Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 98
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Artigo em Inglês | MEDLINE | ID: mdl-32035737

RESUMO

Diabetes mellitus (DM) is a devastating metabolic disease. Stem cell therapy provides great hope to all diabetic patients. Umbilical cord (UC) Wharton's jelly mesenchymal stem cells (WJ-MSCs) specifically provides a potential cell therapy for DM. In this article, we discuss major advantages of WJ-MSCs and challenges facing their clinical utility in DM.

2.
Ann Vasc Surg ; 2020 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-32007594

RESUMO

PURPOSE: Endovascular intervention for Chronic Symptomatic Type B Aortic Dissection (CS-TBAD) induces aortic wall stress with negative haemodynamic cardiovascular consequences. CSTBAD risks increasing morbidity and mortality due to septum maturation with significant impact on false lumen modulation, and partial lumen thrombosis conveying the worst outcome. The aim of the TIGER technique is total aortic remodeling with true lumen expansion, false lumen regression and complete thrombosis, and stabilization of overall aortic diameter. METHODS: We report five cases of aortic dissection with a mean follow-up of 16 months (6-28 months). All had aneurysmal dilation, with three having acute pan aortic dissection and two having CS-TBAD. All were managed by sTaged HybrId sinGle lumEn Reconstruction (TIGER). Our first approach was to create one single lumen from the supra-celiac, infra-diaphragmatic aorta to both common iliac arteries with open surgical patching of the visceral arteries; then we performed a TEVAR three months later. RESULTS: Three patients required a left subclavian artery chimney graft and one required bilateral subclavian to carotid artery transposition. No spinal drainage was required, and all patients had intraoperative transoesophageal echo for wire guidance. We had no aortic rupture or retrograde type A dissection, and we experienced no renal, visceral, cardiac, pulmonary or spinal complications. All patients, but one, went off their antihypertensive medication. All patients had normal estimated Glomerular Filtration Rate (eGFR) postoperatively, and they all demonstrated accelerated aortic modulation. CONCLUSION: TIGER was not only effective at the semi-acute stage to initiate remodeling and prevent malperfusion, it also facilitated a straightforward TEVAR at stage 2, which was made easier by avoiding visceral branch stenting. Moreover, it decreased the length of aortic segment, which was stented, thereby avoiding critical shattering, branch dislodgment and visceral compromise; spinal ischaemia; and negative cardiovascular consequences.

3.
Sci Rep ; 10(1): 2877, 2020 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-32051507

RESUMO

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

4.
Am J Clin Dermatol ; 21(1): 119-131, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31823222

RESUMO

BACKGROUND: Atopic dermatitis is a chronic inflammatory condition with substantial burden and limited treatment options for adolescents with moderate-to-severe disease. Significantly more patients treated with dupilumab vs. placebo achieved Investigator's Global Assessment 0/1 at week 16. OBJECTIVE: The objective of this study was to assess the impact of dupilumab treatment vs. placebo on the achievement of clinically meaningful improvements in atopic dermatitis signs, symptoms and quality of life. METHODS: R668-AD-1526 LIBERTY AD ADOL was a randomized, double-blinded, parallel-group, phase III clinical trial. Two hundred and fifty-one adolescents with moderate-to-severe atopic dermatitis received dupilumab 300 mg every 4 weeks (q4w; n = 84), dupilumab 200 or 300 mg every 2 weeks (q2w; n = 82), or placebo (n = 85). A post-hoc subgroup analysis was performed on 214 patients with Investigator's Global Assessment > 1 at week 16. Measures of atopic dermatitis signs, symptoms, and quality of life were assessed. Clinically meaningful improvement in one or more of three domains of signs, symptoms, and quality of life was defined as an improvement of ≥ 50% in Eczema Area and Severity Index, ≥ 3 points in Peak Pruritus Numerical Rating Scale, or ≥ 6 points in the Children's Dermatology Life Quality Index from baseline. RESULTS: Of patients receiving dupilumab q2w, 80.5% [66/82] experienced clinically meaningful improvements in atopic dermatitis signs, symptoms, or quality of life at week 16 (vs. placebo, 20/85 [23.5%], difference 57.0% [95% confidence interval 44.5-69.4]; q4w vs. placebo, 53/84 [63.1%], difference 39.6% [95% confidence interval 25.9-53.3]; both p < 0.0001). Results were similar in adolescents with Investigator's Global Assessment > 1 at week 16 (q2w, 46/62 [74.2%] vs. placebo, 18/83 [21.7%], difference 52.5% [95% confidence interval 38.5-66.6]; q4w, 38/69 [55.1%] vs. placebo, difference 33.4% [95% confidence interval 18.7-48.1]; both p < 0.0001). CONCLUSIONS: Dupilumab provided clinically meaningful improvements in signs, symptoms, and quality of life in adolescents with moderate-to-severe atopic dermatitis among patients with Investigator's Global Assessment > 1 at week 16. Treatment responses should be interpreted in the context of such clinically relevant patient-reported outcome measures. TRIAL REGISTRATION: ClinicalTrials.gov; NCT03054428. Adolescents with atopic dermatitis: does dupilumab improve their signs, symptoms, and quality of life? (MP4  212916 kb).

