RESUMO
BACKGROUND: Canadian-born children of South Asian [SA] ethnicity develop inflammatory bowel disease [IBD] at similar rates to those among Caucasian children. We evaluated the variation in phenotypic spectrum of IBD in SA and Caucasian children in a national paediatric inception cohort of new-onset IBD. METHODS: Patients aged <17 years, enrolled in a Canadian nationwide inception cohort study, were included. Baseline demographic and IBD phenotypic features were compared between SA and Caucasian children. Longitudinal outcomes through 18 months of follow-up were compared matched by propensity scores. RESULTS: Of 1156 children enrolled over 2014 to 2019, 623 were Caucasian [98% and 88% parents Canadian born] and 114 SA [79% Canadian born, 87% parents SA born]. Fewer SAs have a first-degree relative with IBD, 6% vs 19% in Caucasians, p = 0.002. SAs present at a younger age, median age 11.4 years (interquartile range [IQR] 9.2-14.3) vs 13 years [IQR 10.9-15 years], p = 0.03 and more commonly with a UC/IBD-U [ulcerative colitis/IBD-unclassified] subtype [ratio of UC/IBD-U to CD 1.2:1 vs 1:1.8 for Caucasians, p <0.001]. Additionally, a greater proportion of SA CD patients present with colonic-only disease [colonic-only CD/UC/IBD-U in SAs 67% vs 57% for Caucasians, p = 0.001], and among those with CD, colonic CD in SAs 31% vs 23% in Caucasians, p = 0.20]. Perianal fistulising disease was also numerically more common in SAs (14 [27%] vs 64 [18%], p = 0.06]. Adjusting for differences in phenotypic presentation, anti-tumour necrosis factor [TNF] exposure, and time to initiation was similar, and two-thirds of children, whether anti-TNF exposed or naïve, were in corticosteroid-free clinical remission at 18 months irrespective of ethnicity. CONCLUSIONS: The phenotypic spectrum of new-onset IBD in SA children differs from that of Caucasian children, but treatment and clinical course are similar within phenotypic subgroups.
Assuntos
Colite Ulcerativa , Doença de Crohn , Doenças Inflamatórias Intestinais , Adolescente , Canadá/epidemiologia , Criança , Estudos de Coortes , Colite Ulcerativa/terapia , Doença de Crohn/terapia , Etnicidade , Humanos , Estudos Prospectivos , Inibidores do Fator de Necrose TumoralRESUMO
HYPOTHESIS: Because they have self-similar low-surface-energy microstructures throughout the whole material block, fabricating superhydrophobic monoliths has been currently a promising remedy for the mechanical robustness of non-wetting properties. Noticeably, porous materials have microstructured interfaces throughout the complete volume, and silanization can make surfaces low-surface-energy. Therefore, the porous structure and surface silane-treatment can be combined to render hydrophilic inorganics into mechanically durable superhydrophobic monoliths. EXPERIMENTS: Superhydrophobic diatomaceous earth pellets were produced by thermal-sintering, followed by a silanization process with octyltriethoxysilane. The durability of superhydrophobicity was evaluated by changes in wetting properties, surface morphology, and chemistry after a systematic abrasion sliding test. FINDINGS: The intrinsic porosity of diatomite facilitated surface silanization throughout the whole sintered pellet, thus producing the water-repelling monolith. The abrasion sliding converted multimodal porosity of the volume to hierarchical roughness of the surface comprised of silanized particles, thereby attaining superhydrophobic properties of high contact angles over 150° and sliding angles below 20°. The tribological properties revealed useful information about the superhydrophobicity duration of the non-wetting monolith against friction. The result enables the application of porous structures in the fabrication of the anti-abrasion superhydrophobic materials even though they are originally hydrophilic.
