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1.
Leuk Res ; 86: 106226, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31541941

RESUMO

To summarize the clinical characteristics and prognostic factors of Chinese patients with systemic light chain amyloidosis with liver involvement. We retrospectively analyzed the clinical features and natural history data of 102 patients diagnosed with systemic light chain amyloidosis with liver involvement at Peking Union Medical College Hospital between March 2007 and May 2018. More than 95% of patients showed the involvement of other organs. Kidney and heart were the most frequently involved organs, accounting for 71.6% and 68.6% of cases, respectively. Hepatomegaly was the most frequently observed physical sign, accounting for 67.6% of cases. Elevated levels of alkaline phosphatase (ALP) and gamma-glutamyl transferase (GGT) were frequently observed, accounting for 85.3% and 88.2% of cases, respectively. A significantly better prognosis was observed in patients with normal total bilirubin levels, as compared with those with elevated levels of total bilirubin. Patients in the normal total bilirubin group showed a significantly better progression-free survival (PFS) (38 months) as compared the elevated total bilirubin group (4 months; P < 0.001). The median overall survival (OS) in the normal total bilirubin group was not reached compared with the elevated total bilirubin group (4 months, P < 0.001). Notably, the early death rate was significantly lower in the normal total bilirubin group as compared to the elevated total bilirubin group (14.5% vs 48.5%, P < 0.001). In conclusion, the elevation of total bilirubin indicated an early death and worse PFS and OS. Early diagnosis is therefore essential, and requires appropriate treatment and intensive care.

2.
Int J Biol Macromol ; 140: 196-205, 2019 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-31430489

RESUMO

A porous microsphere with good biocompatibility was fabricated based on collagen (COL) and bacterial cellulose (BC). The adsorption and release behaviors of the COL/BC porous microspheres were studied using BSA as the model protein, and employing quasi-primary, quasi-secondary, and Kannan-Sundaram intragranular diffusion models, zero-order, first-order, Higuchi and Korsmeyer-Peppas models. The results showed that the COL/BC porous microspheres are beneficial to the proliferation of MC3T3 E1-cells. The linear Langmuir equation can accurately describe the adsorption equilibrium relationship of BSA to the COL/BC microspheres. The pseudo-second-order model can more accurately explain and predict the membrane diffusion kinetics of BSA than both pseudo-primary-order and Kannan-Sundaram intragranular diffusion models. The adsorption rate was affected by both membrane and intragranular diffusions. The drug release behavior indicated that the microsphere-loaded BSA was primarily adsorbed at the inner wall of the pore, and exhibited the characteristics of a scaffold-based matrix meanwhile. The drug release kinetics can be accurately described by the first-order release model. The present study elucidated the mechanism of drug adsorption and release of COL/BC porous microspheres and provided a theoretical basis for its application in controlled release technology.

3.
JAMA Netw Open ; 2(5): e193348, 2019 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-31050781

RESUMO

Importance: Thyrotoxic periodic paralysis (TPP) is a potentially lethal complication of hyperthyroidism. However, only 1 specific susceptibility locus for TPP has been identified. Additional genetic determinants should be detected so that a prediction model can be constructed. Objective: To investigate the genetic architecture of TPP and distinguish TPP from Graves disease cohorts. Design, Setting, and Participants: This population-based case-control study used a 2-stage genome-wide association study to investigate the risk loci of TPP and weighted genetic risk score to construct a TPP prediction model with data from a Chinese Han population recruited in hospitals in China from March 2003 to December 2015. The analysis was conducted from November 2014 to August 2016. Main Outcomes and Measures: Loci specifically associated with TPP risk and those shared with Graves disease and prediction model of joint effects of TPP-specific loci. Results: A total of 537 patients with TPP (mean [SD] age, 35 [11] years; 458 male) 1519 patients with Graves disease and no history of TPP (mean [SD] age, 38 [13] years; 366 male), and 3249 healthy participants (mean [SD] age, 46 [10] years; 1648 male) were recruited from the Han population by hospitals throughout China. Two new TPP-specific susceptibility loci were identified: DCHS2 on 4q31.3 (rs1352714: odds ratio [OR], 1.58; 95% CI, 1.35-1.85; P = 1.24 × 10-8) and C11orf67 on 11q14.1 (rs2186564: OR, 1.50; 95% CI, 1.29-1.74; P = 2.80 × 10-7). One previously reported specific locus was confirmed on 17q24.3 near KCNJ2 (rs312729: OR, 2.08; 95% CI, 1.83-2.38; P = 8.02 × 10-29). Meanwhile, 2 risk loci (MHC and Xq21.1) were shared by Graves disease and TPP. After 2 years of treatment, the ratio of persistent thyrotropin receptor antibody positivity was higher in patients with TPP than in patients with Graves disease and no history of TPP (OR, 3.82; 95% CI, 2.04-7.16; P = 7.05 × 10-6). The prediction model using a weighted genetic risk score and 11 candidate TPP-specific single-nucleotide polymorphisms had an area under the curve of 0.80. Conclusions and Relevance: These findings provide evidence that TPP is a novel molecular subtype of Graves disease. The newly identified loci, along with other previously reported loci, demonstrate the growing complexity of the heritable contribution to TPP pathogenesis. A complete genetic architecture will be helpful to understand the pathophysiology of TPP, and a useful prediction model could prevent the onset of TPP.