5.
Sci Rep ; 9(1): 17470, 2019 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-31767951

RESUMO

Circulating tumor cells (CTCs) shed from solid tumors can serve as a minimally invasive liquid biopsy for monitoring disease progression. Because CTCs are rare and heterogeneous, their biological properties need to be investigated at the single cell level, which requires efficient ways to isolate and analyze live single CTCs. Current methods for CTC isolation and identification are either performed on fixed and stained cells or need multiple procedures to isolate pure live CTCs. Here, we used the AccuCyte-RareCyte system to develop a Protocol for Integrated Capture and Retrieval of Ultra-pure single live CTCs using Negative and positive selection (PIC&RUN). The positive selection module of PIC&RUN identifies CTCs based on detection of cancer surface markers and exclusion of immune markers. Combined with a two-step cell picking protocol to retrieve ultrapure single CTCs, the positive selection module is compatible for downstream single cell transcriptomic analysis. The negative selection module of PIC&RUN identifies CTCs based on a live cell dye and the absence of immune markers, allowing retrieval of viable CTCs that are suitable for ex vivo culture. This new assay combines the CTC capture and retrieval in one integrated platform, providing a valuable tool for downstream live CTC analyses.

6.
JAMA Dermatol ; 2019 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-31693077

RESUMO

Importance: Adolescents with atopic dermatitis (AD) have high disease burden negatively affecting quality of life, with limited treatment options. The efficacy and safety of dupilumab, a monoclonal antibody, approved for treatment in adolescent patients with inadequately controlled AD, remain unknown in this patient population. Objective: To assess the efficacy and safety of dupilumab monotherapy in adolescents with moderate to severe inadequately controlled AD. Design, Setting, and Participants: A randomized, double-blind, parallel-group, phase 3 clinical trial was conducted at 45 US and Canadian centers between March 21, 2017, and June 5, 2018. A total of 251 adolescents with moderate to severe AD inadequately controlled by topical medications or for whom topical therapy was inadvisable were included. Interventions: Patients were randomized (1:1:1; interactive-response system; stratified by severity and body weight) to 16-week treatment with dupilumab, 200 mg (n = 43; baseline weight <60 kg), or dupilumab, 300 mg (n = 39; baseline weight ≥60 kg), every 2 weeks; dupilumab, 300 mg, every 4 weeks (n = 84); or placebo (n = 85). Main Outcomes and Measures: Proportion of patients with 75% or more improvement from baseline in Eczema Area and Severity Index (EASI-75) (scores range from 0 to 72, with higher scores indicating greater severity) and Investigator's Global Assessment (IGA) 0 or 1 on a 5-point scale (scores range from 0 to 4, with higher scores indicating greater severity) at week 16. Results: A total of 251 patients were randomized (mean [SD] age, 14.5 [1.7] years; 148 [59.0%] male). Of 250 patients with data available on concurrent allergic conditions, most had comorbid type 2 diseases (asthma, 134 [53.6%]; food allergies, 60.8%; allergic rhinitis, 65.6%). A total of 240 patients (95.6%) completed the study. Dupilumab achieved both coprimary end points at week 16. The proportion of patients with EASI-75 improvement from baseline increased (every 2 weeks, 41.5%; every 4 weeks, 38.1%; placebo, 8.2%) with differences vs placebo of 33.2% (95% CI, 21.1%-45.4%) for every 2 weeks and 29.9% (95% CI, 17.9%-41.8%) for every 4 weeks (P < .001). Efficacy of the every-2-week regimen was generally superior to the every-4-week regimen. Patients in the dupilumab arms had higher percentage values of conjunctivitis (every 2 weeks, 9.8%; every 4 weeks, 10.8%; placebo, 4.7%) and injection-site reactions (every 2 weeks, 8.5%; every 4 weeks, 6.0%; placebo, 3.5%), and lower nonherpetic skin infections (every 2 weeks, 9.8%; every 4 weeks, 9.6%; placebo, 18.8%). Conclusions and Relevance: In this study, dupilumab significantly improved AD signs, symptoms, and quality of life in adolescents with moderate to severe AD, with an acceptable safety profile. Placebo-corrected efficacy and safety of dupilumab were similar in adolescents and adults. Trial Registration: ClinicalTrials.gov identifier: NCT03054428.