RESUMO
The discovery of Pickering emulsion templated assembly enables the design of a hybrid colloidal capsule with engineered properties. However, the underlying mechanisms by which nanoparticles affect the mechanical properties of the shell are poorly understood. Herein, in situ mechanical compression on the transmission electron microscope and aberration-corrected scanning transmission microscope are unprecedentedly implemented to study the intrinsic effect of nanoparticles on the mechanical properties of the calcium carbonate (CaCO3 )-decorated silica (SiO2 ) colloidal capsule. The stiff and brittle nature of the colloidal capsule is due to the interfacial chemical bonding between the CaCO3 nanoparticles and SiO2 inner shell. Such bonding strengthens the mechanical strength of the SiO2 shell (166 ± 14 nm) from the colloidal capsule compared to the thicker single SiO2 shell (310 ± 70 nm) from the silica hollow sphere. At elevated temperature, this interfacial bonding accelerates the formation of the single calcium silicate shell, causing shell morphology transformation and yielding significantly enhanced mechanical strength by 30.9% and ductility by 94.7%. The superior thermal durability of the heat-treated colloidal capsule holds great potential for the fabrication of the functional additives that can be applied in the wide range of applications at elevated temperatures.
RESUMO
BACKGROUND AND AIMS: Incidence of paediatric inflammatory bowel disease [IBD] in Canada is among the highest worldwide, and age of onset may be decreasing. In a multicentre nationwide inception cohort study, we examined variation in phenotype of IBD throughout the paediatric age spectrum. METHODS: Children aged ≥2 years [y] and <17y [A1 age at diagnosis], with new onset IBD, were systematically evaluated at sites of the Canadian Children IBD Network. Prospectively recorded phenotypic data were compared between age groups. RESULTS: Among 1092 children (70% Caucasian; 64% Crohn's disease [CD], 36% ulcerative colitis/inflammatory bowel disease unclassified [UC/IBD-U]; median age 13 y, interquartile range [IQR] 11-15 y), 210 [19%] were diagnosed before the age of age 10 y [Paris A1a] and 43 [4%] before age 6 y (very-early-onset [VEO-IBD]). CD was less common in younger children [42%, 56%, 66%, respectively, of VEO-IBD, A1a; A1b]. Colon-only IBD [UC/IBDU or CD-colon] was present in 81% of VEO-IBD and 65% of A1a; ileal disease increased progressively, reaching plateau at age 10 y. CD location was ileocolonic [L3] in 53% overall. Ileitis [L1] increased with age [6% of VEO-IBD; 13% of A1a; 21% of A1b], as did stricturing/penetrating CD [4% of A1a; 11% of A1b]. At all ages UC was extensive [E3/E4] in >85%, and disease activity moderate to severe according to Physician's Global Assessment [PGA] and weighted Paediatric Crohn's Disease Activity Index/Paediatric Ulcerative Colitis Activity Index [wPCDAI/PUCAI] in >70%. Heights were modestly reduced in CD [mean height z score -0.30 ± 1.23], but normal in UC/IBD-U. CONCLUSIONS: Paris classification of age at diagnosis is supported by age-related increases in ileal disease until age 10 years. Other phenotypic features, including severity, are similar across all ages. Linear growth is less impaired in CD than in historical cohorts, reflecting earlier diagnosis.
Assuntos
Colite Ulcerativa , Doença de Crohn , Idade de Início , Variação Biológica da População , Canadá/epidemiologia , Criança , Estudos de Coortes , Colite Ulcerativa/diagnóstico , Colite Ulcerativa/epidemiologia , Colite Ulcerativa/fisiopatologia , Doença de Crohn/diagnóstico , Doença de Crohn/epidemiologia , Doença de Crohn/fisiopatologia , Progressão da Doença , Feminino , Humanos , Incidência , Masculino , Estudos Prospectivos , Índice de Gravidade de DoençaRESUMO
INTRODUCTION: The term 'hedonic hunger' refers to one's preoccupation with and desire to consume foods for the purposes of pleasure and in the absence of physical hunger. The Power of Food Scale (PFS) was developed as a quantitative measure of this construct in 2009. Since then, over 50 published studies have used the PFS to predict appetite-related outcomes including neural, cognitive, behavioural, anthropometric and clinical measures. OBJECTIVE: This narrative review evaluates how closely the PFS captures the construct it was originally presumed to assess and to more clearly define hedonic hunger itself. METHODS: The measure's relationship to four domains is reviewed and summarized: motivation to consume palatable foods; level of actual consumption of such foods; body mass; and subjective loss-of-control over one's eating behaviour. Findings are synthesized to generate a more accurate understanding of what the PFS measures and how it may relate to the broader definition of hedonic hunger. RESULTS: Results suggest that the PFS is closely related to motivation to consume palatable foods and, in extreme cases, occurrence of loss-of-control eating episodes. PFS scores are not consistently predictive of amount of food consumed or body mass. CONCLUSIONS: Implications of these findings are discussed in the context of behavioural health, and avenues for further inquiry are identified.
