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1.
Int J Surg ; 73: 113-122, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31756546

RESUMO

BACKGROUND: Advanced colorectal has poor survival and are difficult to treat. Therefore, there is an urgent need for biomarkers to diagnose this cancer at earlier manageable stages. Micro-RNAs (miRNAs) are amongst the most significant biomarkers that have shown promise in improving management and early detection of different types of cancers. However, since MiRNAs are non-coding, the main limitation of using them as biomarkers is that they do not have associated phenotype and therefore difficult to validate using other techniques. This makes it difficult to understand the mechanism of miRNA is disease initiation and progression, therefore any methodology that can provide semantics to miRNA expression would enhance the understanding of the role of miRNA in disease. METHODS: Here we report an integrative meta-analysis and bioinformatics methodology that showed microRNA-21 and its associated target mRNA to be the most significant predictive biomarkers for colorectal adenoma and adenocarcinoma. After drawing key inferences by meta-analysis, the authors then developed a bioinformatics method to identify mir-21 gene targeting in a specific tissue using two different bioinformatics approaches; absolute GSEA (Gene Set Enrichment Analysis) and LIMMA (Linear Models for MicroArray data) to identify differentially expressed genes of miRNA-21. RESULTS: Results from GSEA intersection with mir-21 gene targets was a subset of longer gene list that was obtained from the GEO2R intersect. In our study, both of longer GEO2R gene target list and the more focused GSEA list established the fact that mir-21 target numerous functional pathways that are mostly interconnected. Our three steps bioinformatics approach identified ABCB1, HPGD, BCL2, TIAM1, TLR3, and PDCD4 as common targets for mir-21 in both of adenoma as well as adenocarcinoma suggesting they are biomarkers for early CRC. CONCLUSIONS: The approach in this study proposed combining the big data from the scientific literature together with novel bioinformatics to bring about a methodology that can be used to first identify which microRNAs are involved in a specific disease, and then to identify a panel of biomarkers derived from the microRNAs target genes, and from these target genes the functional significance of these microRNAs can be inferred providing better clinical value for the surgeon.

2.
PLoS One ; 14(12): e0226957, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31881055

RESUMO

Increased body mass index (BMI) has been associated with an increased prevalence of asthma in children, however the association between BMI status and asthma severity has been less well defined. The aim of this study was to describe the association between childhood obesity and asthma severity, frequency of hospital and emergency department visits as well as pattern of aeroallergen sensitization. A retrospective study was conducted at pediatric outpatient clinics in University Hospital Sharjah. All consecutive patients aged 6 years and above, with confirmed diagnosis of asthma visiting the outpatient pediatric clinics during 2018 were included in this study. Sources of information were the patient's medical file, laboratory data, pharmacy data, as well as reports from the pediatric in charge. This study included 164 children with asthma. 63% of asthma patients were male. The vast majority of patients were from Arab ethnicities (n = 154, 94%), majority had mild asthmatic conditions (n = 133, 81%), and one-third were either overweight or obese (n = 52, 32%). Overweight or obese asthmatic children with BMI percentile of equal or more than 85% was associated with more asthma severity (odds ratio [OR]: 3.27, 95% confidence interval [CI]: 1.42-7.54; P = 0.005), as well as more frequent asthma related hospital visits (OR: 2.53, 95% CI: 1.22-5.26; P = 0.013). Overweight asthmatic children with BMI between the 85th and 94th percentiles and obese asthmatic children with BMI equal to or greater than 95th percentile are associated with more severe asthma phenotype and more frequent hospital and emergency department visits.

3.
Sci Rep ; 9(1): 17437, 2019 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-31767874

RESUMO

The economic growth has paralleled the rise of diabetes and its complications in multiethnic population of United Arab Emirates (UAE). Previous studies have shown that characteristics of diabetes is variable across different ethnicities. The objective of this study was to compare diabetes prevalence and risk factors between UAE nationals and different expatriate's ethnic groups in UAE using data from UAE National Diabetes and Lifestyle Study (UAEDIAB). The UAE nationals made one-fourth (n = 797, 25%) of total cohort and the remaining 75% belonged to immigrants. Across different ethnicities, adjusted prevalence of prediabetes ranged from 8% to 17%, while adjusted prevalence of newly diagnosed diabetes ranged from 3% to 13%. UAE nationals, Arabs non-nationals and Asians had the highest number of pre-diabetic as well as newly diagnosed diabetic patients. Adjusted prevalence of diabetes was highest in UAE nationals (male 21% and female 23%) as well as Asian non-Arabs (male 23% and female 20%), where 40% of both groups fell under the range of either prediabetes or diabetes conditions. Multivariate factors of diabetes versus non-diabetes included older age, ethnicities of Asian non-Arabs and local UAE nationals, family history of diabetes, obesity, snoring, decreased level of high density lipoprotein, elevated levels of triglycerides and blood pressure. In conclusion, diabetes prevalence and risk factors vary across the different ethnic groups in UAE, and hence interventions towards identification and prevention of diabetes should not treat all patients alike.

4.
Immunotargets Ther ; 8: 29-41, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31687364

RESUMO

Introduction: Although natural killer (NK) are major cells used to treat cancer patients, recent clinical trials showed that NK92 cells can be also used for the same purpose due to their high anti-tumor activity. Here, we examined whether these cells might be inflammatory due to the release of interleukin-1ß (IL-1ß), and whether the anti-inflammatory molecules dimethyl fumarate (DMF), or monomethyl fumarate (MMF) impair this activity. Methods: NK92 cells were examined for the synthesis and release of IL-1ß utilizing RT-PCR and ELISA assay, respectively. The expression of hydroxy-carboxylic acid receptors (HCA)1, HCA2 and HCA3 was detected by immunoblotting, flow cytometry, immunofluorescence and RT-PCR assays. The activation of caspase-1 and Gasdermin D (GSDMD) was evaluated by immunoblot assay. Pyroptosis was demonstrated by immunofluorescence imaging. Expression of DNA methyltransferases (DNMTs) mRNA was determined by whole transcriptome and immunoblot analyses. Results: LPS-induced the release of IL-1ß from NK92 cells, whereas DMF or MMF inhibited this induction. The effect of these drugs was due to inhibiting the conversion of procaspase-1 into active caspase-1. NK92 cells highly expressed GSDMD, a pyroptotic-mediated molecule. However, LPS induced the distribution of GSDMD into the cell membranes, corroborated with the presence of pyroptotic bodies, an activity that was inhibited by DMF or MMF. These molecule also inhibited the generation of GSDMD through DNMT-mediated hypermethylation of the promoter region of GSDMD gene. These results were supported by increased expression of DNMTs mRNA as determined by whole transcriptome analysis. Discussion: Our results are the first to show that NK92 cells utilize GSDMD pathway to release IL-1ß. Further, DMF and MMF which were previously shown to enhance NK cell cytotoxicity, also inhibit the inflammatory effects of these cells, making them most suitable for treating cancer patients. .

5.
Sci Data ; 6(1): 257, 2019 10 31.
Artigo em Inglês | MEDLINE | ID: mdl-31672996

RESUMO

Integrative analysis of multi-omics data is a powerful approach for gaining functional insights into biological and medical processes. Conducting these multifaceted analyses on human samples is often complicated by the fact that the raw sequencing output is rarely available under open access. The Personal Genome Project UK (PGP-UK) is one of few resources that recruits its participants under open consent and makes the resulting multi-omics data freely and openly available. As part of this resource, we describe the PGP-UK multi-omics reference panel consisting of ten genomic, methylomic and transcriptomic data. Specifically, we outline the data processing, quality control and validation procedures which were implemented to ensure data integrity and exclude sample mix-ups. In addition, we provide a REST API to facilitate the download of the entire PGP-UK dataset. The data are also available from two cloud-based environments, providing platforms for free integrated analysis. In conclusion, the genotype-validated PGP-UK multi-omics human reference panel described here provides a valuable new open access resource for integrated analyses in support of personal and medical genomics.

6.
Pharmgenomics Pers Med ; 12: 181-199, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31692590

RESUMO

Background: : With the increasing incidence of asthma, more attention is focused on the diverse and complex nutritional and environmental triggers of asthma exacerbations. Currently, there are no established risk assessment tools to evaluate asthma triggering potentials of most of the nutritional and environmental triggers encountered by asthmatic patients. Purpose:  The objective of this study is to devise a reliable workflow, capable of estimating the toxicogenomic effect of such factors on key player genes in asthma pathogenesis. Methods: Gene expression extracted from publicly available datasets of asthmatic bronchial epithelium were subjected to a comprehensive analysis of differential gene expression to identify significant genes involved in asthma development and progression. The identified genes were subjected to Gene Set Enrichment Analysis using a total of 31,826 gene sets related to chemical, toxins, and drugs to identify common agents that share similar asthma-related targets genes and signaling pathways. Results: Our analysis identified 225 differentially expressed genes between severe asthmatic and healthy bronchial epithelium. Gene Set Enrichment Analysis of the identified genes showed that they are involved in response to toxic substances and organic cyclic compounds and are targeted by 41 specific diets, plants products, and plants related toxins (eg adenine, arachidonic acid, baicalein, caffeic acid, corilagin, curcumin, ellagic acid, luteolin, microcystin-RR, phytoestrogens, protoporphyrin IX, purpurogallin, rottlerin, and salazinic acid). Moreover, the identified chemicals share interesting inflammation-related pathways like NF-κB. Conclusion: Our analysis was able to explain and predict the toxicity in terms of stimulating the differentially expressed genes between severe asthmatic and healthy epithelium. Such an approach can pave the way to generate a cost-effective and reliable source for asthma-specific toxigenic reports thus allowing the asthmatic patients, physicians, and medical researchers to be aware of the potential triggering factors with fatal consequences.

7.
Artigo em Inglês | MEDLINE | ID: mdl-31614370

RESUMO

Silencing of Chl1 gene expression has been previously reported to reduce insulin secretion. Nevertheless, the mechanism underlying this effect remains unclear. In this study, we performed a serial of studies to investigate how Chl1 affects insulin secretion in INS-1 cells. RNA-sequencing was used to investigate the expression of CHL1 in human adipose, liver, muscle, and human islets. Silencing of Chl1 in INS-1 cells was done to assess its impact on the insulin secretion, content, cell viability, and apoptosis. In addition, gene set enrichment analysis (GSEA) was performed to identify possible molecular signatures that associate with Chl1 expression silencing.RNA sequencing data revealed a high expression of CHL1 in pancreatic islets and adipose tissues compared to liver and muscles tissues. Diabetic islets exhibited a lower expression of CHL1 as compared to non-diabetic islets. CHL1 expression was found to correlate positively with insulin secretory index, GLP1R but inversely with HbA1c and BMI. Silencing of Chl1 in INS-1 cells markedly reduced insulin content and secretion. The expression of key molecules of ß-cell function including Insulin, Pdx1, Gck, Glut2, and Insrß was down-regulated in Chl1-silenced cells at transcriptional and translational levels. Cell viability, apoptosis, and proliferation rate were not affected. GSEA showed that the insulin-signaling pathway was influenced in Chl1-silenced cells. Silencing of Chl1 impairs ß-cell function by disrupting the activity of key signaling pathways of importance for insulin biosynthesis and secretion.

8.
PLoS One ; 14(10): e0223808, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31622411

RESUMO

BACKGROUND: The risk of obesity is determined by complex interactions between genetic and environmental factors. Little research to date has investigated the interaction between gene and food intake. The aim of the current study is to explore the potential effect of fat mass and obesity-associated protein gene (FTO) rs9939609 and rs9930506 single nucleotide polymorphism (SNP) on the pattern of food intake in the Emirati population. METHODS: Adult healthy Emirati subjects with Body mass index (BMI) of 16-40 kg/m2 were included in the study. Genotyping for FTO rs9939609(A>T) and rs9930506(A>G) was performed using DNA from saliva samples. Subjects were categorized according to the WHO classification by calculating the BMI to compare different classes. Dietary intake was assessed by a sixty-one-item FFQ that estimated food and beverage intakes over the past year. The daily energy, macronutrient, and micronutrient consumption were computed. RESULTS: We included 169 subjects in the final analysis (mean age 30.49± 9.1years, 57.4% females). The mean BMI of the study population was 26.19 kg/m2. Both SNPs were in Hardy Weinberg Equilibrium. The rs9939609 AA genotype was significantly associated with higher BMI (p = 0.004); the effect was significant in females (p = 0.028), but not in males (p = 0.184). Carbohydrate intake was significantly higher in AA subjects with a trend of lower fat intake compared to other genotypes. The odds ratio for the AA was 3.78 in the fourth quartile and 2.67 for the A/T in the second quartile of total carbohydrate intake, considering the first quartile as a reference (95% CI = 1.017-14.1 and 1.03-6.88, respectively). Fat intake was significantly lower in the FTO rs9930506 GG subjects. The presence of FTO rs9930506 GG genotype decreased the fat intake in subjects with FTO rs9939609 AA (p = 0.037). CONCLUSIONS: The results of this study highlight the interaction of the FTO risk alleles on the food intake in Emirati subjects. The FTO rs9939609 AA subjects had higher carbohydrate and lower fat intake. The latter was accentuated in presence of rs9930506 GG genotype.

9.
Sci Rep ; 9(1): 13126, 2019 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-31511569

RESUMO

Metabolic profiling of cancer cells can play a vital role in revealing the molecular bases of cancer development and progression. In this study, gas chromatography coupled with mass spectrometry (GC-MS) was employed for the determination of signatures found in ER+/PR+ breast cancer cells derived from MCF-7 using different extraction solvents including: A, formic acid in water; B, ammonium hydroxide in water; C, ethyl acetate; D, methanol: water (1:1, v/v); and E, acetonitrile: water (1:1, v/v). The greatest extraction rate and diversity of metabolites occurs with extraction solvents A and E. Extraction solvent D showed moderate extraction efficiency, whereas extraction solvent B and C showed inferior metabolite diversity. Metabolite set enrichment analysis (MSEA) results showed energy production pathways to be key in MCF-7 cell lines. This study showed that mass spectrometry could identify key metabolites associated with cancers. The highest enriched pathways were related to energy production as well as Warburg effect pathways, which may shed light on how energy metabolism has been hijacked to encourage tumour progression and eventually metastasis in breast cancer.

10.
PLoS One ; 14(5): e0217000, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31095649

RESUMO

BACKGROUND: HPV-16-positive HNSCC and HPV-16-negative HNSCC have different clinical factors, representing distinct forms of cancers. The study aimed to identify patient-specific factors for HPV-16-positive HNSCC based on baseline clinical data. METHOD: Factors associated with HPV-16-positive HNSCC were identified using the data from 210 patients diagnosed with HNSCC at University College of London Hospital between January 1, 2003, and April 30, 2015, inclusive. A series of models were developed using logistic regression methods, and the overall model fit was compared using Akaike Information Criterion. Survival analysis was carried with Cox proportional hazards model for survival-time outcomes. The survival time for individual patients was defined as the time from diagnosis of HNSCC to the date of death from any cause. For patients who did not die, they were censored at the end of study on April 30, 2015. RESULTS: Of the 210 patients, 151 (72%) were found to have HPV-16-positive HNSCC. The logistic regression model showed that the prevalence of developing HPV-16-positive HNSCC was 3.79 times higher in patients with Type 2 Diabetes Mellitus (T2DM) (odd ratio [OR], 3.79; 95% CI, 1.70-8.44) than in those without T2DM, and 8.84 times higher in patients with history of primary HNSCC (OR, 8.84; 95% CI, 2.30-33.88) than in those without a history of primary HNSCC. HPV-16-positive HNSCC was also observed more in tonsils (OR, 4.02; 95% CL, 1.56-10.36) and less in non-alcohol drinker's oral cavity (OR, 0.14; 95% CI, 0.03-0.56). Furthermore, individual patients were followed-up for 1 to 13 years (median of 1 year). Patients with HPV-positive HNSCC had a median survival of 5 years (95% CI, 2.6-7.3 years). Among HPV-16-positive HNSCC cohort, T2DM was a risk for poorer prognosis (hazard ratio, 2.57; 95% Cl, 1.09-6.07), and had lower median survival of 3 years (95% CI, 1.8-4.1 years), as compared to 6 years (95% CI, 2.8-9.1 years) in non-T2DM. CONCLUSIONS: Patient-specific factors for HPV-positive HNSCC are T2DM, history of primary HNSCC and tonsillar site. T2DM is associated with poorer prognosis. These findings suggest that it might be beneficial if routine HPV-16 screening is carried out in T2DM patients which can provide better therapeutic and management strategies.

11.
J Clin Exp Hematop ; 59(1): 1-16, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30918139

RESUMO

The microenvironment influences the behavior of follicular lymphoma (FL) but the specific roles of the immunomodulatory BTLA and TNFRSF14 (HVEM) are unknown. Therefore, we examined their immunohistochemical expression in the intrafollicular, interfollicular and total histological compartments in 106 FL cases (57M/49F; median age 57-years), and in nine relapsed-FL with transformation to DLBCL (tFL). BTLA expression pattern was of follicular T-helper cells (TFH) in the intrafollicular and of T-cells in the interfollicular compartments. The mantle zones were BTLA+ in 35.6% of the cases with similar distribution of IgD. TNFRSF14 expression pattern was of neoplastic B lymphocytes (centroblasts) and "tingible body macrophages". At diagnosis, the averages of total BTLA and TNFRSF14-positive cells were 19.2%±12.4STD (range, 0.6%-58.2%) and 46.7 cells/HPF (1-286.5), respectively. No differences were seen between low-grade vs. high-grade FL but tFL was characterized by low BTLA and high TNFRSF14 expression. High BTLA correlated with good overall survival (OS) (total-BTLA, Hazard Risk=0.479, P=0.022) and with high PD-1 and FOXP3+Tregs. High TNFRSF14 correlated with poor OS and progression-free survival (PFS) (total-TNFRSF14, HR=3.9 and 3.2, respectively, P<0.0001), with unfavorable clinical variables and higher risk of transformation (OR=5.3). Multivariate analysis including BTLA, TNFRSF14 and FLIPI showed that TNFRSF14 and FLIPI maintained prognostic value for OS and TNFRSF14 for PFS. In the GSE16131 FL series, high TNFRSF14 gene expression correlated with worse prognosis and GSEA showed that NFkB pathway was associated with the "High-TNFRSF14/dead-phenotype".In conclusion, the BTLA-TNFRSF14 immune modulation pathway seems to play a role in the pathobiology and prognosis of FL.


Assuntos
Linfoma Folicular/diagnóstico , Linfoma Difuso de Grandes Células B/diagnóstico , Receptores Imunológicos/metabolismo , Membro 14 de Receptores do Fator de Necrose Tumoral/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Linfócitos B/química , Linfócitos B/patologia , Transformação Celular Neoplásica , Feminino , Humanos , Fatores Imunológicos , Linfoma Folicular/mortalidade , Linfoma Difuso de Grandes Células B/mortalidade , Masculino , Pessoa de Meia-Idade , Prognóstico , Análise de Sobrevida , Linfócitos T/química
12.
Histochem Cell Biol ; 152(1): 75-84, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30778673

RESUMO

One of the main aspects investigated in potential therapeutic compounds is their effect on cells viability and proliferative ability. Although various methods have been developed to investigate these aspects, these methods present with shortcomings in terms of either cost, availability, accuracy, precision, or throughput. This study describes a simple, economic, reproducible, and high-throughput assay to quantify cell death and proliferation. In this assay, adherent cells are fixed, stained with trypan blue, and measured for trypan blue internalization using a spectrophotometric absorbance plate reader. Corresponding cell counts to the absorbance measurements are extrapolated from a standard curve. This assay was used to measure the effect of dimethyl sulfoxide (DMSO) on the viability of breast and lung cancer cells. Decrease in cell count associated with the increase in DMSO percentage and exposure time. The assay's results closely correlated with the conventional trypan blue exclusion assay (Pearson correlation coefficient (r) > 0.99; p < 0.0001), but with higher precision. The assay developed in this study can be used for various applications such as optimization, cell treatment investigations, proliferation, and cytotoxicity studies.


Assuntos
Neoplasias da Mama/patologia , Dimetil Sulfóxido/farmacologia , Neoplasias Pulmonares/patologia , Azul Tripano/análise , Células A549 , Sobrevivência Celular/efeitos dos fármacos , Humanos , Espectrofotometria , Azul Tripano/química
13.
Histol Histopathol ; 34(6): 697-709, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30506545

RESUMO

AIMS: To identify the role of securin (PTTG) as a prognostic marker in invasive breast carcinoma and its possible relation to ki67 and to evaluate the use of ImmunoRatio® as a tool for calculating ki67 and securin labelling indices. METHODS: Securin and ki67 immunohistochemical staining were performed on tissue microarray sections representative of 118 patients diagnosed with invasive breast carcinoma from 2005 to 2011. Assessment of immunohistochemical staining was carried out using both visual counting and ImmunoRatio®. The 118 cases were categorized into 2 groups according to their clinical outcome; the first group (G1) (n=77) comprised patients who were disease-free while the second group (G2) (n=41) included patients who developed either recurrence and/or metastasis at the end of 24 months follow-up duration. RESULTS: Both securin and ki67 labelling indices (LIs) obtained by visual counting were significantly higher in G2, while only securin LIs acquired by ImmunoRatio® were significantly higher in G2. Securin assessment by visual counting was the most accurate (AUC=0.775) in identifying patients who will likely suffer from recurrence and/or distant metastasis. Pearson correlation showed r=0.638, p<0.001 for Ki67 and r=0.671, p<0.001 for securin. Linear regression analysis showed a significant correlation between ki67 and securin, B=1.75, p<0.001. CONCLUSION: The present results suggest that securin may add to the prognostic value of ki67 in highlighting intra-tumoural heterogeneity in invasive breast carcinoma patients with poor clinical outcome. In addition, the study showed that since securin has a visual counting cutoff with more than 1%, making it easier to use as a breast cancer biomarker in conjunction with ki67 to predict the outcome of the cases more accurately than using only ki67. However, a multivariate analysis on a larger cohort of patients is mandatory to test its potential prognostic value.


Assuntos
Neoplasias da Mama/metabolismo , Carcinoma/metabolismo , Regulação Neoplásica da Expressão Gênica , Antígeno Ki-67/metabolismo , Securina/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Área Sob a Curva , Biomarcadores Tumorais/metabolismo , Feminino , Perfilação da Expressão Gênica , Humanos , Imuno-Histoquímica , Mastectomia , Pessoa de Meia-Idade , Método de Monte Carlo , Metástase Neoplásica , Recidiva Local de Neoplasia , Prognóstico , Análise Serial de Tecidos , Resultado do Tratamento
14.
Eur Urol Focus ; 5(1): 62-68, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-28753883

RESUMO

BACKGROUND: Multiparametric magnetic resonance imaging (mp-MRI) is becoming an increasingly important diagnostic tool for prostate cancer. So far there has been little focus on management for indeterminate mp-MRI results. OBJECTIVE: To describe outcomes for a cohort of men rated as having an indeterminate mp-MRI result. DESIGN, SETTING, AND PARTICIPANTS: Patients were identified retrospectively from a single UK centre between October 2010 and January 2015. Patients were included if they had a Likert score of 3/5 on a first MRI scan without any prior prostate biopsy. Patients were offered one of two initial management strategies. Strategy 1 was an immediate targeted biopsy of the MRI lesion. Strategy 2 was a surveillance process comprising prostate-specific antigen monitoring and/or mp-MRI at intervals of 6-12 mo, with biopsy on a for-cause basis. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Cancer detection and treatment outcomes were compared for the two strategies. RESULTS AND LIMITATIONS: Of 168 patients, 73 (43%) chose strategy 1 and 95 (57%) chose strategy two. The overall proportion of men with clinically significant cancer detected was 14% (23/168). The risk profile for cancer identified in the initial surveillance group was similar to that identified in the immediate biopsy group. Limitations of the study include the short follow-up. CONCLUSIONS: Men with indeterminate mp-MRI were willing to forego immediate biopsy for a strategy of surveillance involving PSA measurement and/or mp-MRI repeated at intervals. The risk profile of the cancers identified by both strategies appeared similar, but many men in the surveillance group avoided the risks, complications, and costs of biopsy. Long-term results are awaited. PATIENT SUMMARY: This report compares two approaches for an uncertain magnetic resonance imaging result for clinically important prostate cancer: immediate biopsy versus surveillance with delayed biopsy if required. Delayed biopsy did not result in identification of cancer with adverse features, and many men benefited from avoiding a biopsy and its complications.


Assuntos
Biópsia Guiada por Imagem/métodos , Neoplasias da Próstata/diagnóstico , Conduta Expectante/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Prognóstico , Antígeno Prostático Específico/metabolismo , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Estudos Retrospectivos , Tamanho da Amostra
15.
Diabetes Ther ; 9(5): 1853-1868, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30043211

RESUMO

INTRODUCTION: Diabetes mellitus (DM) is associated with multiple complications, including cardiovascular diseases. Previously, it was believed that the latter are mainly caused by hypertension and increased systolic blood pressure. However, recent studies have challenged this concept, by showing that diastolic dysfunction may also be involved in the cardiovascular events that are associated with DM. Pharmacologic management of hypertension in patients with type 2 DM appears to adversely influence diastolic function. METHODS: Four hundred and eight medical records of hypertensive and obese Emirati patients with type 2 DM were included in the present retrospective study. The main objectives of the present study were (1) to determine the prevalence of low diastolic blood pressure (DBP) and diastolic hypotension in this group of patients and (2) to investigate the associations, if any, between the use of various antihypertensive medications and low DBP and diastolic hypotension. RESULTS: The results of the present study showed that low DBP (< 70 mmHg) was experienced by 40% of the hypertensive type 2 DM patients, whereas diastolic hypotension (< 60 mmHg) was reported to occur in about 10% of the patients. Another important factor that has been significantly correlated with diastolic hypotension is age (p < 0.01). Association trends have been reported between low DBP and diastolic hypotension and several antihypertensive therapies, including (1) monotherapies such as angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs), (2) dual therapies such as ACE inhibitors in combination with thiazide-like diuretics (THLDs) or beta blockers, and (3) triple therapy combinations of ACE inhibitors with THLDs and potassium-sparing diuretics. CONCLUSION: The use of antihypertensive medications, in particular ACE inhibitors and ARBs, appears to be a risk factor for the development of low DBP and diastolic hypotension in obese hypertensive Emirati patients with type 2 DM, whereas calcium channel blockers seem to be a safer option for this group of patients.

16.
Oncotarget ; 9(33): 22945-22959, 2018 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-29796164

RESUMO

Early oesophageal adenocarcinoma (OA) and pre-neoplastic dysplasia may be treated with endoscopic resection and ablative techniques such as photodynamic therapy (PDT). Though effective, discrete areas of disease may be missed leading to recurrence. PDT further suffers from the side effects of off-target photosensitivity. A tumour specific and light targeted therapeutic agent with optimised pharmacokinetics could be used to destroy residual cancerous cells left behind after resection. A small molecule antibody-photosensitizer conjugate was developed targeting human epidermal growth factor receptor 2 (HER2). This was tested in an in vivo mouse model of human OA using a xenograft flank model with clinically relevant low level HER2 expression and heterogeneity. In vitro we demonstrate selective binding of the conjugate to tumour versus normal tissue. Light dependent cytotoxicity of the phototherapy agent in vitro was observed. In an in vivo OA mouse xenograft model the phototherapy agent had desirable pharmacokinetic properties for tumour uptake and blood clearance time. PDT treatment caused tumour growth arrest in all the tumours despite the tumours having a clinically defined low/negative HER2 expression level. This new phototherapy agent shows therapeutic potential for treatment of both HER2 positive and borderline/negative OA.

17.
Int J Exp Pathol ; 99(1): 10-14, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29473241

RESUMO

Non-dysplastic Barrett's oesophagus (NDBE) occurs as a consequence of an inflammatory response triggered through prolonged gastro-oesophageal reflux and it may precede the development of oesophageal adenocarcinoma. NF-κB activation as a result of the inflammatory response has been shown in NDBE, but the possible mechanism involved in the process is unknown. The aim of this study was to assess, using immunohistochemistry, Survivin and Bcl3 expression as potential biomarkers for NF-κB activation along the oesophageal metaplasia-dysplasia-adenocarcinoma sequence. Survivin is an NF-κB-inducible anti-apoptotic protein, and Bcl3 is a negative regulator of NF-κB. There was progressive upregulation of Survivin expression along the oesophageal metaplasia-dysplasia-adenocarcinoma sequence. Bcl3 expression was upregulated in non-dysplastic Barrett's oesophagus, low-grade, high-grade dysplasia and oesophageal adenocarcinoma when compared to squamous group. The study shows the differential expression of Bcl3 between the squamous and Barrett's stage, suggesting that Bcl3 could be a surrogate marker for early event involving constitutive NF-κB activation. In addition, the study suggests that NF-κB activation may infer resistance to apoptosis through the expression of anti-apoptotic genes such as Survivin, which showed progressive increase in expression throughout the oesophageal metaplasia-dysplasia-adenocarcinoma sequence. This ability to avoid apoptosis may underlie the persistence and malignant predisposition of Barrett's metaplasia.


Assuntos
Adenocarcinoma/química , Esôfago de Barrett/metabolismo , Biomarcadores Tumorais/análise , Transformação Celular Neoplásica/química , Neoplasias Esofágicas/química , Esôfago/química , Imuno-Histoquímica , Proteínas Inibidoras de Apoptose/análise , NF-kappa B/análise , Proteínas Proto-Oncogênicas/análise , Fatores de Transcrição/análise , Adenocarcinoma/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Apoptose , Esôfago de Barrett/patologia , Biópsia , Transformação Celular Neoplásica/patologia , Neoplasias Esofágicas/patologia , Esôfago/patologia , Feminino , Humanos , Masculino , Metaplasia , Pessoa de Meia-Idade , Transdução de Sinais , Survivina , Adulto Jovem
18.
J Control Release ; 262: 192-200, 2017 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-28764995

RESUMO

Magnetically responsive microbubbles (MagMBs), consisting of an oxygen gas core and a phospholipid coating functionalised with Rose Bengal (RB) and/or 5-fluorouracil (5-FU), were assessed as a delivery vehicle for the targeted treatment of pancreatic cancer using combined antimetabolite and sonodynamic therapy (SDT). MagMBs delivering the combined 5-FU/SDT treatment produced a reduction in cell viability of over 50% when tested against a panel of four pancreatic cancer cell lines in vitro. Intravenous administration of the MagMBs to mice bearing orthotopic human xenograft BxPC-3 tumours yielded a 48.3% reduction in tumour volume relative to an untreated control group (p<0.05) when the tumour was exposed to both external magnetic and ultrasound fields during administration of the MagMBs. In contrast, application of an external ultrasound field alone resulted in a 27% reduction in tumour volume. In addition, activated caspase and BAX protein levels were both observed to be significantly elevated in tumours harvested from animals treated with the MagMBs in the presence of magnetic and ultrasonic fields when compared to expression of those proteins in tumours from either the control or ultrasound field only groups (p<0.05). These results suggest MagMBs have considerable potential as a platform to enable the targeted delivery of combined sonodynamic/antimetabolite therapy in pancreatic cancer.


Assuntos
Antimetabólitos Antineoplásicos/administração & dosagem , Fluoruracila/administração & dosagem , Nanopartículas Metálicas/administração & dosagem , Microbolhas , Sonicação , Animais , Antimetabólitos Antineoplásicos/química , Avidina/administração & dosagem , Avidina/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Compostos Férricos/administração & dosagem , Compostos Férricos/química , Fluoruracila/química , Humanos , Fenômenos Magnéticos , Nanopartículas Metálicas/química , Camundongos SCID , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/patologia , Rosa Bengala/administração & dosagem , Rosa Bengala/química , Carga Tumoral/efeitos dos fármacos
19.
Endoscopy ; 49(12): 1219-1228, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28732392

RESUMO

Background and study aims Enhanced endoscopic imaging with chromoendoscopy may improve dysplasia recognition in patients undergoing assessment of Barrett's esophagus (BE). This may reduce the need for random biopsies to detect more dysplasia. The aim of this study was to assess the effect of magnification endoscopy with I-SCAN (Pentax, Tokyo, Japan) and acetic acid (ACA) on dysplasia detection in BE using a novel mucosal and vascular classification system. Methods BE segments and suspicious lesions were recorded with high definition white-light and magnification endoscopy enhanced using all I-SCAN modes in combination. We created a novel mucosal and vascular classification system based on similar previously validated classifications for narrow-band imaging (NBI). A total of 27 videos were rated before and after ACA application. Following validation, a further 20 patients had their full endoscopies recorded and analyzed to model use of the system to detect dysplasia in a routine clinical scenario. Results The accuracy of the I-SCAN classification system for BE dysplasia improved with I-SCAN magnification from 69 % to 79 % post-ACA (P = 0.01). In the routine clinical scenario model in 20 new patients, accuracy of dysplasia detection increased from 76 % using a "pull-through" alone to 83 % when ACA and magnification endoscopy were combined (P = 0.047). Overall interobserver agreement between experts for dysplasia detection was substantial (0.69). Conclusions A new I-SCAN classification system for BE was validated against similar systems for NBI with similar outcomes. When used in combination with magnification and ACA, the classification detected BE dysplasia in clinical practice with good accuracy.Trials registered at ISRCTN (58235785).


Assuntos
Esôfago de Barrett/classificação , Esôfago de Barrett/diagnóstico por imagem , Endoscopia Gastrointestinal/métodos , Mucosa Esofágica/diagnóstico por imagem , Ácido Acético , Idoso , Idoso de 80 Anos ou mais , Esôfago de Barrett/patologia , Mucosa Esofágica/irrigação sanguínea , Mucosa Esofágica/patologia , Feminino , Humanos , Indicadores e Reagentes , Masculino , Microvasos/diagnóstico por imagem , Pessoa de Meia-Idade , Variações Dependentes do Observador , Reprodutibilidade dos Testes , Sensibilidade e Especificidade
20.
Oncotarget ; 8(15): 25080-25096, 2017 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-28212575

RESUMO

BACKGROUND: Mucin glycoprotein 1 (MUC1) is a glycosylated transmembrane protein on epithelial cells. We investigate MUC1 as a therapeutic target in Barrett's epithelium (BE) and esophageal adenocarcinoma (EA) and provide proof of concept for a light based therapy targeting MUC1. RESULTS: MUC1 was present in 21% and 30% of significantly enriched pathways comparing BE and EA to squamous epithelium respectively. MUC1 gene expression was x2.3 and x2.2 higher in BE (p=<0.001) and EA (p=0.03). MUC1 immunohistochemical expression increased during progression to EA and followed tumor invasion. HuHMFG1 based photosensitive antibody drug conjugates (ADC) showed cell internalization, MUC1 selective and light-dependent cytotoxicity (p=0.0006) and superior toxicity over photosensitizer alone (p=0.0022). METHODS: Gene set enrichment analysis (GSEA) evaluated pathways during BE and EA development and quantified MUC1 gene expression. Immunohistochemistry and flow cytometry evaluated the anti-MUC1 antibody HuHMFG1 in esophageal cells of varying pathological grade. Confocal microscopy examined HuHMFG1 internalization and HuHMFG1 ADCs were created to deliver a MUC1 targeted phototoxic payload. CONCLUSIONS: MUC1 is a promising target in EA. Molecular and light based targeting of MUC1 with a photosensitive ADC is effective in vitro and after development may enable treatment of locoregional tumors endoscopically.


Assuntos
Adenocarcinoma/genética , Antineoplásicos Imunológicos/farmacologia , Neoplasias Esofágicas/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Imunoconjugados/farmacologia , Luz , Mucina-1/genética , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Biomarcadores , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Biologia Computacional , Progressão da Doença , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/patologia , Perfilação da Expressão Gênica , Glicoproteínas/genética , Glicoproteínas/metabolismo , Humanos , Imuno-Histoquímica , Mucina-1/metabolismo , Gradação de Tumores , Metástase Neoplásica
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