8.
Toxicol Appl Pharmacol ; 383: 114780, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31618661

RESUMO

Radiotherapy is a common treatment modality for cancer patients; however, its use is limited by decreasing the probability of fertility in male cancer survivors. Therefore, this study aimed to define the capability of coenzyme Q10 (CoQ10), a potent stimulator of mitochondrial function, in attenuating ionizing radiation (IR)-induced spermatogenesis impairments. Male Sprague Dawley rats were exposed to a single dose of ϒ-rays (10 Gy) and/or treated with CoQ10 (10 mg/kg, orally, for 2 consecutive weeks). IR mediated irregular seminiferous tubules, which were emerged with typical morphological characteristics of apoptosis, and nuclear condensation, while CoQ10 significantly preserved the testicular structure and maintained spermatogenesis, which was displayed by higher levels of serum estradiol and testosterone. CoQ10 remarkably augmented sperm count, motility, and viability while diminished the rate of sperm-defects relatively to their counterparts after IR exposure. CoQ10 modulations in reproductive parameters were underpinned by attenuating IR-induced oxidative stress as evidenced by decreasing lipid peroxidation and increasing the antioxidant enzymes glutathione peroxidase and glutathione-s-transferase activities, and glutathione level. Supporting the involvement of CoQ10 in the anti-apoptotic response, the reduced mRNA expression levels of p53, Puma, and Bax accompanied by the increased Bcl-2 mRNA expression were observed. Subsequently, CoQ10 ameliorated the mitochondria dependent apoptotic pathway through diminishing Bax/Bcl-2 ratio, caspase-3 protein expression, and DNA fragmentation in testes of irradiated rats. Taken together, our findings showed that CoQ10 conserved against IR-induced steroidogenesis disruption through subsiding mitochondria-mediated oxidative stress injury in germinal cells.

9.
Adv Healthc Mater ; 8(17): e1900564, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31328434

RESUMO

Bacterial invasion into eukaryotic cells and the establishment of intracellular infection has proven to be an effective means of resisting antibiotic action, as anti-infective agents commonly exhibit a poor permeability across the host cell membrane. Encapsulation of anti-infectives into nanoscaled delivery systems, such as liposomes, is shown to result in an enhancement of intracellular delivery. The aim of the current work is, therefore, to formulate colistin, a poorly permeable anti-infective, into liposomes suitable for oral delivery, and to functionalize these carriers with a bacteria-derived invasive moiety to enhance their intracellular delivery. Different combinations of phospholipids and cholesterol are explored to optimize liposomal drug encapsulation and stability in biorelevant media. These liposomes are then surface-functionalized with extracellular adherence protein (Eap), derived from Staphylococcus aureus. Treatment of HEp-2 and Caco-2 cells infected with Salmonella enterica using colistin-containing, Eap-functionalized liposomes resulted in a significant reduction of intracellular bacteria, in comparison to treatment with nonfunctionalized liposomes as well as colistin alone. This indicates that such bio-invasive carriers are able to facilitate intracellular delivery of colistin, as necessary for intracellular anti-infective activity. The developed Eap-functionalized liposomes, therefore, present a promising strategy for improving the therapy of intracellular infections.