RESUMO
Suboptimal vitamin D (vitD) status and reduced lean body mass are highly prevalent in pediatric inflammatory bowel diseases (IBD). The study objective was to determine sarcopenia prevalence and associations with vitD status in newly diagnosed pediatric IBD. Children with Crohn's disease (CD; n = 58) and ulcerative colitis (UC; n = 27) were included. Primary outcomes included body composition (total/regional/percent fat mass (FM), fat-free mass (FFM), skeletal muscle mass (SMM)), and vitD status (serum 25(OH)D). Sarcopenia was defined as SMM-z < -2. Additional variables measured included serum CRP, ESR, anthropometric, Pediatric Crohn's Disease Activity Index (PCDAI), and the Pediatric Ulcerative Colitis Disease Activity index (PUCAI). Sarcopenia and suboptimal 25(OH)D levels (< 50 nmol/l) were found in 23.5% (n = 20) and 52% (n = 44) of children, respectively. Younger children (< 13 years) with CD with suboptimal 25(OH)vitD (< 50 nmol/l) had the greatest frequency of sarcopenia (57.1%) (p = 0.004). Sarcopenia was prevalent in newly diagnosed, young children with CD with vitD deficiency.
Assuntos
Doenças Inflamatórias Intestinais , Sarcopenia , Deficiência de Vitamina D , Vitamina D/sangue , Adolescente , Criança , Pré-Escolar , Estudos de Coortes , Humanos , Doenças Inflamatórias Intestinais/complicações , Doenças Inflamatórias Intestinais/epidemiologia , Estado Nutricional , Fatores de Risco , Sarcopenia/complicações , Sarcopenia/epidemiologia , Deficiência de Vitamina D/complicações , Deficiência de Vitamina D/epidemiologiaRESUMO
BACKGROUND: Treatment with sorafenib, although associated with inhibition of tumour growth and angiogenesis in in vivo studies, leads to up-regulation of pERK. The addition of MEK inhibition could potentially abrogate this effect and potentiate anti-tumour activity. This phase I study investigated the maximum tolerated dose (MTD), safety, tolerability, pharmacokinetics (PK) and biomarker correlates of selumetinib combined with sorafenib in patients with advanced hepatocellular carcinoma (HCC). METHODS: Patients with Child-Pugh (CP) score ≤7 were treated with 400 mg twice daily of sorafenib with escalating doses of selumetinib in a 3 + 3 study design. The dose-limiting toxicity (DLT) evaluation period was 28 days. PK of selumetinib was determined. Angiogenic effect was evaluated with dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). RESULTS: Twenty-seven patients of Asian ethnicity were enrolled. The MTD was selumetinib 75 mg daily with sorafenib 400 mg twice daily. DLT included grade 3 transaminitis, diarrhoea and fatigue. Most common treatment-related adverse events at MTD (all grades) were diarrhoea (85%), rash (59%), hypertension (44%), fatigue (30%), anorexia (22%) and hand-foot syndrome (22%). Four patients (15%) had PR and 13 (48%) had SD. PR or SD was observed for ≥6 months in seven patients. The median overall survival was 14.4 months. Selumetinib exposures in combination with sorafenib were comparable to other monotherapy studies. A reduction in permeability-surface area product noted in DCE-MRI with treatment correlated with worse survival outcomes. CONCLUSION: The MTD of selumetinib was 75 mg daily when combined with sorafenib 400 mg twice a day in CP ≤7 HCC. Acceptable adverse events and encouraging anti-tumour activity warrant further evaluation. DCE-MRI findings deserve prospective evaluation. CLINICALTRIALSGOV IDENTIFIER: NCT01029418.