4.
Anticancer Agents Med Chem ; 19(6): 731-739, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30848214

RESUMO

BACKGROUND: Pemetrexed (PMT) is a multitargeted antifolate agent that is used for treating patients with Non-Small Cell Lung Cancer (NSCLC). However, patients have presented clinical responses of drug resistance to PMT. OBJECTIVE: This study aimed to explore the underlying mechanisms of PMT resistance in NSCLC cells. METHODS: PMT-resistant NCI-H460/PMT cells were established by treating with PMT in a concentrationescalation manner. MTT assay and colony formation were performed to detect cell proliferation. Immunofluorescence was used to detect the expression of Ki-67. Transwell assay was performed to measure cell migration ability. qPCR and Western blot were used to detect the mRNA and protein expression levels of indicated genes. Small interfering RNAs (siRNA) were used to knockdown ATP binding cassette subfamily B member 1 (ABCB1) and Thymidylate Synthase (TYMS). RESULTS: This study showed that compared with the parental cells, the NCI-H460/PMT cells displayed weakened proliferation and enhanced cell mobility. In addition, the NCI-H460/PMT cells demonstrated cellular senescence, which might result in PMT resistance. The NCI-H460/PMT cells exhibited cross-resistance to other chemotherapeutics, including fluorouracil, paclitaxel, doxorubicin, etoposide and gemcitabine, possibly because of the upregulated expression of ABCB1. However, the ABCB1 knockdown by siRNA failed to eradicate PMT resistance. Moreover, TYMS, a target of PMT, was obviously upregulated in the resistant cells. The genetic silence of TYMS partially abrogated PMT resistance, suggesting that the overexpression of TYMS was a key resistant mechanism of PMT. CONCLUSION: The overexpression of TYMS was an important resistance mechanism of PMT for KRAS-mutated NCI-H460 cells. Cross-resistance to other chemotherapeutics should be considered in addressing PMT resistance.

5.
Bioinformatics ; 35(20): 4129-4139, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-30887023

RESUMO

MOTIVATION: With the abundant medical resources, especially literature available online, it is possible for people to understand their own health status and relevant problems autonomously. However, how to obtain the most appropriate answer from the increasingly large-scale database, remains a great challenge. Here, we present a biomedical question answering framework and implement a system, Health Assistant, to enable the search process. METHODS: In Health Assistant, a search engine is firstly designed to rank biomedical documents based on contents. Then various query processing and search techniques are utilized to find the relevant documents. Afterwards, the titles and abstracts of top-N documents are extracted to generate candidate snippets. Finally, our own designed query processing and retrieval approaches for short text are applied to locate the relevant snippets to answer the questions. RESULTS: Our system is evaluated on the BioASQ benchmark datasets, and experimental results demonstrate the effectiveness and robustness of our system, compared to BioASQ participant systems and some state-of-the-art methods on both document retrieval and snippet retrieval tasks. AVAILABILITY AND IMPLEMENTATION: A demo of our system is available at https://github.com/jinzanxia/biomedical-QA.

6.
J Biosci Bioeng ; 127(6): 698-702, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30709705

RESUMO

Coenzyme Q10 (CoQ10) plays an important role in the human respiratory chain and is widely used as medicine and dietary supplement. To improve the fermentation efficiency of CoQ10, a modified version of atmospheric and room temperature plasma (ARTP) treatment was used to mutate Rhodobacter sphaeroides. Meanwhile, Vitamin K3, a structural analog of CoQ10, was used as an inhibitor for mutant selection. In the first round of screening in 24-well plates, three mutants were obtained, with the production of CoQ10 at 311 mg/L, 307 mg/L, and 309 mg/L, which were increased from the parent's production at 265 mg/L. Furthermore, a second round of mutation and screening was performed based on the mutant strain with the highest production in the first round, leading to the identification of a mutant AR01 with the production of CoQ10 at ∼330 mg/L. Finally, 590 mg/L CoQ10 was obtained for AR01 after 100 h fermentation, which was ∼25.5% higher than that of the original parent strain. It is the first report of ARTP treatment usage for the selection of CoQ10 producing bacteria and the results show that plasma jet, driven by helium-based ARTP, can be a feasible strategy for mutation feeding.


Assuntos
Atmosfera , Mutagênese , Gases em Plasma/farmacologia , Rhodobacter sphaeroides/efeitos dos fármacos , Rhodobacter sphaeroides/genética , Temperatura Ambiente , Ubiquinona/análogos & derivados , Fermentação/efeitos dos fármacos , Mutação , Rhodobacter sphaeroides/metabolismo , Ubiquinona/biossíntese
7.
Hepatobiliary Pancreat Dis Int ; 18(2): 117-124, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30655073

RESUMO

BACKGROUND: Irreversible electroporation (IRE) is a novel ablative technique for hepatobiliary and pancreatic cancers. This review summarizes the data regarding the safety and efficacy of IRE in the treatment of hepatobiliary and pancreatic cancers. DATA SOURCES: Studies were identified by searching PubMed and Embase for articles published in English from database inception through July 31, 2017. For inclusion, each clinical study had to report morbidity and survival data on hepatobiliary and pancreatic cancers treated with IRE and contain at least 10 patients. Studies that met these criteria were included for analysis. Two authors assessed each clinical study for data extraction. The controversial parts were resolved through discussion with seniors. RESULTS: A total of 24 clinical studies were included. Fourteen focused on hepatic ablation with IRE comprising 437 patients with 666 lesions of different tumor types. Two patients (0.5%) died after the IRE procedure. Morbidity of hepatic ablation with IRE ranged from 7% to 35%. Most complications were mild. Complete response for hepatic tumors was reported as 57%-97%. Ten studies with 455 patients focused on pancreatic IRE. The overall mortality of IRE in pancreatic cancer was 2%. Overall severe morbidity of IRE in pancreatic cancer ranged from 0 to 20%. The median overall survival after IRE ranged from 7 to 23 months. Patients treated with IRE combined with surgical resection showed a longer overall survival. CONCLUSIONS: IRE significantly improves the prognosis of advanced hepatobiliary and pancreatic malignances, and companied with less complications. Hence, IRE is a relatively safe and effective non-thermal ablation strategy and potentially recommended as an option for therapy of patients with hepatobiliary and pancreatic malignances.