10.
Neuro Oncol ; 21(6): 775-785, 2019 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-30953587

RESUMO

BACKGROUND: Glioblastoma (GBM) is a lethal, heterogeneous human brain tumor, with regulatory mechanisms that have yet to be fully characterized. Previous studies have indicated that the transcriptional repressor REST (repressor element-1 silencing transcription factor) regulates the oncogenic potential of GBM stem cells (GSCs) based on level of expression. However, how REST performs its regulatory role is not well understood. METHODS: We examined 2 independent high REST (HR) GSC lines using genome-wide assays, biochemical validations, gene knockdown analysis, and mouse tumor models. We analyzed in-house patient tumors and patient data present in The Cancer Genome Atlas (TCGA). RESULTS: Genome-wide transcriptome and DNA-binding analyses suggested the dopamine receptor D2 (DRD2) gene, a dominant regulator of neurotransmitter signaling, as a direct target of REST. Biochemical analyses and mouse intracranial tumor models using knockdown of REST and double knockdown of REST and DRD2 validated this target and suggested that DRD2 is a downstream target of REST regulating tumorigenesis, at least in part, through controlling invasion and apoptosis. Further, TCGA GBM data support the presence of the REST-DRD2 axis and reveal that high REST/low DRD2 (HRLD) and low REST/high DRD2 (LRHD) tumors are specific subtypes, are molecularly different from the known GBM subtypes, and represent functional groups with distinctive patterns of enrichment of gene sets and biological pathways. The inverse HRLD/LRHD expression pattern is also seen in in-house GBM tumors. CONCLUSIONS: These findings suggest that REST regulates neurotransmitter signaling pathways through DRD2 in HR-GSCs to impact tumorigenesis. They further suggest that the REST-DRD2 mechanism forms distinct subtypes of GBM.

11.
Sci Rep ; 8(1): 12083, 2018 08 14.
Artigo em Inglês | MEDLINE | ID: mdl-30108242

RESUMO

Overexpression of REST has been implicated in brain tumors, ischemic insults, epilepsy, and movement disorders such as Huntington's disease. However, owing to the lack of a conditional REST overexpression animal model, the mechanism of action of REST overexpression in these disorders has not been established in vivo. We created a REST overexpression mouse model using the human REST (hREST) gene. Our results using these mice confirm that hREST expression parallels endogenous REST expression in embryonic mouse brains. Further analyses indicate that REST represses the dopamine receptor 2 (Drd2) gene, which encodes a critical nigrostriatal receptor involved in regulating movement, in vivo. Overexpression of REST using Drd2-Cre in adult mice results in increased REST and decreased DRD2 expression in the striatum, a major site of DRD2 expression, and phenocopies the spontaneous locomotion deficits seen upon global DRD2 deletion or specific DRD2 deletion from indirect-pathway medium spiny neurons. Thus, our studies using this mouse model not only reveal a new function of REST in regulating spontaneous locomotion but also suggest that REST overexpression in DRD2-expressing cells results in spontaneous locomotion deficits.


Assuntos
Corpo Estriado/metabolismo , Locomoção/fisiologia , Neurônios/metabolismo , Receptores de Dopamina D2/metabolismo , Proteínas Repressoras/metabolismo , Animais , Corpo Estriado/citologia , Embrião de Mamíferos , Feminino , Perfilação da Expressão Gênica , Técnicas de Introdução de Genes , Masculino , Camundongos , Camundongos Transgênicos , Modelos Animais , Receptores de Dopamina D2/genética , Proteínas Repressoras/genética , Análise de Sequência de RNA
12.
Bioconjug Chem ; 29(9): 3026-3041, 2018 09 19.
Artigo em Inglês | MEDLINE | ID: mdl-30110148