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Benzimidazóis/administração & dosagem , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Niacinamida/análogos & derivados , Compostos de Fenilureia/administração & dosagem , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Benzimidazóis/efeitos adversos , Carcinoma Hepatocelular/patologia , Intervalo Livre de Doença , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Feminino , Humanos , Estimativa de Kaplan-Meier , Neoplasias Hepáticas/patologia , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Niacinamida/administração & dosagem , Niacinamida/efeitos adversos , Compostos de Fenilureia/efeitos adversos , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , SorafenibeRESUMO
Dental calculus, a material observed in the majority of adults worldwide, emerged as a source for correlating paleomicrobiology with human health and diet. This mini review of 48 articles on the paleomicrobiology of dental calculus over 7550 years discloses a secular core microbiota comprising nine bacterial phyla - Firmicutes, Actinobacteria, Proteobacteria, Bacteroidetes, TM7, Synergistetes, Chloroflexi, Fusobacteria, Spirochetes - and one archaeal phylum Euryarchaeota; and some accessory microbiota that appear and disappear according to time frame. The diet residues and oral microbes, including bacteria, archaea, viruses and fungi, consisting of harmless organisms and pathogens associated with local and systemic infections have been found trapped in ancient dental calculus by morphological approaches, immunolabeling techniques, isotope analyses, fluorescent in situ hybridization, DNA-based approaches, and protein-based approaches. These observations led to correlation of paleomicrobiology, particularly Streptococcus mutans and archaea, with past human health and diet.
Assuntos
Archaea/isolamento & purificação , Bactérias/isolamento & purificação , Cálculos Dentários/história , Adulto , Archaea/genética , Bactérias/genética , Bacteroidetes/genética , Bacteroidetes/isolamento & purificação , Cálculos Dentários/microbiologia , Cálculos Dentários/virologia , Dieta/história , Fusobacterium/genética , Fusobacterium/isolamento & purificação , História Antiga , Humanos , Imuno-Histoquímica , Marcação por Isótopo , Microbiota , Paleodontologia , Filogenia , Proteobactérias/genética , Proteobactérias/isolamento & purificação , Streptococcus mutans/genéticaRESUMO
Methanobrevibacter oralis is the major methanogenic archaea found in the oral cavity. It has been implicated in periodontitis, including the severe form. It is unknown whether certain M. oralis genetic variants are associated with severe periodontitis. Here, we developed multispacer sequence typing (MST) as a sequencing-based genotyping method for the assessment of M. oralis. The sequencing of four intergenic spacers from a collection of 17 dental plaque M. oralis isolates obtained from seven individuals revealed 482 genetic polymorphisms, including 401 single nucleotide polymorphisms (83.2 %), 55 deletions (11.4 %) and 26 insertions (5.4 %). Concatenation of the four spacers yielded nine genotypes, which were clustered into six groups with an index of discrimination of 0.919. One periodontitis patient may have harboured up to three genetic variants of M. oralis, revealing the previously unknown diversity of this archaea. MST will allow for the study of the dynamics of M. oralis populations, including inter-individual transmission and any correlations with the severity of periodontitis.
