-cell function is inhibited by negative signals in the microenvironment of solid tumors. CTLA4 is a well-known immune checkpoint molecule, thus we developed a novel CAR by converting this negative signal to positive signal. The CAR developed consists of the extracellular and transmembrane domains of CTLA4 and the cytoplasmic domains of CD28 and CD3z (CTLA4-CAR T). CTLA4-CAR T cells exhibited superior cytokine secreting activities and cytotoxic to tumor cells in vitro and in xenograft models. CTLA4-CAR T cells were found to accumulate in tumors and are toxic to myeloid-derived suppressor cells (MDSCs) without signs of severe GVHD and CRS in preclinical models. Thus, this chimeric CTLA4-CAR can enhance the antitumor activity of CAR T cells and shed light on the strategy of using armed CAR T cells to target the immunomodulatory tumor microenvironment.

3.
Nat Prod Res ; : 1-6, 2021 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-33749420

RESUMO

Dendrocandins are characteristic chemical structures of D. officinale and have strong physiological bioactivities. In this study, a dendrocandin analogue (1) has been prepared by total synthesis (9 steps, 12.6% overall yield) in which coupling reaction and Wittig reaction as the key steps. Compound 1 was also evaluated for its anticancer activity in vitro against six human cancer cells (MCF-7, A549, A431, SW480, HepG-2 and HL-60) using MTT assays. Compound 1 showed potent cytotoxicity, with the IC50 value 16.27 ± 0.26 µM. The expression levels of apoptotic proteins indicated that compound 1 can up-regulate the expression of apoptotic proteins, leading to apoptosis. This compound suggested that it's potential as anticancer agent for further development.

4.
Mol Med Rep ; 23(5)2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33760200

RESUMO

Proliferative vitreoretinopathy (PVR) is a disease leading to the formation of contractile preretinal membranes (PRMs) and is one of the leading causes of blindness. Connective tissue growth factor (CTGF) has been identified as a possible key determinant of progressive tissue fibrosis and excessive scarring. Therefore, the present study investigated the role and mechanism of action of CTGF in PVR. Immunohistochemical staining was performed to detect the expression of CTGF, fibronectin and collagen type III in PRMs from patients with PVR. The effects and mechanisms of recombinant human CTGF and its upstream regulator, TGF­ß1, on epithelial­mesenchymal transition (EMT) and the synthesis of extracellular matrix (ECM) by retinal pigment epithelium (RPE) cells were investigated using reverse transcription­quantitative PCR, western blotting and a [3H]proline incorporation assay. The data indicated that CTGF, fibronectin and collagen type III were highly expressed in PRMs. In vitro, CTGF significantly decreased the expression of the epithelial markers ZO­1 and E­cadherin and increased that of the mesenchymal markers fibronectin, N­cadherin and α­smooth muscle actin in a concentration­dependent manner. Furthermore, the expression of the ECM protein collagen type III was upregulated by CTGF. However, the trends in expression for the above­mentioned markers were reversed after knocking down CTGF. The incorporation of [3H]proline into RPE cells was also increased by CTGF. In addition, 8­Bromoadenosine cAMP inhibited CTGF­stimulated collagen synthesis and transient transfection of RPE cells with a CTGF antisense oligonucleotide inhibited TGF­ß1­induced collagen synthesis. The phosphorylation of PI3K and AKT in RPE cells was promoted by CTGF and TGF­ß1 and the latter promoted the expression of CTGF. The results of the present study indicated that CTGF may promote EMT and ECM synthesis in PVR via the PI3K/AKT signaling pathway and suggested that targeting CTGF signaling may have a therapeutic or preventative effect on PVR.