RESUMO

In this study, promising approaches of dual-targeted micelles and drug-polymer conjugation were combined to enable injection of poorly soluble anticancer drugs together with site-specific drug release. Ursodeoxycholic acid (UDCA) as a hepatoprotective agent was grafted to maltodextrin (MD) via carbodiimide coupling to develop amphiphilic maltodextrin-ursodeoxycholic acid (MDCA)-based micelles. Sulfasalazine (SSZ), as a novel anticancer agent, was conjugated via a tumor-cleavable ester bond to MD backbone to obtain tumor-specific release, whereas resveratrol (RSV) was physically entrapped within the hydrophobic micellar core. For maximal tumor-targeting, both folic acid (FA) and lactobionic acid (LA) were coupled to the surface of micelles to obtain dual-targeted micelles. The decrease of critical micelle concentration (CMC) from 0.012 to 0.006 mg/mL declares the significance of a dual hydrophobicized core of micelles by both UDCA and SSZ. The dual-targeted micelles showed a great hemocompatibility, as well as enhanced cytotoxicity and internalization into HepG-2 liver cancer cells via binding to overexpressed folate and asialoglycoprotein receptors. In vivo, the micelles demonstrated superior antitumor effects revealed as reduction in the liver/body weight ratio, inhibition of angiogenesis, and enhanced apoptosis. Overall, combined strategies of dual active targeted micelles with bioresponsive drug conjugation could be utilized as a promising approach for tumor-targeted drug delivery.


Assuntos
Antineoplásicos/administração & dosagem , Carcinoma Hepatocelular/tratamento farmacológico , Dissacarídeos/química , Sistemas de Liberação de Medicamentos , Ácido Fólico/química , Neoplasias Hepáticas/tratamento farmacológico , Micelas , Polissacarídeos/química , Resveratrol/administração & dosagem , Sulfassalazina/administração & dosagem , Animais , Antineoplásicos/uso terapêutico , Carcinoma Hepatocelular/patologia , Células Hep G2 , Humanos , Neoplasias Hepáticas/patologia , Camundongos , Resveratrol/uso terapêutico , Sulfassalazina/uso terapêutico , Ensaios Antitumorais Modelo de Xenoenxerto
13.
Can J Diabetes ; 42(6): 588-594, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29980378

RESUMO

OBJECTIVES: Diabetes mellitus is characterized by either complete deficiency of insulin secretion, as in type 1 diabetes, or decompensation of the pancreatic beta cells in type 2 diabetes. Both vitamin D (vitD) and thioredoxin interacting protein (TXNIP) have been shown to be involved in beta-cell dysfunction. Therefore, this study was designed to examine vitD and TXNIP serum levels in patients with diabetes and to correlate these levels with beta-cell function markers in both types of diabetes. METHODS: The routine biochemical parameters and the serum levels of vitD and TXNIP were measured in 20 patients with type 1 diabetes and 20 patients with type 2 diabetes. The levels were then compared to those of 15 healthy control volunteers. Insulin, C-peptide and proinsulin (PI), vitD and TXNIP were measured by ELISA. Beta-cell dysfunction was assessed by homeostatic model assessment (HOMA-beta), proinsulin-to-C-peptide (PI/C) and proinsulin-to-insulin (PI/I) ratios. Correlations among various parameters were studied. RESULTS: Patients with type 1 diabetes had significantly lower HOMA-beta, vitD and TXNIP levels; however, they had higher PI/C levels than the control group. Meanwhile, patients with type 2 diabetes had significantly higher C-peptide, proinsulin, PI/C, HOMA-insulin resistance (HOMA-IR) and lower HOMA-beta and vitD levels, with no significant difference in TXNIP levels as compared to the control group. In addition, vitD was significantly correlated positively with HOMA-beta and TXNIP and negatively with PI, PI/C, PI/I and HOMA-IR. TXNIP correlated positively with HOMA-beta and negatively with PI/C. CONCLUSIONS: Our data showed that vitD and TXNIP were associated with different beta-cell dysfunction markers, indicating their potential abilities to predict the beta-cell status in people with diabetes.