8.
Phytomedicine ; 52: 32-39, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30599910

RESUMO

BACKGROUND: Non-small cell lung cancer (NSCLC) is one of the leading causes of cancer-related death around the world. Epithelial-mesenchymal transition (EMT) has been documented to increase motility and invasiveness of cancer cells, which promotes cancer metastasis. PURPOSE: This study aims to investigate the inhibitory effects and mechanisms of the dinorditerpenoids and norditerpenoids isolated from the seeds of Podocarpus nagi against transforming growth factor (TGF)-ß1-induced EMT. METHODS: A series of dinorditerpenoids and norditerpenoids were isolated from the seeds of P. nagi. Western blot and quantitative real-time PCR assays were performed to determine the expression levels of relative proteins and mRNA, along with immunofluorescence, Smad-binding element (SBE)-luciferase and chromatin immunoprecipitation (ChIP) assays for the mechanism study. Transwell assays were conducted to determine the effect of the compounds on cell migration and invasion. RESULTS: Nagilactone E (NLE) showed the superior inhibitory effect against TGF-ß1-induced EMT. NLE treatment dramatically inhibited TGF-ß1-induced expression of EMT markers in A549 cells. Mechanism study indicated that NLE markedly suppressed TGF-ß1-induced Smad2 and Smad3 activation and nuclear translocation. SBE-luciferase and ChIP assays showed that NLE inhibited the combining of Smad3 to SBE in the promoters of the cell signaling factors. NLE co-treatment attenuated TGF-ß1-induced up-regulation of the protein and mRNA levels of TGF-ß receptor TßRI. Furthermore, NLE inhibited TGF-ß1-stimulated cell migration and invasion, as well as up-regulation of the key signaling proteins related with migration and invasion. CONCLUSION: NLE inhibited TGF-ß/Smad signaling pathway, thereafter suppressed TGF-ß1-induced EMT, migration and invasion in NSCLC A549 cells.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/patologia , Diterpenos/farmacologia , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Neoplasias Pulmonares/patologia , Fator de Crescimento Transformador beta1/farmacologia , Células A549 , Movimento Celular/efeitos dos fármacos , Gleiquênias/química , Humanos , Invasividade Neoplásica , Sementes/química , Transdução de Sinais/efeitos dos fármacos , Proteína Smad2/metabolismo , Proteína Smad3/metabolismo
9.
Curr Drug Targets ; 2018 11 23.
Artigo em Inglês | MEDLINE | ID: mdl-30468124

RESUMO

Hypoxia, which occurs in most cancer cases, disrupts the efficacy of anticarcinogens. Fortunately, hypoxia itself is a potential target for cancer treatment. Hypoxia-activated prodrugs (HAPs) can be selectively activated by reductase under hypoxia. Some promising HAPs have been already achieved, and many clinical trials of HAPs in different types of cancer are ongoing. However, none of them has been approved in clinic to date. From the studies on HAPs began, some achievements are gotten but more challenges are put forward. In this paper, we reviewed the research progress of HAPs to discuss the strategies for HAPs development. According to the research status and results of these studies, administration pattern, reductase activity, and patient selection need to be taken into consideration to further improve the efficacy of existing HAPs. As the requirement of new drug research and development, design of optimal preclinical models and clinical trials are quite important in HAPs development, while different drug delivery systems and anticancer drugs with different mechanisms can be sources of novel HAPs.

10.
Clin Endocrinol (Oxf) ; 89(6): 840-848, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30176063

RESUMO

OBJECTIVE: We aimed to investigate the six susceptibility loci of GD identified from European population in Chinese Han population and further to estimate the genetic heterogeneity of them in stratification of our GD patients. DESIGN: Dense mapping studies based on GWAS. PATIENTS: A total of 1536 GD patients and 1516 controls in GWAS stage and 1994 GD patients and 2085 controls and 5033 GD patients and 5389 controls in two replication stages. MEASUREMENTS: Based on our previous GWAS data, independently GD-associated SNPs in each region were identified by TagSNP analysis and logistic regression analysis. The association of these SNPs was investigated in 1994 GD patients and 2085 controls, and then, the significantly associated SNPs (P < 0.05) were further genotyped in a second cohort including 5033 GD patients and 5389 controls. RESULTS: After the first replication stage, four SNPs from three regions with Pfirst  < 0.05 were further selected and genotyped in another independent cohort. The association of two SNPs with GD was confirmed in combined Chinese cohorts: rs12575636 at 11q21 (Pcombined  = 7.55 × 10-11 , OR = 1.27) and rs1881145 in TRIB2 at 2p25.1 (Pcombined  = 5.59 × 10-8 , OR = 1.14). Further study disclosed no significant difference for these SNPs between GD subsets. However, eQTL data revealed that SESN3 could be a potential susceptibility gene of GD in 11q21 region. CONCLUSIONS: Out of the six susceptibility loci of GD identified from European population, two risk loci were confirmed in a large Chinese Han population. There is variability in GD genetic susceptibility in different ethnic groups. SESN3 is a potential susceptible gene of GD in 11q21.