Assuntos
Fator de Crescimento do Tecido Conjuntivo/genética , Transição Epitelial-Mesenquimal/genética , Pigmentos da Retina/genética , Fator de Crescimento Transformador beta1/genética , Vitreorretinopatia Proliferativa/genética , Western Blotting , Movimento Celular/genética , Matriz Extracelular/genética , Fibronectinas/genética , Humanos , Fosfatidilinositol 3-Quinases/genética , Fosforilação , Proteínas Proto-Oncogênicas c-akt/genética , Epitélio Pigmentado da Retina/crescimento & desenvolvimento , Epitélio Pigmentado da Retina/metabolismo , Transdução de Sinais/genética , Vitreorretinopatia Proliferativa/patologia
5.
Zhongguo Yi Xue Ke Xue Yuan Xue Bao ; 43(1): 37-41, 2021 Feb 28.
Artigo em Chinês | MEDLINE | ID: mdl-33663660

RESUMO

Objective To explore the outcomes in patients who receive the endovascular abdominal aortic aneurysm repair(EVAR)and have concomitant intra-abdominal malignancy.Methods Between January 2014 and December 2019,all the patients who underwent surgery for malignancy and/or EVAR were retrospectively reviewed.Results Twenty-eight abdominal aortic aneurysm(AAA)patients with concomitant intra-abdominal malignancy were included.The patients were treated by two-stage operation and the priority was given for EVAR in 21 patients.There was no perioperative death or major complications.In the follow-up,one patient developed graft thrombosis and one had type Ⅱ endoleak.There was no AAA-associated death.Conclusions It is preferred that EVAR should come first followed by operation for malignancy.Details of treatment strategy still need further investigation.


Assuntos
Neoplasias Abdominais , Aneurisma da Aorta Abdominal , Implante de Prótese Vascular , Procedimentos Endovasculares , Neoplasias Abdominais/complicações , Neoplasias Abdominais/cirurgia , Aneurisma da Aorta Abdominal/complicações , Aneurisma da Aorta Abdominal/cirurgia , Humanos , Estudos Retrospectivos , Fatores de Risco , Resultado do Tratamento
6.
Plant Physiol Biochem ; 162: 603-612, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33774465

RESUMO

Dendrobium candidum stems are used as Chinese medicine and functional food. Red stems of D. candidum are rich in anthocyanins, which attract pollinator insects, protect the plants against environmental stress, and improve human health. The regulatory mechanisms of anthocyanin biosynthesis and stem color differentiation in D. candidum are not fully understood. Using transcriptome profiling, we identified a basic helix-loop-helix transcription factor (DcTT8) involved in anthocyanin biosynthesis in D. candidum stems. Ultraperformance liquid chromatography-tandem mass spectrometry was used to determine pigment contents and compositions in red and green stems, revealing that cyanidin is responsible for the red color. DcTT8 could bind the DcF3'H and DcUFGT promoters and finely regulate DcF3'H and DcUFGT expression. Our data indicate that DcTT8 participates in anthocyanin biosynthesis and offers novel insights into the transcriptional regulation of anthocyanin biosynthesis in D. candidum.


Assuntos
Antocianinas , Dendrobium , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Dendrobium/genética , Dendrobium/metabolismo , Regulação da Expressão Gênica de Plantas , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo
7.
BMC Ecol Evol ; 21(1): 45, 2021 03 17.
Artigo em Inglês | MEDLINE | ID: mdl-33731021

RESUMO

BACKGROUND: Natural model systems are indispensable for exploring adaptations in response to environmental pressures. Sinocyclocheilus of China, the most diverse cavefish clade in the world (75 species), provide unique opportunities to understand recurrent evolution of stereotypic traits (such as eye loss and sensory expansion) in the context of a deep and diverse phylogenetic group. However, they remain poorly understood in terms of their morphological evolution. Therefore, we explore key patterns of morphological evolution, habitat utilization and geographic distribution in these fishes. RESULTS: We constructed phylogenies and categorized 49 species based on eye-related condition (Blind, Micro-eyed, and Normal-eyed), habitat types (Troglobitic-cave-restricted; Troglophilic-cave-associated; Surface-outside caves) and existence of horns. Geometric-morphometric analyses show Normal-eyed morphs with fusiform shapes segregating from Blind/Micro-eyed deeper bodied morphs along the first principal-component axis; second axis accounts for shape complexity related to horns. The body shapes showed a significant association with eye-related condition and horn, but not habitat types. Ancestral reconstructions suggest at least three independent origins of Blind morphs, each with different levels of modification in relation to their ancestral Normal-eyed morphs; Sinocyclocheilus are also pre-adapted for cave dwelling. Our geophylogeny shows an east-to-west diversification spanning Pliocene and Pleistocene, with early-diversifying Troglobitic species dominating subterranean habitats of karstic plains whereas predominantly Surface forms inhabit hills to the west. Evolutionary rates analyses suggest that lineages leading to Blind morphs were characterized by significant rate shifts, such as a slowdown in body size evolution and a 5-20 fold increase in rate of eye regression, possibly explained by limited resource availability. Body size and eye size have undergone reversals, but not horns, a trait entailing considerable time to form. CONCLUSIONS: Sinocyclocheilus occupied cave habitats in response to drying associated with aridification of China during late Miocene and the Pliocene. The prominent cave-adaptations (eye-regression, horn-evolution) occur in clades associated with the extensive subterranean cave system in Guangxi and Guizhou provinces. Integration of morphology, phylogeny, rate analyses, molecular-dating and distribution show not only several remarkable patterns of evolution, but also interesting exceptions to these patterns signifying the diversification of Sinocyclocheilus as an invaluable model system to explore evolutionary novelty.


Assuntos
Evolução Biológica , Cyprinidae , Animais , Cavernas , China , Filogenia
8.
NMR Biomed ; : e4505, 2021 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-33783927

RESUMO

Serum metabolites of healthy controls and esophageal cancer (EC) patients have previously been compared to predict cancer-specific profiles. However, the association between metabolic alterations in serum samples and esophageal tissues in EC patients remains unclear. Here, we analyzed 50 pairs of EC tissues and distant noncancerous tissues, together with patient-matched serum samples, using 1 H NMR spectroscopy and pattern recognition algorithms. EC patients could be differentiated from the controls based on the metabolic profiles at tissue and serum levels. Some overlapping discriminatory metabolites, including valine, alanine, glucose, acetate, citrate, succinate and glutamate, were identified in both matrices. These results suggested deregulation of metabolic pathways, and potentially revealed the links between EC and several metabolic pathways, such as the tricarboxylic acid cycle, glutaminolysis, short-chain fatty acid metabolism, lipometabolism and pyruvate metabolism. Perturbation of the pyruvate metabolism was most strongly associated with EC progression. Consequently, an optimal serum metabolite biomarker panel comprising acetate and pyruvate was developed, as these two metabolites are involved in pyruvate metabolism, and changes in their serum levels were significantly correlated with alterations in the levels of some other esophageal tissue metabolites. In comparison with individual biomarkers, this panel exhibited better diagnostic efficiency for EC, with an AUC of 0.948 in the test set, and a good predictive ability of 82.5% in the validation set. Analysis of key genes related to pyruvate metabolism in EC patients revealed patterns corresponding to the changes in serum pyruvate and acetate levels. These correlation analyses demonstrate that there were distinct metabolic characteristics and pathway aberrations in the esophageal tumor tissue and in the serum. Changes in the serum metabolic signatures could reflect the alterations in the esophageal tumor profile, thereby emphasizing the importance of distinct serum metabolic profiles as potential noninvasive biomarkers for EC.

9.
Eur J Surg Oncol ; 2021 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-33775487

RESUMO

OBJECTIVES: Carotid body tumors (CBTs) are rare head and neck neoplasms, we aimed to propose a modification to the Shamblin's classification of CBTs. MATERIALS AND METHODS: This retrospective study included 105 patients (116 CBTs) operated at our institution from March 2013 to July 2020. CBTs were divided by a modified Shamblin's classification into five subtypes (type I-V) based on the radiographic features. Correlations between modified classification and intraoperative bleeding, internal carotid artery (ICA) bypass and postoperative neural complications, as main outcomes, as well as other outcomes were analyzed. RESULTS: Surgeries for type V and type I CBTs had the most (median: 700 ml, IQR: 375-1575 ml) and least (median: 20 ml, IQR: 20-50 ml) bleeding, respectively. Intraoperatively, ICA bypass was needed in 41.7% (10/24) type V, 18.2% (8/44) type IV and 5.9% (1/17) type III lesions, but not in other subtypes (p = .001). Postoperatively, overall cranial nerve deficits (CND) were found most frequently in type V tumors (17/24, 70.8%) (p = .016). Permanent CND were found in 33.3% (8/24) type V and 4.5% (2/44) type IV lesions, but not in other subtypes (p = .001). Other outcomes including external carotid artery ligation, operation time, blood transfusion, postoperative intensive unit care and postoperative hospitalization also showed significant difference among different subtypes. Patients recovered uneventfully during a follow-up of 23.5 ± 16.2 months except for one ipsilateral recurrence at 42 months after surgery. CONCLUSIONS: The modified classification was correlated with surgical outcomes of CBTs and will be helpful for making surgical plans.

10.
Aging (Albany NY) ; 13(4): 6055-6065, 2021 02 17.
Artigo em Inglês | MEDLINE | ID: mdl-33601338

RESUMO

Numerous studies have reported the important role of microRNAs (miRNAs) in human cancers. Although abnormal miR-29b expression has been linked to tumorigenesis in several cancers, its role in cholangiocarcinoma remains largely unknown. We found that miR-29b expression is frequently downregulated in human cholangiocarcinoma QBC939 cells and in clinical tumor samples. In cholangiocarcinoma patients, low miR-29b expression predicts poor overall survival. Overexpression of miR-29b in QBC939 cells inhibited proliferation, induced G1 phase cycle arrest, and promoted apoptosis. Methylation-specific PCR (MSP) analysis revealed a decreased methylation imprint at the promoter of the cell cycle inhibitor gene CDKN2B in cells overexpressing miR-29b. After identifying the DNA methyltransferase DNMT3B as a putative miR-29b target, luciferase reporter assays confirmed a suppressive effect of miR-29b on DNMT3B expression. Accordingly, we detected an inverse correlation between miR-29b and DNMT3B expression in clinical cholangiocarcinoma specimens. In QBC939 cells, DNMT3B overexpression promoted proliferation and inhibited apoptosis. DNMT3B silencing, in turn, led to increased CDKN2B expression. We also observed significant growth arrest in subcutaneous tumors formed in nude mice by QBC939 cells overexpressing miR-29b. These findings suggest miR-29b functions as a tumor suppressor in cholangiocarcinoma by relieving DNMT3B-mediated repression of CDKN2B expression.

11.
J Clin Lab Anal ; 35(4): e23724, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33543804

RESUMO

BACKGROUND: This article is to explore changes in levels of coagulation parameters in different trimesters among healthy pregnant women in China. METHODS: A total of 760 eligible women were enrolled (first-trimester group: n = 183, second-trimester group: n = 183, third-trimester group: n = 263, non-pregnant group: n = 131). Seven parameters including prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT), fibrinogen (FIB), D-dimer (DD), fibrinogen degradation products (FDP), and antithrombin III (ATIII), of all participants were collected. The non-parametric 2.5th-97.5th percentiles reference intervals were calculated for each parameter. RESULTS: The reference intervals for FIB, PT, APTT, TT, FDP, DD, and ATIII at first trimester were 2.11-4.32 g/L, 10.90-13.85 s, 24.60-39.28 s, 12.95-15.88 s, 0.04-2.55 µg/mL, 0.03-1.15 µg/mL, and 75.57%-125.31%, respectively. The reference intervals at second trimester were 2.31-4.77 g/L, 9.70-12.64 s, 24.16-35.43 s, 12.95-15.88 s, 0.15-7.40 µg/mL, 0.08-2.13 µg/mL, and 74.35%-119.28%, respectively. For the third-trimester, the intervals were 2.39-4.96 g/L, 9.20-11.95 s, 23.90-35.51 s, 13.41-18.00 s, 0.55-13.43 µg/mL, 0.15-3.60 µg/mL, and 71.61%-118.29%, respectively. The third-trimester group showed decreased PT, APTT, and ATIII and increased FIB, TT, DD and FDP as compared with the other groups. CONCLUSION: In this study, level changes of coagulation parameters in different trimesters were observed. And the ranges for coagulation parameters were presented, which may provide some reference for clinicians to more accurately monitor the coagulation and fibrinolytic system in pregnant women.

12.
Nanoscale ; 2021 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-33599650

RESUMO

Photocatalytic overall water splitting to simultaneously obtain abundant hydrogen and oxygen is still the mountain that stands in the way for the practical applications of hydrogen energy, in which composite semiconductor photocatalysts are critical for providing both electrons and holes to promote the following redox reaction. However, the interface between different components forms a deplete layer to hinder the charge transfer to a large extent. In order to enhance the charger transfer from an interface to the surface and promote the spatial separation of electron-hole pairs, a built-in electric field induced by a p-n heterojunction emerges as the best choice. As a touchstone, a p-n heterojunction of TiO2/BiOBr with a strong built-in electric field has been constructed, which presents a wide spectrum response owing to its interleaved band gaps after composition. The built-in electric field greatly enhances the separation and transportation of photogenerated carriers, resulting in fluorescence quenching due to the carrier recombination. The sample also displayed exceptional photoelectron responses: its photocurrent density (43.3 µA cm-2) was over 10 times that of TiO2 (3.5 µA cm-2) or BiOBr (4.2 µA cm-2). In addition, the sample with a molar ratio of 3 : 1 between TiO2 and BiOBr showed the best photocatalytic overall water splitting performance under visible light (λ > 420 nm): the hydrogen and oxygen production rate were 472.7 µmol gcat.-1 h-1 and 95.7 µmol gcat.-1 h-1, respectively, which are the highest values under visible light without other cocatalysts to have been reported in literature for the photocatalyst.

13.
Soc Sci Med ; 270: 113670, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33450469

RESUMO

Initially implemented in 2014 in some U.S. states, the Medicaid expansions under the Affordable Care Act (ACA) aimed to make health insurance coverage more accessible to the low-income population. This paper aims to quantify the impact of the ACA Medicaid expansions on insurance coverage among racial/ethnic minorities, immigrants, single mothers, veterans, and low-education whites-i.e., the sectors of the population identified with some of the highest healthcare needs. We focus on individuals 18-64 years of age earning 138% or less of the federal poverty level from the American Community Survey, 2010-2018 (n = 2,927,402). We use difference-in-differences (DD) and difference-in-difference-in-differences (DDD) approaches with propensity scores matched comparison groups to estimate pre-post ACA insurance coverage differences between individuals living in states that participated in the ACA Medicaid expansions and those living in non-participating states, and to estimate if such differences vary across subgroups. We find that insurance coverage rates increased for all subgroups; yet, the ACA benefits have not been evenly distributed across them. Low-education whites, non-Hispanic whites, females, and non-Hispanic Native Americans exhibited the highest improvements in insurance coverage. Our results contribute to the understanding of recent trends in racial and socioeconomic disparities in healthcare and the appropriate policy prescriptions to ameliorate them.

14.
Photodiagnosis Photodyn Ther ; 33: 102178, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33429096

RESUMO

A novel aromatic-imide-based, thermally activated delayed fluorescence material nano-micelle (TADF-NM) compound was prepared after being encapsulated with DSPE-mPEG2000 amphiphilic copolymers. TADF-NM has preferential characteristics such as biocompatibility, non-toxic and targeted ability, and importantly TADF-NM efficiently isolated oxygen to enhance the fluorescence lifetime, and prevented quenching for using time-resolved fluorescence imaging (TRFI) in tumor cells. The fluorescence lifetime of TADF-NM was about 212 µs in PBS and 112 µs in tumor cells, which was the longest in fluorescence lifetime images based on TADF materials. These studies have shown that TADF-NM have excellent potential ability to overcome the interference of auto-fluorescence while being applied in confocal fluorescence tumor imaging.

15.
JAMA Oncol ; 7(3): 361-369, 2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-33443541

RESUMO

Importance: There is no current consensus on the role of chemotherapy in addition to radiation for postoperative adjuvant treatment of patients with early-stage cervical cancer with adverse pathological factors. Objective: To evaluate the clinical benefits of sequential chemoradiation (SCRT) and concurrent chemoradiation (CCRT) compared with radiation alone (RT) as a postoperative adjuvant treatment in early-stage cervical cancer. Design, Setting, and Participants: After radical hysterectomy at 1 of 8 participating hospitals in China, patients with FIGO (International Federation of Gynecology and Obstetrics) stage IB to IIA cervical cancer with adverse pathological factors were randomized 1:1:1 to receive adjuvant RT, CCRT, or SCRT. Data were collected from February 2008 to December 2018. Interventions: Patients received adjuvant RT (total dose, 45-50 Gy), CCRT (weekly cisplatin, 30-40 mg/m2), or SCRT (cisplatin, 60-75 mg/m2, plus paclitaxel, 135-175 mg/m2) in a 21-day cycle, given 2 cycles before and 2 cycles after radiotherapy, respectively. Main Outcomes and Measures: The primary end point was the rate of disease-free survival (DFS) at 3 years. Results: A total of 1048 women (median [range] age, 48 [23-65] years) were included in the analysis (350 in the RT group, 345 in the CCRT group, and 353 in the SCRT group). Baseline demographic and disease characteristics were balanced among the treatment groups except that the rate of lymph node involvement was lowest in the RT group (18.3%). In the intention-to-treat population, SCRT was associated with a higher rate of DFS than RT (3-year rate, 90.0% vs 82.0%; hazard ratio [HR], 0.52; 95% CI, 0.35-0.76) and CCRT (90.0% vs 85.0%; HR, 0.65; 95% CI, 0.44-0.96). Treatment with SCRT also decreased cancer death risk compared with RT (5-year rate, 92.0% vs 88.0%; HR, 0.58; 95% CI, 0.35-0.95) after adjustment for lymph node involvement. However, neither DFS nor cancer death risk was different among patients treated with CCRT or RT. Conclusions and Relevance: In this randomized clinical trial, conducted in a postoperative adjuvant treatment setting, SCRT, rather than CCRT, resulted in a higher DFS and lower risk of cancer death than RT among women with early-stage cervical cancer. Trial Registration: ClinicalTrials.gov Identifier: NCT00806117.

16.
BMC Infect Dis ; 21(1): 124, 2021 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-33509123

RESUMO

BACKGROUND: Kidney involvement of visceral Leishmaniasis is previously reported, but knowledge is limited. Hypergammaglobulinemia is common in visceral leishmaniasis patients. Whether hypergammaglobulinemia after leishmaniasis depletion can cause kidney injury is not well reported yet. CASE PRESENTATION: We reported a patient who recovered from visceral Leishmaniasis but showed persistent hypergammaglobulinemia and elevated urinary protein. Kidney biopsy showed glomerular hypertrophy with mild segmental mesangial proliferation without tubulointerstitial involvement in light microscopy. No immune complex deposit was found in the mesangial area by neither immunofluorescent staining nor electronic microscope. Increased lysosomes were observed in proximal tubules by electronic microscope. Valsartan was administered to decrease urinary protein, and no immune-suppressive therapy was added. The urinary protein and serum IgG level gradually dropped, and serum creatinine level remained stable during three- month follow up. CONCLUSIONS: Hypergammaglobulinemia is unlikely to cause renal structural or functional damage in the short term. Angiotensin blockade significantly reduced urine protein, with a minor effect on IgG elimination.


Assuntos
Hipergamaglobulinemia/etiologia , Leishmaniose Visceral/complicações , Proteinúria/etiologia , Adulto , Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Humanos , Hipergamaglobulinemia/tratamento farmacológico , Hipergamaglobulinemia/patologia , Rim/patologia , Masculino , Proteinúria/tratamento farmacológico , Proteinúria/patologia , Resultado do Tratamento , Valsartana/uso terapêutico
17.
Artigo em Inglês | MEDLINE | ID: mdl-33370688

RESUMO

C-005 is a novel third-generation EGFR tyrosine kinase inhibitor for the treatment of non-small cell lung cancer (NSCLC). To support its clinical trial, we developed a rapid and sensitive bioanalytical method based on ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) technique for the quantification of C-005 and its major metabolite in NSCLC patients following international bioanalytical guidelines. After a simple and quick protein precipitation step, the supernatant was injected to a Waters Acquity BEH C18 column (2.1 × 50 mm i.d., 1.7 mm), and the column was eluted with a gradient of buffer A (5 mM ammonium acetate and 0.1% formic acid in water) and buffer B (formic acid-acetonitrile (1:1000, v/v)). The eluates were subsequently detected by an AB QTRAP 5500 mass spectrometer with electrospray ionization using multiple-reaction monitoring mode. The method showed good linearity from 2.00 to 1000 ng/mL for C-005 and 1.00 to 500 ng/mL for M1. In conclusion, the validation results demonstrated the robustness of the method and its well-poised to support the first-in-patient study of C-005 in NSCLC patients.

18.
Medicine (Baltimore) ; 99(49): e23492, 2020 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-33285755

RESUMO

RATIONALE: Understanding the association between Henoch-Schönlein purpura (HSP) and malignancy is essential for early diagnosis and treatment of the potential lethal disease. To the best of our knowledge, there has been only one published case of HSP coexisting with oesophageal cancer. Here, we report another patient diagnosed with HSP and oesophageal squamous carcinoma simultaneously. PATIENT CONCERNS: A 60-year-old Chinese male was referred to our hospital because of intermittent abdominal pain, abdominal distension, melena, lower extremities purpura. Positive laboratory values included pancytopenia, microscopic hematuria, nephrotic proteinuria, hematochezia, hypoalbuminemia, hyperlipidaemia, hypocomplementemia, and increased levels of hepatobiliary enzymes and immunoglobulin (Ig) A. Gastrocolonoscopy showed multiple erosion lesion on descending duodenum, terminal ileum, and ileal flap. Biopsy of these lesions suggested non-specific inflammation. DIAGNOSES: HSP (IIIb type) was diagnosed based on renal pathology examination in accordance with the International Study of Kidney Disease in Children (ISKDC) classification. Liver biopsy confirmed the diagnosis of nodular cirrhosis (Ishak 5). Gastroscopy unintentionally revealed three oesophagus lesions. Pathology study suggested intermediate differentiated squamous cell carcinoma (cTNM IB). INTERVENTIONS: Before admission, he was administered intravenous Ig 10 g once daily(qd) for 10 days, methylprednisolone 40 mg qd for a week, followed by prednisolone 50 mg qd for almost 8 weeks. Endoscopic submucosal dissection (ESD) was performed to remove all lesions with negative margin after prednisolone was tapered (5 mg per week until 10 mg qd). OUTCOMES: Despite prednisone being tapered to 2.5 mg qd within 2 months, complete remission of HSP and esophageal malignancy was achieved after the resection of the esophagus lesions during 12 months follow-up. LESSONS: We report a rare case of oesophageal squamous cell carcinoma initially presented as HSP. This case suggests the importance of evaluating adult patients with HSP for an underlying malignancy.

19.
Oxid Med Cell Longev ; 2020: 8184314, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33274006

RESUMO

Diabetic cataract is a common complication of diabetes. The epithelial-mesenchymal transition (EMT) of lens epithelial cells (LECs) is a key event in the development of diabetic cataracts. Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) has been reported to be highly expressed in different tissues of diabetic patients. This study is aimed at investigating the function and mechanism of MALAT1 in the regulation of EMT in human LECs under high glucose conditions. MALAT1, α-smooth muscle actin (α-SMA), fibronectin (FN), and nuclear factor erythroid-derived 2-like 2 (NRF2) were highly expressed in the LECs of diabetic cataract patients and in the human LECs under high glucose conditions; meanwhile, the decreased expressions of E-cadherin and zonula occludens 1 (ZO-1) were detected. Knockdown of MALAT1 could significantly reduce ROS, prevent EMT, arrest S phase cell cycle, and suppress the expression of total NRF2 and its nucleus translocation in LECs. Furthermore, after NRF2 was knocked down, total NRF2, α-SMA, and FN in cells, and NRF2, Notch intracellular domain (NICD), and Snail were decreased in the nucleus. Using bioinformatics methods, we predicted that MALAT1 and NRF2 shared the same microRNA-144-3p (miR-144-3p) combining site. Luciferase reporter coupled with qRT-PCR assays revealed that miR-144-3p was a target of MALAT1, which was confirmed to downregulate miR-144-3p in the LECs. In addition, after transfection of miR-144-3p mimics or inhibitor, western blot assay demonstrated that miR-144-3p negatively regulated the expression of total NRF2, α-SMA, and FN in cells, and NRF2, NICD, and Snail in the nucleus without affecting Kelch-like ECH-associated protein 1 (KEAP1). Finally, we confirmed that transfection of shMALAT1 inhibited NRF2 expression, and its mediated EMT could be rescued by miR-144-3p inhibitor; transfection of pcDNA3.1-MALAT1 promoted NRF2 expression, and its mediated EMT could be reversed by miR-144-3p inhibitor. In summary, we demonstrate that MALAT1 regulates miR-144-3p to facilitate EMT of LECs via the ROS/NRF2/Notch1/Snail pathway.

20.
Drug Des Devel Ther ; 14: 4835-4843, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33204069

RESUMO

Purpose: Precise and timely detection of methotrexate (MTX) concentration played a key role in high-dose MTX individualization therapy in acute lymphoblastic leukemia (ALL) children to avoid serious adverse effects or nonresponse. This report described a sensibility and validation of ultra-high performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) method for therapeutic drug monitoring (TDM) of methotrexate concentration in children's plasma. Methods: One-step protein precipitation of samples was accomplished by adding 200 µL of acetonitrile to 100 µL of plasma sample. The separation of plasma samples was carried out on a ZORBAX Eclipse Plus C18 Rapid Resolution HD column with gradient elution using a mobile phase constituted of acetonitrile and 1% formic acid. The detection was executed by electrospray ionization (ESI) of triple quadrupole tandem mass spectrometer (TQMS) in the multiple reaction monitoring (MRM) mode with the transitions m/z 455.2 → 307.9 for methotrexate and m/z 458.2 → 311.2 for IS, separately. Linear concentration range of the calibration curve was 44-11,000 nmol/L and 44 nmol/L was the lower limit of quantification. Results: The methotrexate elution time was at 1.577 min, and the overall running time was only 3.3 min. The intra- and interday precision for all the analysis results was within 11.24%, and mean recoveries rate of methotrexate exceeded 87.98%. Conclusion: The described and fully validated UHPLC-MS/MS method was successfully applied in clinical TDM after infusion of high-dose methotrexate 1-5 g/m2 to 41 childpatients.

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