Assuntos
Proteínas de Transporte/sangue , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 2/sangue , Células Secretoras de Insulina , Pancreatopatias/sangue , Vitamina D/sangue , Peptídeo C/sangue , Feminino , Homeostase , Humanos , Insulina/sangue , Masculino , Pessoa de Meia-Idade , Proinsulina/sangue
14.
Lancet Infect Dis ; 18(8): 884-893, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29929783

RESUMO

BACKGROUND: REGN3470-3471-3479 is a co-formulated cocktail of three human monoclonal antibodies targeting three non-overlapping epitopes on Ebola virus. We investigated safety, tolerability, pharmacokinetics, and anti-drug antibodies in healthy adults. METHODS: This randomised, double-blind, placebo-controlled, dose-escalation study was done at a phase 1 unit in the USA. Healthy adults, aged 18-60 years, with a body-mass index of 18·0-30·0 kg/m2 were randomly assigned (3:1) to receive a single intravenous dose of REGN3470-3471-3479 or placebo on day 1 (baseline) in one of the four sequential ascending intravenous dose cohorts (3 mg/kg, 15 mg/kg, 60 mg/kg, and 150 mg/kg). Site investigators and participants were masked to the treatment assignment, whereas designated personnel at the site who prepared and generated the study medication were aware of the randomisation treatment assignments. The primary outcome was safety and the secondary outcomes were the pharmacokinetic profiles and immunogenicity. Study assessments were done the day before study drug administration, on the day of drug administration, on day 2 (before discharge), on days 3, 4, 8, 15, 29, 57, 85, 113, and 141, and at the end of study on day 169. The safety analysis included all randomised participants who received study drug. This trial is registered with ClinicalTrials.gov, number NCT002777151. FINDINGS: Between May 18, 2016, and October 27, 2016, 70 adults were screened and 24 participants were enrolled in the study. 18 participants were assigned to and received REGN3470-3471-3479, and six participants were assigned to and received placebo as a single intravenous infusion. 19 treatment-emergent adverse events occurred in the combined REGN3470-3471-3479 treatment groups, and four treatment-emergent adverse events occurred in combined placebo groups. Adverse events were transient and mild-to-moderate in severity. The most common treatment-emergent adverse event was headache (six [33%] of 18 participants in the combined REGN3470-3471-3479 group vs none of six participants in the placebo group. Headaches were mild-to-moderate in severity, with onset between 2 h and 27 days after start of study drug infusion. There were no deaths, serious adverse events, or adverse events that led to study discontinuation. The pharmacokinetics of each antibody was linear, with mean half-lives of 27·3 days for REGN3471, 21·7 days for REGN3470, and 23·3 days for REGN3479. No participants tested positive for anti-REGN3470, anti-REGN3471, or anti-REGN3479 antibodies. INTERPRETATION: REGN3470-3471-3479 was well tolerated, displayed linear pharmacokinetics, and did not lead to detectable immunogenicity. These data support further clinical development of REGN3470-3471-3479 as a single-dose therapeutic drug for acute Ebola virus infection. FUNDING: The Department of Health and Human Services, the Office of the Assistant Secretary for Preparedness and Response, and the Biomedical Advanced Research and Development Authority.


Assuntos
Administração Intravenosa , Anticorpos Monoclonais/farmacocinética , Glicoproteínas , Voluntários Saudáveis , Doença pelo Vírus Ebola/prevenção & controle , Segurança do Paciente , Adolescente , Adulto , Anticorpos Antivirais/sangue , Método Duplo-Cego , Ebolavirus/isolamento & purificação , Feminino , Cefaleia/etiologia , Humanos , Masculino , Pessoa de Meia-Idade , Estados Unidos , Adulto Jovem
15.
J Egypt Natl Canc Inst ; 30(2): 45-48, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29779937