11.
Apoptosis ; 23(9-10): 521-531, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30084053

RESUMO

The pseudokinase mixed lineage kinase domain-like protein (MLKL) is a core effector of necroptosis, and its function in necroptosis is widely studied. However, the function of MLKL in apoptosis remains unclear. In the present study, the role of MLKL in chelerythrine (CHE)-promoted apoptosis was studied. A special band of MLKL (i.e., *MLKL) was observed after treatment with CHE. MLKL and *MLKL were accumulated in the nucleus upon treatment with CHE and MLKL silencing reversed the CHE-induced apoptosis. Blockade of CHE-triggered reactive oxygen species (ROS) generation or inhibition of CHE-activated protein kinase-like endoplasmic reticulum kinase (PERK)-eukaryotic initiation factor 2 α subunit (eIF2α) pathway reversed the apoptosis. A decreased ROS level inhibited CHE-mediated nuclear translocation of MLKL and *MLKL and the activation of eIF2α, whereas MLKL or eIF2α silencing did not affect the CHE-triggered ROS generation. Furthermore, MLKL silencing prevented the CHE-activated eIF2α signal, and eIF2α silencing blocked the CHE-induced nuclear translocation of MLKL and *MLKL. Our studies suggested that CHE possibly induces apoptosis through the nuclear translocation of MLKL and *MLKL, which is promoted by a mutual regulation between MLKL and PERK-eIF2α pathway in response to ROS formation. The present study clarified the new function of MLKL in apoptosis.

12.
Chin Med ; 13: 35, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29997684

RESUMO

Cancer is still presenting a serious threat to human health worldwide. The understanding of the complex biology of cancer and the development of oncotherapy have led to increasing treatment approaches such as targeted therapy and immunotherapy. Chinese medicinal herbs have attracted considerable attention due to their potential anticancer effects. Some natural products or formulae from Chinese medicinal herbs with directly or indirectly anticancer effects have been reported. In this article, we summarized the current progression on development of anticancer drugs from Chinese medicinal herbs, toward providing ideas for further development and application of Chinese medicinal herbs in cancer therapy.

13.
Eur J Endocrinol ; 178(6): 623-633, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29650690

RESUMO

OBJECTIVE: Congenital hypothyroidism (CH), the most common neonatal metabolic disorder, is characterized by impaired neurodevelopment. Although several candidate genes have been associated with CH, comprehensive screening of causative genes has been limited. DESIGN AND METHODS: One hundred ten patients with primary CH were recruited in this study. All exons and exon-intron boundaries of 21 candidate genes for CH were analyzed by next-generation sequencing. And the inheritance pattern of causative genes was analyzed by the study of family pedigrees. RESULTS: Our results showed that 57 patients (51.82%) carried biallelic mutations (containing compound heterozygous mutations and homozygous mutations) in six genes (DUOX2, DUOXA2, DUOXA1, TG, TPO and TSHR) involved in thyroid hormone synthesis. Autosomal recessive inheritance of CH caused by mutations in DUOX2, DUOXA2, TG and TPO was confirmed by analysis of 22 family pedigrees. Notably, eight mutations in four genes (FOXE1, NKX2-1, PAX8 and HHEX) that lead to thyroid dysgenesis were identified in eight probands. These mutations were heterozygous in all cases and hypothyroidism was not observed in parents of these probands. CONCLUSIONS: Most cases of congenital hypothyroidism in China were caused by thyroid dyshormonogenesis rather than thyroid dysgenesis. This study identified previously reported causative genes for 57/110 Chinese patients and revealed DUOX2 was the most frequently mutated gene in these patients. Our study expanded the mutation spectrum of CH in Chinese patients, which was significantly different from Western countries.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Hipotireoidismo Congênito/genética , China , Oxidases Duais/genética , Feminino , Fatores de Transcrição Forkhead/genética , Estudos de Associação Genética , Sequenciamento de Nucleotídeos em Larga Escala , Proteínas de Homeodomínio/genética , Humanos , Lactente , Recém-Nascido , Iodeto Peroxidase/genética , Masculino , Proteínas de Membrana/genética , Mutação , Fator de Transcrição PAX8/genética , Linhagem , Receptores da Tireotropina/genética , Análise de Sequência de DNA , Tireoglobulina/genética , Disgenesia da Tireoide/genética , Fator Nuclear 1 de Tireoide/genética , Fatores de Transcrição/genética
14.
Eur J Pharmacol ; 830: 17-25, 2018 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-29680228