Assuntos
Placa Dentária/microbiologia , Variação Genética , Genótipo , Methanobrevibacter/classificação , Methanobrevibacter/genética , Adulto , Idoso , Análise por Conglomerados , DNA Arqueal/química , DNA Arqueal/genética , DNA Intergênico , Feminino , Técnicas de Genotipagem , Humanos , Masculino , Methanobrevibacter/isolamento & purificação , Pessoa de Meia-Idade , Dados de Sequência Molecular , Análise de Sequência de DNA , Homologia de SequênciaRESUMO
BACKGROUND & AIMS: Preclinical studies have demonstrated the additive effect of rapamycin with bevacizumab for hepatocellular carcinoma treatment. We conducted a Phase 1 study to evaluate the safety and pharmacokinetics of the combination in patients with hepatocellular carcinoma. METHODS: Adult participants with advanced hepatocellular carcinoma received intravenous bevacizumab (5mg/kg every 14 days) and oral rapamycin (1-6 mg/day; 3+3 dose escalation design). Computed tomography assessed tumour response and treatment safety. Pharmacokinetics assessment established rapamycin blood concentrations pre- and post-dose. Dynamic contrast-enhanced computed tomography analysed the tumour region for blood flow, permeability surface area product, fractional intravascular blood volume and extracellular-extravascular volume. RESULTS: Twenty-four participants were treated. There were two dose limiting toxicities with rapamycin 5mg: grade 3 thrombocytopenia and grade 3 mucositis. The maximally tolerated dose of rapamycin was 4 mg. Adverse events (grade 1-2) included hyperglycaemia (83%), thrombocytopenia (75%), fatigue (46%), mucositis (46%), anorexia (42%), diarrhoea (33%) and proteinuria (12.5%). Of 20 evaluable participants, one reached complete response that lasted 4.5 months, two reached partial response, 14 reached stable disease and three had progressive disease. Median overall survival was 9.4 months; progression-free survival was 5.5 months. Dose level and steady state area under the concentration time curve for hour zero to infinity of rapamycin correlated inversely with blood flow rate and change in permeability-surface area. After 22 days of treatment, there were significant reductions from baseline in blood flow rate, permeability-surface area and fractional intracellular blood volume. CONCLUSIONS: The recommended Phase 2 dose of rapamycin is 4 mg in combination with bevacizumab. Evidence of anti-vascular activity was observed together with promising clinical activity.
Assuntos
Anticorpos Monoclonais Humanizados/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Sirolimo/farmacocinética , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bevacizumab , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Relação Dose-Resposta a Droga , Feminino , Hepatectomia , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Sirolimo/administração & dosagem , Sirolimo/efeitos adversos , Resultado do TratamentoRESUMO
Hepatocellular carcinoma (HCC) is usually refractory to the available treatments. For cancer gene therapy purposes, real-time imaging of therapeutic gene expression is of great importance because there are multiple factors that modulate the therapeutic gene expression in a complex tumor microenvironment. As a consequence, multiple doses of therapeutic viral vectors may be required for improved efficacy. In the present study, the luciferase reporter gene and the yeast cytosine deaminase (yCD) genes were bicistronically expressed using the foot-and-mouth disease virus 2A peptide under the regulation of the cytomegalovirus (CMV) promoter. The effectiveness of the yCD/5-FC (5-fluorocytosine) killing efficacy mediated by the herpes simplex virus type 1 (HSV-1) amplicon viral vector was shown using HCC and non-HCC cell lines in vitro. In addition, in vivo experiment also showed tumor regression of a primary HCC 26-1004 tumor xenograft in tumor expressing high levels of the yCD gene (as determined by noninvasive imaging) after intratumoral injection of 1.5 × 10(6) TU HGCX-L2C HSV-1 amplicon viral vector and 5-FC administration. The HSV-1 amplicon viral vector coupled with the yCD/5-FC prodrug activated suicide gene could potentially be of use in clinical gene therapy for HCC.
Assuntos
Carcinoma Hepatocelular/terapia , Citosina Desaminase/genética , Flucitosina/uso terapêutico , Genes Transgênicos Suicidas , Terapia Genética/métodos , Neoplasias Hepáticas/terapia , Animais , Carcinoma Hepatocelular/genética , Linhagem Celular Tumoral , Vírus da Febre Aftosa/genética , Genes Reporter , Vetores Genéticos , Proteínas de Fluorescência Verde , Herpesvirus Humano 1/genética , Humanos , Neoplasias Hepáticas/genética , Luciferases/genética , Medições Luminescentes/métodos , Camundongos , Camundongos Nus , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Hepatocellular carcinoma (HCC) is the fifth most common and third deadliest malignancy. Sorafenib has demonstrated 44% survival advantage over placebo and has emerged as a standard of care in advanced HCC. The therapeutic effects of sorafenib are however transient and hence additional treatment options are warranted. In this study, we aimed to compare the efficacy of sunitinib relative to sorafenib, two potent inhibitors of protein tyrosine kinases involved in tumor growth, metastasis, or angiogenesis. We reported that sorafenib and sunitinib suppressed tumor growth, angiogenesis, cell proliferation, and induced apoptosis in both orthotopic and ectopic models of HCC. However, the antitumor effect of 50 mg/kg sorafenib was greater than that of 40 mg/kg sunitinib. Sorafenib inhibited p-eIF4E Ser209, p-p38 Thr180/Tyr182 and reduced survivin expression. This was not seen with sunitinib. In addition, the antitumor and apoptotic effects of sorafenib, which are associated with upregulation of fast migrating Bim and ASK1 and downregulation of survivin, were greater than that of sunitinib. These observations explained in part the apparent superior anti-tumor activity of sorafenib compared to sunitinib. In conclusion, sunitinib demonstrated an inferior anti-tumor activity compared to sorafenib in ectopic and orthotopic models of human HCC. It remains to be seen whether such observations would be recapitulated in humans.