RESUMO

BACKGROUND AND OBJECTIVES: Breast cancer (BC) is classified according to estrogen receptor (ER) status into ER+ and ER- tumors. ER+ tumors have a worse response to chemotherapy compared to ER- tumors. BCL-2, TP53, BAX and NF-ΚB are involved in drug resistance in the ER+ tumors. Recently it was shown that Cancer Stem Cells (CSCs) play an important role in drug resistance. In this study we tested the hypothesis that CSCs of the ER+ tumors resist drug through the overexpression of BCL-2, TP53, BAX and NF-ΚB. METHODS: CSCs were isolated by anoikis resistance assay from MCF7 (ER+) and MDA-MB-231 (ER-) cell lines. Isolated CSCs were treated with doxorubicin (DOX) and the mRNA expression levels of BCL-2, TP53, BAX and NFKB were investigated by quantitative real time PCR (qPCR) with and without treatment. RESULTS: BCL-2, BAX and NF-ΚB showed decreased expression in MCF7 bulk cancer cells after DOX treatment whereas only BCL-2 and BAX showed decreased expression in MDA-MB-231 bulk cancer cells. Interestingly TP53 was the only gene showed a considerable increase in its expression in CSCs of the ER+ MCF7 cell line compared to bulk cancer cells. Moreover, TP53 was the only gene showing exceptionally higher level of expression in MCF7-CSCs compared to MDA-MB-231-CSCs. CONCLUSION: Our results suggest that CSCs in the ER+ cells escape the effect of DOX treatment by the elevation of p53 expression.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/genética , Receptores Estrogênicos/genética , Proteína Supressora de Tumor p53/genética , Apoptose/efeitos dos fármacos , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Doxorrubicina/efeitos adversos , Doxorrubicina/farmacologia , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Células MCF-7 , NF-kappa B/genética , Células-Tronco Neoplásicas/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteína X Associada a bcl-2/genética
17.
Anticancer Res ; 38(2): 1073-1076, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29374743

RESUMO

Lung cancer is the leading cause of cancer-related deaths worldwide. Most patients present with advanced inoperable disease. Traditionally, responses to treatments are evaluated using different imaging modalities, which can sometimes be confusing. This is particularly more relevant in stage 3 disease where, after radiation therapy, persistent tumors on scans can represent active disease or scar tissue. We have been evaluating role of circulating tumor cells (CTCs) in that setting. Here we present the case of a 68-year-old male with stage 3 disease whose primary tumor responded to chemoradiotherapy on imaging, but whose CTC count was higher than the pre-treatment value. The patient later developed liver metastases. In this case, the CTC count more accurately predicted the patient's prognosis and highlights the need for exploration of the CTC count as a tool supplemental to imaging modalities.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma de Células Escamosas/patologia , Neoplasias Hepáticas/secundário , Neoplasias Pulmonares/patologia , Células Neoplásicas Circulantes/patologia , Idoso , Carcinoma Pulmonar de Células não Pequenas/terapia , Carcinoma de Células Escamosas/terapia , Quimiorradioterapia , Humanos , Neoplasias Hepáticas/terapia , Neoplasias Pulmonares/terapia , Masculino , Prognóstico , Cintilografia , Taxa de Sobrevida
18.
Cell Tissue Res ; 372(1): 91-98, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29159483

RESUMO

In vitro-generation of ß-cells from Wharton's jelly mesenchymal stem cells (WJ-MSCs) could provide a potential basis for diabetes mellitus cell therapy. However, the generation of functional insulin-producing cells (IPCs) from WJ-MSCs remains a challenge. Recently, obestatin, a gut hormone, was found to promote ß-cell generation from pancreatic precursor cells. Accordingly, we hypothesize that obestatin can induce the differentiation of WJ-MSCs into IPCs. Therefore, the purpose of the current study is to examine the ability of obestatin to generate IPCs in comparison to well-known extrinsic factors that are commonly used in IPCs differentiation protocols from MSCs, namely exendin-4 and glucagon-like peptide-1 (GLP-1). To achieve our aims, WJ-MSCs were isolated, cultured and characterized by immunophenotyping and adipocytes differentiation. Afterwards, WJ-MSCs were induced to differentiate into IPCs using two differentiation protocols incorporating either exendin-4, GLP-1 or obestatin. The pancreatic progenitor marker, nestin and ß-cell differentiation markers were assessed by qRT-PCR, while the functionality of the generated IPCs was assessed by glucose-stimulated insulin secretion (GSIS). Our results showed that WJ-MSCs exhibit all the characteristics of MSCs. Interestingly, using obestatin in both the short and long differentiation protocols managed to induce the expression of ß-cell markers, similar to exendin-4. In GSIS, IPCs generated using either GLP-1 or obestatin showed higher secretion of insulin as compared to those generated using exendin-4 under low-glucose conditions but failed to show a significant response to increased glucose. These results indicate obestatin can be considered as a novel potential factor to consider for generation of IPCs from WJ-MSCs.