RESUMO

Non-small cell lung cancer (NSCLC) is one of the most common forms and leading causes of cancer-related mortality worldwide, and discovery of new effective drugs still remains imperative to improve the survival rate. Nagilactone E (NLE) is a natural product isolated from Podocarpus nagi seeds, which has been used as raw materials for edible oil and industrial oil extraction. This study aimed to investigate the anticancer potential of NLE against NSCLC A549 and NCI-H1975 cells. MTT assay revealed that NLE inhibited the proliferation of A549 and NCI-H1975 cells with IC50s of 5.18 ±â€¯0.49 and 3.57 ±â€¯0.29 µM, respectively. NLE treatment inhibited clone formation in both cancer cell lines. Cell cycle analysis indicated that NLE treatment effectively induced G2 phase cell cycle arrest in A549 and NCI-H1975 cells. NLE downregulated the phosphorylation of cdc2 (Tyr15) and cdc25C (Ser216) as well as the expression level of the protein kinase Wee1 in concentration- and time-dependent manners. In addition, NLE treatment decreased the protein level of Cyclin B1 as well as its nuclear localization, which might decrease the activity of the Cyclin B1/cdc2 complex and induce G2 phase arrest. Long-term NLE treatment also induced caspase-dependent cell apoptosis, as evidenced by increase in Annexin V positive cells and the cleavage of PARP. To sum, NLE inhibited proliferation, induced G2 phase arrest, and triggered caspase-dependent apoptosis in NSCLC cells, suggesting it to be a potential leading compound for cancer treatment.


Assuntos
Antineoplásicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Ciclina B1/metabolismo , Diterpenos/farmacologia , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Neoplasias Pulmonares/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ciclina B1/genética , Regulação para Baixo , Humanos
15.
Medicine (Baltimore) ; 97(2): e9499, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29480839

RESUMO

RATIONALE: Currently, percutaneous catheter drainage (PCD) is regarded as the first-line treatment modality of pyogenic liver abscess. Severe complications associated with PCD were uncommon. Hepatic rupture is an uncommon but life-threatening liver trauma with high mortality. Its management is challenging because a delay in the diagnosis may lead to fatal hemorrhagic shock. To our knowledge, PCD-associated hepatic rupture has never been reported. PATIENT CONCERNS: We report herein a rare case of PCD-associated hepatic rupture. Its clinical courses and our therapeutic approaches are presented. Moreover, the clinical significance, underlying causes, and current views on severe liver trauma management will be discussed briefly. DIAGNOSES: A diabetic patient suffering from fever and malaise was diagnosed with a pyogenic liver abscess. PCD was performed because intravenous antibiotics were ineffective. The patient developed a liver rupture following PCD, with clinical and imaging confirmation but without further progression. INTERVENTIONS: Surgical repair and vascular intervention were both inappropriate. As a result, medical treatments with supportive care were adopted and were found to be effective. OUTCOMES: The patient's condition improved gradually, with stabilized imaging and laboratory performance. He recovered uneventfully during follow-ups. LESSONS: Hepatic rupture should be listed as an extremely rare but severe complication of PCD. Immediate suspicion and effective intervention may avoid an unfavorable consequence.


Assuntos
Cateteres , Drenagem , Abscesso Hepático Piogênico/terapia , Fígado/lesões , Ruptura/etiologia , Idoso , Complicações do Diabetes/diagnóstico por imagem , Drenagem/instrumentação , Humanos , Fígado/diagnóstico por imagem , Abscesso Hepático Piogênico/complicações , Abscesso Hepático Piogênico/diagnóstico por imagem , Masculino
16.
Oncotarget ; 8(56): 96126-96138, 2017 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-29221192

RESUMO

Background: Studies have shown an association of the UNC5D gene with kidney and bladder cancer and neuroblastoma. We investigated whether UNC5D acts as a tumor suppressor in papillary thyroid carcinoma (PTC). Methods: Primary PTC tumors and matched normal thyroid tissues were obtained from 112 patients to detect UNC5D mRNA by real-time PCR. Genomic DNA sequencing was performed to detect BRAF mutation in PTC tumors. The association between UNC5D expression and clinicopathological data from PTC patients was reviewed retrospectively. PTC-derived cancer cell lines TPC-1 and K1 with stable transfection of UNC5D were used to investigate the functions of UNC5D. Flow cytometry, CCK-8, Transwell assay and scratch tests were used to examine cell cycle distribution, proliferation and migration. Results: The expression of UNC5D was significantly decreased in PTC compared with adjacent normal thyroid tissues. Lower UNC5D expression was significantly associated with aggressive tumor behaviors, such as lymph node metastasis and BRAF mutation. Overexpression of UNC5D significantly suppressed malignant cell behaviors, including cell proliferation and migration, as well as tumor growth in vivo. Conclusions: These findings suggest a potential tumor suppressor role of UNC5D in PTC progression; and provide insight into potential clinical relevance for the prognosis of PTC.

17.
Acta Pharmacol Sin ; 38(11): 1512-1520, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28880013

RESUMO

Osimertinib (AZD9291) is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) that has been approved for the treatment of EGFR-mutated non-small cell lung cancer (NSCLC). In NSCLC patients, an EGFR mutation is likely to be correlated with high levels of expression of programmed death ligand-1 (PD-L1). Here, we showed that osimertinib decreased PD-L1 expression in human EGFR mutant NSCLC cells in vitro. Osimertinib (125 nmol/L) markedly suppressed PD-L1 mRNA expression in both NCI-H1975 and HCC827 cells. Pretreatment with the N-linked glycosylation inhibitor tunicamycin, osimertinib clearly decreased the production of new PD-L1 protein probably due to a reduction in mRNA. After blocking transcription and translation processes with actinomycin D and cycloheximide, respectively, osimertinib continued to reduce the expression of PD-L1, demonstrating that osimertinib might degrade PD-L1 at the post-translational level, which was confirmed by a cycloheximide chase assay, revealing that osimertinib (125 nmol/L) decreased the half-life of PD-L1 from approximately 17.8 h and 13.8 h to 8.6 h and 4.6 h, respectively, in NCI-H1975 and HCC827 cells. Pretreatment with the proteasome inhibitors (MG-132 or bortezomib) blocked the osimertinib-induced degradation of PD-L1, but an inhibitor of autophagy (chloroquine) did not. In addition, inhibition of GSK3ß by LiCl prevented osimertinib-induced PD-L1 degradation. The results demonstrate that osimertinib reduces PD-L1 mRNA expression and induces its protein degradation, suggesting that osimertinib may reactivate the immune activity of T cells in the tumor microenvironment in EGFR-mutated NSCLC patients.


Assuntos
Antineoplásicos/farmacologia , Antígeno B7-H1/metabolismo , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Neoplasias Pulmonares/tratamento farmacológico , Mutação , Piperazinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Antígeno B7-H1/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Regulação para Baixo , Regulação Neoplásica da Expressão Gênica , Glicogênio Sintase Quinase 3 beta/metabolismo , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Fosforilação , Complexo de Endopeptidases do Proteassoma , Proteólise , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Fatores de Tempo , Microambiente Tumoral
18.
Sci Rep ; 7(1): 12230, 2017 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-28947756

RESUMO

The U.S. Food and Drug Administration (FDA) approves new drugs every year. Drug targets are some of the most important interactive molecules for drugs, as they have a significant impact on the therapeutic effects of drugs. In this work, we thoroughly analyzed the data of small molecule drugs approved by the U.S. FDA between 2000 and 2015. Specifically, we focused on seven classes of new molecular entity (NME) classified by the anatomic therapeutic chemical (ATC) classification system. They were NMEs and their corresponding targets for the cardiovascular system, respiratory system, nerve system, general anti-infective systemic, genito-urinary system and sex hormones, alimentary tract and metabolisms, and antineoplastic and immunomodulating agents. To study the drug-target interaction on the systems level, we employed network topological analysis and multipartite network projections. As a result, the drug-target relations of different kinds of drugs were comprehensively characterized and global pictures of drug-target, drug-drug, and target-target interactions were visualized and analyzed from the perspective of network models.

19.
Front Immunol ; 8: 1122, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28955339

RESUMO

Persistent activation and inflammation impair immune response and trigger disease progression in HIV infection. Emerging evidence supports the supposition that excessive production of interferon-inducible protein 10 (IP-10), a critical inflammatory cytokine, leads to immune dysfunction and disease progression in HIV infection. In this study, we sought to elucidate the cause of the upregulated production of IP-10 in HIV infection and explore the underlying mechanisms. Bolstering miR-21 levels using mimics resulted in the obvious suppression of lipopolysaccharide (LPS)-induced IP-10 in monocyte leukemia cells THP-1 and vice versa. The analysis of the primary monocytes of HIV patients revealed significantly less miR-21 than in healthy controls; this was opposite to the tendency of IP-10 levels in plasma. The secretion of IP-10 due to LPS stimulation was not affected by miR-21 modulation in the differentiated THP-1 macrophages (THP-1-MA). We found a novel switch, IFN-stimulated gene 15 (ISG15), which triggers the expression of IP-10 and is significantly upregulated during the differentiation of THP-1 into THP-1-MA. The inhibition of ISG15 can restore the regulation of IP-10 by miR-21. In summary, IP-10 expression in monocytes is regulated by miR-21, whereas in macrophages, this fine-tuning is attenuated by the enhanced expression of ISG15. This study paves the way to a comprehensive understanding of the molecular regulatory mechanism of IP-10, a key point in immune intervention strategy.

20.
J Transl Med ; 15(1): 191, 2017 09 12.
Artigo em Inglês | MEDLINE | ID: mdl-28899396

RESUMO

BACKGROUND: A small proportion of HIV-infected patients remain clinically and/or immunologically stable for years, including elite controllers (ECs) who have undetectable viremia (<50 copies/ml) and long-term nonprogressors (LTNPs) who maintain normal CD4+ T cell counts for prolonged periods (>10 years). However, the mechanism of nonprogression needs to be further resolved. In this study, a transcriptome meta-analysis was performed on nonprogressor and progressor microarray data to identify differential transcriptome pathways and potential biomarkers. METHODS: Using the INMEX (integrative meta-analysis of expression data) program, we performed the meta-analysis to identify consistently differentially expressed genes (DEGs) in nonprogressors and further performed functional interpretation (gene ontology analysis and pathway analysis) of the DEGs identified in the meta-analysis. Five microarray datasets (81 cases and 98 controls in total), including whole blood, CD4+ and CD8+ T cells, were collected for meta-analysis. RESULTS: We determined that nonprogressors have reduced expression of important interferon-stimulated genes (ISGs), CD38, lymphocyte activation gene 3 (LAG-3) in whole blood, CD4+ and CD8+ T cells. Gene ontology (GO) analysis showed a significant enrichment in DEGs that function in the type I interferon signaling pathway. Upregulated pathways, including the PI3K-Akt signaling pathway in whole blood, cytokine-cytokine receptor interaction in CD4+ T cells and the MAPK signaling pathway in CD8+ T cells, were identified in nonprogressors compared with progressors. In each metabolic functional category, the number of downregulated DEGs was more than the upregulated DEGs, and almost all genes were downregulated DEGs in the oxidative phosphorylation (OXPHOS) and tricarboxylic acid (TCA) cycle in the three types of samples. CONCLUSIONS: Our transcriptomic meta-analysis provides a comprehensive evaluation of the gene expression profiles in major blood types of nonprogressors, providing new insights in the understanding of HIV pathogenesis and developing strategies to delay HIV disease progression.


Assuntos
Progressão da Doença , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Infecções por HIV/genética , Infecções por HIV/patologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Regulação para Baixo/genética , Ontologia Genética , Humanos , Redes e Vias Metabólicas/genética , Transcriptoma/genética , Regulação para Cima/genética
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