Assuntos
Antineoplásicos/uso terapêutico , Benzenossulfonatos/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Indóis/uso terapêutico , Neoplasias Hepáticas/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Piridinas/uso terapêutico , Pirróis/uso terapêutico , Ensaios Antitumorais Modelo de Xenoenxerto/métodos , Inibidores da Angiogênese/uso terapêutico , Animais , Apoptose/efeitos dos fármacos , Proteínas Reguladoras de Apoptose/metabolismo , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Camundongos , Camundongos SCID , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/metabolismo , Neovascularização Patológica/prevenção & controle , Niacinamida/análogos & derivados , Compostos de Fenilureia , Proteínas Tirosina Quinases/antagonistas & inibidores , Distribuição Aleatória , Sorafenibe , SunitinibeRESUMO
BACKGROUND: It is widely recognised that sorafenib inhibits a range of molecular targets in renal cell carcinoma (RCC). In this study, we aim to use patient-derived RCC xenografts to delineate the angiogenic and non-angiogenic molecular targets of sorafenib therapy for advanced RCC (aRCC). METHODS: We successfully generated three patient RCC-derived xenografts in severe combined immunodeficient mice, consisting of three different RCC histological subtypes: conventional clear cell, poorly differentiated clear cell RCC with sarcomatoid changes, and papillary RCC. This study also used clear cell RCC cells (786-0/EV) harbouring mutant VHL to investigate the clonogenic survival of cells transfected with survivin sense and antisense oligonucleotides. RESULTS: All three xenografts retain their original histological characteristics. We reported that sorafenib inhibited all three RCC xenograft lines regardless of histological subtypes in a dose-dependant manner. Sorafenib-induced growth suppression was associated with not only inhibition of angiogenic targets p-PDGFR-ß, p-VEGFR-2, and their downstream signalling pathways p-Akt and p-ERK, cell cycle, and anti-apoptotic proteins that include cyclin D1, cyclin B1, and survivin but also upregulation of proapoptotic Bim. Survivin knockdown by survivin-specific antisense-oligonucleotides inhibited colony formation and induced cell death in clear cell RCC cells. CONCLUSION: This study has shed light on the molecular mechanisms of sorafenib in RCC. Inhibition of non-angiogenic molecules by sorafenib could contribute in part to its anti-tumour activities observed in vivo, in addition to its anti-angiogenic effects.
Assuntos
Benzenossulfonatos/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Neovascularização Patológica/tratamento farmacológico , Piridinas/uso terapêutico , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/uso terapêutico , Benzenossulfonatos/administração & dosagem , Carcinoma de Células Renais/irrigação sanguínea , Carcinoma de Células Renais/patologia , Relação Dose-Resposta a Droga , Regulação para Baixo/efeitos dos fármacos , Humanos , Neoplasias Renais/irrigação sanguínea , Neoplasias Renais/patologia , Masculino , Camundongos , Camundongos SCID , Terapia de Alvo Molecular , Neovascularização Patológica/patologia , Niacinamida/análogos & derivados , Compostos de Fenilureia , Piridinas/administração & dosagem , Sorafenibe , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: Patients with inflammatory bowel disease (IBD) often do not take their medications as prescribed. OBJECTIVE: To examine self-reported adherence rates in IBD patients at the Stollery Children's Hospital (Edmonton, Alberta) and to determine predictors of medication adherence. METHODS: A survey was mailed to 212 pediatric IBD patients of the Stollery Children's Hospital. A chart review was completed for those who returned the survey. RESULTS: A total of 119 patients completed the survey. The nonresponders were significantly older than responders (14.5 years versus 13.2 years; P=0.032). The overall adherence rate was 80%. Nonadherence was associated with older age (14.6 years versus 13.0 years; P=0.04), longer disease duration (5.0 years versus 3.1 years; P=0.004) and reported use of herbal medications (40.0% versus 13.6%; P=0.029). The most common reasons reported for missing medications were forgetfulness, feeling better and too many medications. In addition, patients reported being more likely to take anti-inflammatory medications and less likely to take herbal medicines. CONCLUSION: Identified predictors of nonadherence such as age, disease duration and use of herbal treatments may enable the development of specific strategies to improve adherence in adolescents with IBD.
Assuntos
Doenças Inflamatórias Intestinais/tratamento farmacológico , Adesão à Medicação , Fitoterapia , Adolescente , Fatores Etários , Alberta , Anti-Inflamatórios/uso terapêutico , Criança , Estudos Transversais , Coleta de Dados , Feminino , Hospitais Pediátricos , Humanos , Masculino , Fatores de TempoRESUMO
Hepatocellular carcinoma (HCC) is the fifth most common and third deadliest primary neoplasm. Since HCC is a particularly vascular solid tumor, we determined the antitumor and antiangiogenic activities of sunitinib malate, a potent inhibitor of two receptors involved in angiogenesis - vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR). In the present study, we reported that treatment of HepG2 and SK-Hep-1 cells with sunitinib led to growth inhibition and apoptosis in a dose-dependent fashion. Sunitinib inhibited phosphorylation of VEGFR-2 at Tyr951 and PDGFR-beta at Tyr1021 both in vitro and in vivo. Sunitinib also suppressed tumor growth of five patient-derived xenografts. Sunitinib-induced tumor growth inhibition was associated with increased apoptosis, reduced microvessel density and inhibition of cell proliferation. This study provides a strong rationale for further clinical investigation of sunitinib in patients with hepatocellular carcinoma.
Assuntos
Apoptose/efeitos dos fármacos , Carcinoma Hepatocelular/tratamento farmacológico , Proliferação de Células/efeitos dos fármacos , Indóis/uso terapêutico , Neoplasias Hepáticas Experimentais/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Pirróis/uso terapêutico , Ensaios Antitumorais Modelo de Xenoenxerto , Inibidores da Angiogênese/farmacologia , Inibidores da Angiogênese/uso terapêutico , Animais , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Bevacizumab , Linhagem Celular Tumoral , Células Hep G2 , Humanos , Indóis/farmacologia , Camundongos , Camundongos SCID , Neovascularização Patológica/tratamento farmacológico , Fosforilação/efeitos dos fármacos , Pirróis/farmacologia , SunitinibeRESUMO
Intestinal failure (IF) is a complex, chronic illness, of increasing importance in the pediatric critical care setting. We can expect an increase in pediatric IF given an increase in the survivors of extreme prematurity and complex congenital heart disease. Overall priorities for management of this condition include surgical and medical strategies to promote intestinal adaptation and to reduce complications, particularly related to malnutrition, liver disease and sepsis. In this review the authors propose that the optimal care for children with IF are multidisciplinary teams abreast of the newest strategies for intestinal rehabilitation. Early listing for intestinal transplantation for children at greatest risk of long-term parenteral nutrition dependency and its life threatening complications is appropriate.
Assuntos
Cuidados Críticos , Síndromes de Malabsorção , Criança , Tratamento de Emergência/métodos , Humanos , Intestinos/transplante , Hepatopatias/prevenção & controle , Síndromes de Malabsorção/complicações , Síndromes de Malabsorção/etiologia , Síndromes de Malabsorção/mortalidade , Síndromes de Malabsorção/terapia , Desnutrição/prevenção & controle , Equipe de Assistência ao Paciente , Fatores de Risco , Sepse/prevenção & controle , Resultado do TratamentoRESUMO
AIMS: To evaluate the efficacy of bovine lactoferrin (BLf), recombinant human lactoferrin (rHLf) and desferrioxamine against Helicobacter pylori in vitro and in mice and also to determine whether BLf or rHLf alter gastric inflammation. METHODS AND RESULTS: In vitro: Broth dilution susceptibility tests were performed using different concentrations of desferrioxamine, BLf and rHLf. Murine trials: In the prevention trial, C57BL/6 female mice were treated with BLf or rHLF, and then infected with the SS1 strain of H. pylori. In the treatment trial, mice were gavaged with either BLf, rHLf or desferrioxamine. In addition, gastric myeloperoxidase activity (MPO) was measured to assess gastric inflammation. Desferoxamine was found to have a direct bactericidal effect, while BLf and rHLf only partially suppressed H. pylori growth in vitro. However, in both prevention and treatment trials all three forms of treatment failed to reduce H. pylori load in mice. Gastric MPO activity and H. pylori load were noted to be higher with lactoferrin treatments. CONCLUSIONS: Our study does not support the use of BLf or rHLF in the treatment of human H. pylori infection. Interestingly, H. pylori growth and gastric inflammation appear to be enhanced by lactoferrin treatment. SIGNIFICANCE AND IMPACT OF THE STUDY: The mouse model is ideal for testing novel H. pylori eradicating agents.
Assuntos
Antibacterianos/farmacologia , Desferroxamina/farmacologia , Mucosa Gástrica/imunologia , Infecções por Helicobacter/tratamento farmacológico , Helicobacter pylori/crescimento & desenvolvimento , Lactoferrina/farmacologia , Animais , Antibacterianos/efeitos adversos , Desferroxamina/efeitos adversos , Feminino , Mucosa Gástrica/efeitos dos fármacos , Mucosa Gástrica/microbiologia , Infecções por Helicobacter/imunologia , Infecções por Helicobacter/microbiologia , Helicobacter pylori/efeitos dos fármacos , Humanos , Inflamação/tratamento farmacológico , Inflamação/microbiologia , Lactoferrina/efeitos adversos , Camundongos , Resultado do TratamentoRESUMO
This is the first reported case of respiratory failure associated with human metapneumovirus (hMPV) infection in a liver transplant recipient or in a pediatric solid transplant recipient. A 9-month-old female developed respiratory distress 8 days following a liver transplant. hMPV was detected and she required intubation followed by extracorporeal membrane oxygenation for 26 days. Immunosuppressive medications were stopped during the acute infection except for methylprednisolone as treatment for acute respiratory distress. Serial Doppler ultrasounds were used to monitor for hepatic vessel thromboses and serum liver function tests to assess for hepatic dysfunction and there was no evidence of allograft rejection. The patient recovered from the nosocomial hMPV infection with satisfactory pulmonary function and possible mild developmental delay.
Assuntos
Transplante de Fígado , Metapneumovirus , Insuficiência Respiratória/virologia , Feminino , Humanos , Lactente , Infecções por ParamyxoviridaeRESUMO
We report on two Aboriginal patients with the hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome. Both presented with acute hepatic failure with severe hypertransaminasemia and coagulopathy, prompting evaluation for emergent liver transplantation. The diagnosis of HHH syndrome was based on the presence of typical metabolic abnormalities. A protein-restricted diet and L-arginine or L-citrulline supplementation were immediately started, with rapid normalization of liver function test results and other biochemical abnormalities. Molecular analysis of the SLC25A15 gene showed that the two patients were homozygous for the common French Canadian mutation (F188Delta). The diagnosis of HHH syndrome should be considered in patients with unexplained fulminant hepatic failure. There does not appear to be a genotype-phenotype correlation for this presentation, inasmuch as the only other reported patient presenting with this picture had two different point mutations. Early identification and prompt treatment of these patients is crucial to avoid liver transplantation and can be life saving.