Assuntos
Diferenciação Celular/efeitos dos fármacos , Grelina/farmacologia , Células Secretoras de Insulina/citologia , Células-Tronco Mesenquimais/citologia , Geleia de Wharton/citologia , Criopreservação , Exenatida/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Peptídeo 1 Semelhante ao Glucagon/farmacologia , Humanos , Células Secretoras de Insulina/efeitos dos fármacos
19.
Saudi J Anaesth ; 11(3): 312-318, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28757833

RESUMO

CONTEXT: Tracheal intubation is frequently facilitated with sevoflurane induction without the use of muscle relaxants in children. AIM: The aim of this study was to compare the effects of two different doses of propofol preceded by a fixed dose of fentanyl during sevoflurane induction on quality of tracheal intubation in children. SETTINGS AND DESIGN: This was a prospective randomized study. SUBJECTS AND METHODS: Ninety American Society of Anesthesiologists I-II children aged 2-6 years were randomly assigned to one of two equal groups to receive 2 µg/kg of fentanyl with 2 mg/kg of propofol (Group I) or 2 µg/kg of fentanyl with 3 mg/kg of propofol (Group II) during sevoflurane induction. The intubating conditions and hemodynamic responses were evaluated. The time from sevoflurane induction to loss of consciousness, to intravenous line insertion, and to intubation was measured. The occurrence of any adverse effect was recorded. STATISTICAL ANALYSIS USED: Results were analyzed using Student's t-test, paired t-test, and Chi-square test. P < 0.05 was considered statistically significant. RESULTS: The incidence of excellent intubating conditions was achieved more significantly in Group II (41/45 patients, 91%) than that in Group I (31/45 patients, 69%) (P = 0.008) (95% confidence interval [CI] =0.39-0.8). Whereas, there were no significant differences between the two groups in terms of the overall acceptable intubating conditions in Group I (40/45 patients, 89%) and Group II (43/45 patients, 96%) (P = 0.81) (95% CI = 0.71-1.31). No patient developed any adverse effect. CONCLUSION: The administration of 3 mg/kg propofol preceded by 2 µg/kg fentanyl provided a higher proportion of excellent intubating conditions compared with 2 mg/kg propofol preceded by 2 µg/kg fentanyl during sevoflurane induction in children without muscle relaxants.

20.
Exp Clin Transplant ; 15(3): 277-281, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28587588

RESUMO

OBJECTIVES: We report on the long-term follow-up of managing allograft stones at a single tertiary referral institution and review the relevant literature. MATERIALS AND METHODS: A retrospective analysis of renal allograft recipient charts was performed to identify patients who developed allograft lithiasis between 1974 and 2009. Patient and stone characteristics, diagnoses, treatments, and outcomes were described. RESULTS: Sixteen patients developed 22 stones after a median follow-up of 170 months (range, 51-351 mo). The mean (standard deviation) and median diameter of the stones were 13.8 (8.5) mm and 11 mm. Among these, 3 stones were treated conservatively, 3 by shock-wave lithotripsy, and 7 by cystolitholapaxy. Seven patients underwent percutaneous treatment in the form of percutaneous nephrostomy tube fixation and spontaneous passage of stone (1 stone), shock-wave lithotripsy (1 stone), antegrade stenting (1 stone), and percutaneous nephrolithotomy (6 stones). All patients were stone free after treatment, except for 2 patients whose stones were stable and peripheral on long-term follow-up. CONCLUSIONS: Allograft lithiasis requires a multimodal treatment tailored according to stone and graft characteristics. Protocols regarding spontaneous passage can be adopted if there is no harm to the graft and the patient is compliant. Careful attention to the anatomy during percutaneous nephrostomy tube placement is mandatory to avoid intestinal loop injury. A more attentive follow-up is required for early stone management.


Assuntos
Transplante de Rim/efeitos adversos , Litotripsia , Nefrolitíase/terapia , Nefrolitotomia Percutânea , Adulto , Aloenxertos , Intervalo Livre de Doença , Egito , Feminino , Humanos , Litotripsia/efeitos adversos , Masculino , Pessoa de Meia-Idade , Nefrolitíase/diagnóstico , Nefrolitíase/etiologia , Nefrolitotomia Percutânea/efeitos adversos , Nefrolitotomia Percutânea/instrumentação , Recidiva , Estudos Retrospectivos , Stents , Fatores de Tempo , Resultado do Tratamento
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA