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1.
Ann Surg Oncol ; 2022 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-35181812

RESUMO

BACKGROUND: Recurrence rates of intrahepatic cholangiocarcinoma (iCCA) after curative hepatectomy are as high as 50% to 70%, and about half of these recurrences occur within 2 years. This systematic review aims to define prognostic factors (PFs) for early recurrence (ER, within 24 months) and 24-month disease-free survival (DFS) after curative-intent iCCA resections. METHODS: Systematic searching was performed from database inception to 14 January 2021. Duplicate independent review and data extraction were performed. Data on 13 predefined PFs were collected. Meta-analysis was performed on PFs for ER and summarized using forest plots. The Quality in Prognostic Factor Studies tool was used for risk-of-bias assessment. RESULTS: The study enrolled 10 studies comprising 4158 patients during an accrual period ranging from 1990 to 2016. In the risk-of-bias assessment of patients who experienced ER after curative-intent iCCA resection, six studies were rated as low risk and four as moderate risk (49.6%; 95% confidence interval [CI], 49.2-50.0). Nine studies were pooled for meta-analysis. Of the postoperative PFs, multiple tumors, microvascular invasion, macrovascular invasion, lymph node metastasis, and R1 resection were associated with an increased hazard for ER or a reduced 24-month DFS, and the opposite was observed for receipt of adjuvant chemo/radiation therapy. Of the preoperative factors, cirrhosis, sex, HBV status were not associated with ER or 24-month DFS. CONCLUSION: The findings from this systematic review could allow for improved surveillance, prognostication, and treatment decision-making for patients with resectable iCCAs. Further well-designed prospective studies are needed to explore prognostic factors for iCCA ER with a focus on preoperative variables.

2.
Bioconjug Chem ; 30(3): 703-713, 2019 03 20.
Artigo em Inglês | MEDLINE | ID: mdl-30582799

RESUMO

Hepatocellular carcinoma (HCC) is the sixth most common cancer worldwide with poor prognosis and limited options for treatment. Life expectancy after diagnosis is short; the currently available treatments are not well tolerated and have limited clinical benefit. There is a clear unmet clinical need for the development of new treatments. In this study, ultrasmall, 2 nm gold core nanoparticles (MidaCore) conjugated with the potent maytansine analogue DM1 (MTC-100038) were assessed as a systemic nanomedicine for the treatment of hepatocellular carcinoma. The platform improved overall tolerability of DM1, permitting ∼3-fold higher levels of drug to be administered compared to free drug. Dose for dose, MTC-100038 also facilitated delivery of ∼2.0-fold higher ( p = 0.039) levels of DM1 to the tumor compared to free DM1. MTC-100038 produced significant efficacy (tumor growth index ∼102%; p = <0.0001), in several murine xenograft models of HCC, and was superior to both free DM1 and the current standard of care, sorafenib. Furthermore, MTC-100038 displayed potent (nM) in vitro activity in various HCC primary patient derived cell lines and across various other different cancer cell types. These data demonstrate the potential of MidaCore nanoparticles to enhance tumor delivery of cytotoxic drugs and indicate MTC-100038 is worthy of further investigation as a potential treatment for HCC and other cancer types.


Assuntos
Antineoplásicos Fitogênicos/administração & dosagem , Carcinoma Hepatocelular/tratamento farmacológico , Ouro/química , Neoplasias Hepáticas/tratamento farmacológico , Maitansina/administração & dosagem , Nanopartículas Metálicas/química , Animais , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacocinética , Linhagem Celular Tumoral , Modelos Animais de Doenças , Portadores de Fármacos , Feminino , Humanos , Maitansina/análogos & derivados , Nanopartículas Metálicas/toxicidade , Camundongos , Camundongos Endogâmicos BALB C , Tamanho da Partícula , Ensaios Antitumorais Modelo de Xenoenxerto
3.
Am J Physiol Endocrinol Metab ; 308(10): E860-7, 2015 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-25783892

RESUMO

Dogs consuming a hypercaloric high-fat and -fructose diet (52 and 17% of total energy, respectively) or a diet high in either fructose or fat for 4 wk exhibited blunted net hepatic glucose uptake (NHGU) and glycogen deposition in response to hyperinsulinemia, hyperglycemia, and portal glucose delivery. The effect of a hypercaloric diet containing neither fructose nor excessive fat has not been examined. Dogs with an initial weight of ≈25 kg consumed a chow and meat diet (31% protein, 44% carbohydrate, and 26% fat) in weight-maintaining (CTR; n = 6) or excessive (Hkcal; n = 7) amounts for 4 wk (cumulative weight gain 0.0 ± 0.3 and 1.5 ± 0.5 kg, respectively, P < 0.05). They then underwent clamp studies with infusions of somatostatin and intraportal insulin (4× basal) and glucagon (basal). The hepatic glucose load was doubled with peripheral (Pe) glucose infusion for 90 min (P1) and intraportal glucose at 4 mg·kg(-1)·min(-1) plus Pe glucose for the final 90 min (P2). NHGU was blunted (P < 0.05) in Hkcal during both periods (mg·kg(-1)·min(-1); P1: 1.7 ± 0.2 vs. 0.3 ± 0.4; P2: 3.6 ± 0.3 vs. 2.3 ± 0.4, CTR vs. Hkcal, respectively). Terminal hepatic glucokinase catalytic activity was reduced nearly 50% in Hkcal vs. CTR (P < 0.05), although glucokinase protein did not differ between groups. In Hkcal vs. CTR, liver glycogen was reduced 27% (P < 0.05), with a 91% increase in glycogen phosphorylase activity (P < 0.05) but no significant difference in glycogen synthase activity. Thus, Hkcal impaired NHGU and glycogen synthesis compared with CTR, indicating that excessive energy intake, even if the diet is balanced and nutritious, negatively impacts hepatic glucose metabolism.


Assuntos
Glucose/farmacocinética , Hiperfagia/metabolismo , Fígado/metabolismo , Animais , Glicemia/metabolismo , Peptídeo C/sangue , Doença Crônica , Cães , Ingestão de Alimentos , Técnica Clamp de Glucose , Insulina/metabolismo , Masculino , Aumento de Peso
4.
Am J Physiol Endocrinol Metab ; 307(2): E151-60, 2014 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-24865981

RESUMO

In dogs consuming a high-fat and -fructose diet (52 and 17% of total energy, respectively) for 4 wk, hepatic glucose uptake (HGU) in response to hyperinsulinemia, hyperglycemia, and portal glucose delivery is markedly blunted with reduction in glucokinase (GK) protein and glycogen synthase (GS) activity. The present study compared the impact of selective increases in dietary fat and fructose on liver glucose metabolism. Dogs consumed weight-maintaining chow (CTR) or hypercaloric high-fat (HFA) or high-fructose (HFR) diets diet for 4 wk before undergoing clamp studies with infusion of somatostatin and intraportal insulin (3-4 times basal) and glucagon (basal). The hepatic glucose load (HGL) was doubled during the clamp using peripheral vein (Pe) glucose infusion in the first 90 min (P1) and portal vein (4 mg·kg(-1)·min(-1)) plus Pe glucose infusion during the final 90 min (P2). During P2, HGU was 2.8 ± 0.2, 1.0 ± 0.2, and 0.8 ± 0.2 mg·kg(-1)·min(-1) in CTR, HFA, and HFR, respectively (P < 0.05 for HFA and HFR vs. CTR). Compared with CTR, hepatic GK protein and catalytic activity were reduced (P < 0.05) 35 and 56%, respectively, in HFA, and 53 and 74%, respectively, in HFR. Liver glycogen concentrations were 20 and 38% lower in HFA and HFR than CTR (P < 0.05). Hepatic Akt phosphorylation was decreased (P < 0.05) in HFA (21%) but not HFR. Thus, HFR impaired hepatic GK and glycogen more than HFA, whereas HFA reduced insulin signaling more than HFR. HFA and HFR effects were not additive, suggesting that they act via the same mechanism or their effects converge at a saturable step.


Assuntos
Dieta Hiperlipídica , Gorduras na Dieta/farmacologia , Frutose/farmacologia , Glucose/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Animais , Glicemia/metabolismo , Dieta Hiperlipídica/veterinária , Carboidratos da Dieta/farmacologia , Cães , Glucoquinase/metabolismo , Glicerol/metabolismo , Ácido Láctico/metabolismo , Masculino , Triglicerídeos/metabolismo
5.
Thin Solid Films ; 519(6): 2003-2010, 2011 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-21494321

RESUMO

Hydrogen silsesquioxane (HSQ) is a material with the potential for studying the effect of surface stiffness on stem cell differentiation. Here, the effects of electron beam dose on the topography and the mechanical properties of HSQ obtained with or without trimethylamine (TMA) development are characterised by atomic force microscopy imaging and indentation. A correlation between the surface stiffness (uniform across the sample) and electron beam exposure is observed. Surface roughness of HSQ samples developed in TMA decreases exponentially with increasing electron beam exposure. Surface coating with plasma polymerised allylamine (ppAAm) leads to an overall decrease in stiffness values. However, the increase in surface stiffness with increasing electron beam exposure is still evident. The ppAAm coating is shown to facilitate human mesenchymal stem cell adhesion.

6.
BMJ Open ; 11(3): e040481, 2021 03 19.
Artigo em Inglês | MEDLINE | ID: mdl-33741659

RESUMO

INTRODUCTION: Blood pressure (BP) is normally measured on the upper arm, and guidelines for the diagnosis and treatment of high BP are based on such measurements. Leg BP measurement can be an alternative when brachial BP measurement is impractical, due to injury or disability. Limited data exist to guide interpretation of leg BP values for hypertension management; study-level systematic review findings suggest that systolic BP (SBP) is 17 mm Hg higher in the leg than the arm. However, uncertainty remains about the applicability of this figure in clinical practice due to substantial heterogeneity. AIMS: To examine the relationship between arm and leg SBP, develop and validate a multivariable model predicting arm SBP from leg SBP and investigate the prognostic association between leg SBP and cardiovascular disease and mortality. METHODS AND ANALYSIS: Individual participant data (IPD) meta-analyses using arm and leg SBP measurements for 33 710 individuals from 14 studies within the Inter-arm blood pressure difference IPD (INTERPRESS-IPD) Collaboration. We will explore cross-sectional relationships between arm and leg SBP using hierarchical linear regression with participants nested by study, in multivariable models. Prognostic models will be derived for all-cause and cardiovascular mortality and cardiovascular events. ETHICS AND DISSEMINATION: Data originate from studies with prior ethical approval and consent, and data sharing agreements are in place-no further approvals are required to undertake the secondary analyses proposed in this protocol. Findings will be published in peer-reviewed journal articles and presented at conferences. A comprehensive dissemination strategy is in place, integrated with patient and public involvement. PROSPERO REGISTRATION NUMBER: CRD42015031227.


Assuntos
Hipertensão , Perna (Membro) , Pressão Sanguínea , Determinação da Pressão Arterial , Estudos Transversais , Humanos , Hipertensão/diagnóstico , Metanálise como Assunto
7.
Am J Physiol Endocrinol Metab ; 299(6): E887-98, 2010 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-20823448

RESUMO

The objective of this study was to assess the response of a large animal model to high dietary fat and fructose (HFFD). Three different metabolic assessments were performed during 13 wk of feeding an HFFD (n = 10) or chow control (CTR, n = 4) diet: oral glucose tolerance tests (OGTTs; baseline, 4 and 8 wk), hyperinsulinemic-euglycemic clamps (HIEGs; baseline and 10 wk) and hyperinsulinemic-hyperglycemic clamps (HIHGs, 13 wk). The ΔAUC for glucose during the OGTTs more than doubled after 4 and 8 wk of HFFD feeding, and the average glucose infusion rate required to maintain euglycemia during the HIEG clamps decreased by ≈30% after 10 wk of HFFD feeding. These changes did not occur in the CTR group. The HIHG clamps included experimental periods 1 (P1, 0-90 min) and 2 (P2, 90-180 min). During P1, somatostatin, basal intraportal glucagon, 4 × basal intraportal insulin, and peripheral glucose (to double the hepatic glucose load) were infused; during P2, glucose was also infused intraportally (4.0 mg·kg(-1)·min(-1)). Net hepatic glucose uptake during P1 and P2 was -0.4 ± 0.1 [output] and 0.2 ± 0.8 mg·kg(-1)·min(-1) in the HFFD group, respectively, and 1.8 ± 0.8 and 3.5 ± 1.0 mg·kg(-1)·min(-1) in the CTR group, respectively (P < 0.05 vs. HFFD during P1 and P2). Glycogen synthesis through the direct pathway was 0.5 ± 0.2 and 1.5 ± 0.4 mg·kg(-1)·min(-1) in the HFFD and CTR groups, respectively (P < 0.05 vs. HFFD). In conclusion, chronic consumption of an HFFD diminished the sensitivity of the liver to hormonal and glycemic cues and resulted in a marked impairment in NHGU and glycogen synthesis.


Assuntos
Gorduras na Dieta/metabolismo , Frutose/metabolismo , Intolerância à Glucose/metabolismo , Glucose/metabolismo , Fígado/metabolismo , Análise de Variância , Animais , Área Sob a Curva , Transporte Biológico , Carboidratos da Dieta/administração & dosagem , Carboidratos da Dieta/efeitos adversos , Carboidratos da Dieta/metabolismo , Gorduras na Dieta/administração & dosagem , Gorduras na Dieta/efeitos adversos , Cães , Frutose/administração & dosagem , Frutose/efeitos adversos , Glucagon/metabolismo , Técnica Clamp de Glucose , Intolerância à Glucose/etiologia , Teste de Tolerância a Glucose , Masculino
9.
Nanoscale Adv ; 1(2): 807-816, 2019 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-36132240

RESUMO

Ultra-small gold nanoparticles, surface functionalised with a 50 : 50 ratio of a thiolated α-galactose derivative and a thiolated hexaethylene glycol amine, are toxic to HSC-3 oral squamous carcinoma cells. Differences in nanoparticle toxicity were found to be related to the synthesis duration, with 1 h reaction nanoparticles being less toxic than 5 h reaction nanoparticles. The ligand density decreased with longer reaction time, although the size, charge and ligand ratio remained similar. The concentration of sodium borohydride in the reaction decreased logarithmically over 5 h but remained within a concentration range sufficient to desorb weakly bound ligands, possibly explaining the observed gradual decrease in ligand density. Nanoparticle toxicity was abrogated by inhibition of either caspase 3/7 or caspase 8, but not by inhibition of caspase 9, consistent with extrinsic apoptosis. Electron microscopic analysis of cellular uptake demonstrated predominantly cytoplasmic localization. However, when energy-dependent transport was inhibited, by lowering the temperature to 4 °C, a remarkable adhesion of nanoparticles to filopodia was observed. Inhibition of filopodial assembly with a fascin inhibitor prevented nanoparticle adhesion to HSC-3 cells at 4 °C, while fascin inhibition at 37 °C resulted in less cytoplasmic uptake. More adhesion to HSC-3 filopodia was seen with the higher toxicity 5 h reaction time nanoparticles than with the 1 h nanoparticles. By including two further cell types (HaCaT keratinocytes and hCMEC/D3 endothelial cells), a pattern of increasing toxicity with filopodial binding of 5 h reaction nanoparticles became apparent.

10.
Diabetes ; 68(6): 1143-1155, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30936143

RESUMO

This study assessed the effectiveness of surgical sympathetic denervation of the common hepatic artery (CHADN) in improving glucose tolerance. CHADN eliminated norepinephrine content in the liver and partially decreased it in the pancreas and the upper gut. We assessed oral glucose tolerance at baseline and after 4 weeks of high-fat high-fructose (HFHF) feeding. Dogs were then randomized to sham surgery (SHAM) (n = 9) or CHADN surgery (n = 11) and retested 2.5 or 3.5 weeks later while still on the HFHF diet. CHADN improved glucose tolerance by ∼60% in part because of enhanced insulin secretion, as indicated by an increase in the insulinogenic index. In a subset of dogs (SHAM, n = 5; CHADN, n = 6), a hyperinsulinemic-hyperglycemic clamp was used to assess whether CHADN could improve hepatic glucose metabolism independent of a change in insulin release. CHADN reduced the diet-induced defect in net hepatic glucose balance by 37%. In another subset of dogs (SHAM, n = 4; CHADN, n = 5) the HFHF diet was continued for 3 months postsurgery and the improvement in glucose tolerance caused by CHADN continued. In conclusion, CHADN has the potential to enhance postprandial glucose clearance in states of diet-induced glucose intolerance.


Assuntos
Dieta Hiperlipídica , Açúcares da Dieta , Intolerância à Glucose/metabolismo , Artéria Hepática/inervação , Fígado/metabolismo , Norepinefrina/metabolismo , Simpatectomia , Animais , Cães , Frutose , Técnica Clamp de Glucose , Teste de Tolerância a Glucose , Masculino , Pâncreas/metabolismo , Distribuição Aleatória , Trato Gastrointestinal Superior/metabolismo
11.
Biophys J ; 94(4): 1233-40, 2008 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-17965134

RESUMO

R. Bension has proposed that single molecules of DNA could be sequenced rapidly, in long sequential reads, by reading off the force required to pull a tightly fitting molecular ring over each base in turn using an atomic force microscope (AFM). We present molecular dynamics simulations that indicate that pulling DNA very rapidly (m/s) could generate large force peaks as each base is passed ( approximately 1 nN) with significant differences ( approximately 0.5 nN) between purine and pyrimidine. These speeds are six orders of magnitude faster than could be read out by a conventional AFM, and extending the calculations to accessible speeds using Kramers' theory shows that thermal fluctuations dominate the process with the result that purine and pyrimidine cannot be distinguished with the pulling speeds attained by current AFM technology.


Assuntos
DNA/química , DNA/ultraestrutura , Microscopia de Força Atômica/métodos , Modelos Químicos , Modelos Moleculares , Nanoestruturas/química , Análise de Sequência de DNA/métodos , Simulação por Computador , Elasticidade , Nanoestruturas/ultraestrutura , Conformação de Ácido Nucleico , Estresse Mecânico
12.
Transplantation ; 85(3): 331-7, 2008 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-18301328

RESUMO

BACKGROUND: Pancreatic islet transplantation has shown great success in the treatment of diabetic patients. However, the required immunosuppressive therapy exposes patients to serious side effects. METHODS: We have designed a novel five-component/three-membrane capsule and encapsulation system to protect the transplanted islet cells from immune system attack while allowing the influx of molecules and nutrients necessary for cell function/survival and efflux of the desired cellular product, specifically insulin, for making recipients healthy. RESULTS: We transplanted encapsulated canine pancreatic islets into the peritoneal cavity of pancreatectomized canines. Transplantation normalized fasting blood glucose levels in nine out of nine dogs for up to 214 days with a single transplantation. Retransplantation was assessed in three animals and encapsulated islets were effective in providing fasting glycemic control after the initial transplantation had run its course. No immunosuppression or anti-inflammatory therapy was used. CONCLUSION: This advancement in transplantation may lead to an alternative approach for islet transplantation treatment for diabetic patients. This approach may also benefit patients suffering from other hormone deficiency diseases including liver disease and Parkinson's disease.


Assuntos
Diabetes Mellitus/cirurgia , Transplante das Ilhotas Pancreáticas/imunologia , Transplante das Ilhotas Pancreáticas/métodos , Pancreatectomia , Animais , Glicemia/metabolismo , Diabetes Mellitus/metabolismo , Diabetes Mellitus/patologia , Modelos Animais de Doenças , Cães , Feminino , Terapia de Imunossupressão , Transplante das Ilhotas Pancreáticas/patologia , Masculino , Porosidade , Transplante Homólogo/imunologia
13.
Diabetes ; 67(6): 1173-1181, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29540491

RESUMO

We evaluated the hepatic and nonhepatic responses to glucose-responsive insulin (GRI). Eight dogs received GRI or regular human insulin (HI) in random order. A primed, continuous intravenous infusion of [3-3H]glucose began at -120 min. Basal sampling (-30 to 0 min) was followed by two study periods (150 min each), clamp period 1 (P1) and clamp period 2 (P2). At 0 min, somatostatin and GRI (36 ± 3 pmol/kg/min) or HI (1.8 pmol/kg/min) were infused intravenously; basal glucagon was replaced intraportally. Glucose was infused intravenously to clamp plasma glucose at 80 mg/dL (P1) and 240 mg/dL (P2). Whole-body insulin clearance and insulin concentrations were not different in P1 versus P2 with HI, but whole-body insulin clearance was 23% higher and arterial insulin 16% lower in P1 versus P2 with GRI. Net hepatic glucose output was similar between treatments in P1. In P2, both treatments induced net hepatic glucose uptake (HGU) (HI mean ± SEM 2.1 ± 0.5 vs. 3.3 ± 0.4 GRI mg/kg/min). Nonhepatic glucose uptake in P1 and P2, respectively, differed between treatments (2.6 ± 0.3 and 7.4 ± 0.6 mg/kg/min with HI vs. 2.0 ± 0.2 and 8.1 ± 0.8 mg/kg/min with GRI). Thus, glycemia affected GRI but not HI clearance, with resultant differential effects on HGU and nonHGU. GRI holds promise for decreasing hypoglycemia risk while enhancing glucose uptake under hyperglycemic conditions.


Assuntos
Avaliação Pré-Clínica de Medicamentos , Drogas em Investigação/efeitos adversos , Metabolismo Energético/efeitos dos fármacos , Hipoglicemiantes/efeitos adversos , Insulina Regular Humana/análogos & derivados , Fígado/efeitos dos fármacos , Absorção Fisiológica/efeitos dos fármacos , Animais , Glicemia/análise , Glicemia/metabolismo , Cães , Relação Dose-Resposta a Droga , Drogas em Investigação/administração & dosagem , Drogas em Investigação/farmacocinética , Gluconeogênese/efeitos dos fármacos , Técnica Clamp de Glucose , Glicosilação , Humanos , Hiperglicemia/metabolismo , Hiperglicemia/prevenção & controle , Hipoglicemia/induzido quimicamente , Hipoglicemia/metabolismo , Hipoglicemia/prevenção & controle , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/sangue , Hipoglicemiantes/farmacocinética , Infusões Intravenosas , Insulina Regular Humana/administração & dosagem , Insulina Regular Humana/efeitos adversos , Insulina Regular Humana/farmacocinética , Fígado/metabolismo , Masculino , Taxa de Depuração Metabólica , Distribuição Aleatória , Somatostatina/administração & dosagem , Somatostatina/efeitos adversos
14.
Metabolism ; 56(6): 814-24, 2007 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-17512315

RESUMO

We examined the role of vagus nerves in the transmission of the portal glucose signal in conscious dogs. At time 0, somatostatin infusion was started along with intraportal insulin and glucagon at 4-fold basal and basal rates, respectively. Glucose was infused via a peripheral vein to create hyperglycemia ( approximately 2 fold basal). At t = 90, hollow coils around the vagus nerves were perfused with -10 degrees C or 37 degrees C solution in the vagally cooled (COOL) and sham-cooled (SHAM) groups, respectively (n = 6 per group). Effectiveness of vagal blockade was demonstrated by increase in heart rate during perfusion in the COOL vs SHAM groups (183 +/- 3 vs 102 +/- 5 beats per minute, respectively) and by prolapse of the third eyelid in the COOL group. Arterial plasma insulin (22 +/- 2 and 24 +/- 3 micro U/mL) and glucagon (37 +/- 5 and 40 +/- 4 pg/mL) concentrations did not change significantly between the first experimental period and the coil perfusion period in either the SHAM or COOL group, respectively. The hepatic glucose load throughout the entire experiment was 46 +/- 1 and 50 +/- 2 mg . kg(-1) . min(-1) in the SHAM and COOL groups, respectively. Net hepatic glucose uptake (NHGU) did not differ in the SHAM and COOL groups before (2.2 +/- 0.5 and 2.9 +/- 0.8 mg . kg(-1) . min(-1), respectively) or during the cooling period (3.0 +/- 0.5 and 3.4 +/- 0.6 mg . kg(-1) . min(-1), respectively). Likewise, net hepatic glucose fractional extraction and nonhepatic glucose uptake and clearance were not different between groups during coil perfusion. Interruption of vagal signaling in the presence of hyperinsulinemia and hyperglycemia resulting from peripheral glucose infusion did not affect NHGU, further supporting our previous suggestion that vagal input to the liver is not a primary determinant of NHGU.


Assuntos
Glucose/metabolismo , Hiperglicemia/metabolismo , Fígado/metabolismo , Nervo Vago/fisiologia , Animais , Glicemia/análise , Temperatura Baixa , Cães , Ácido Láctico/metabolismo , Circulação Hepática
15.
PLoS One ; 12(7): e0181103, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28700660

RESUMO

Two nanometre gold nanoparticles (AuNPs), bearing sugar moieties and/or thiol-polyethylene glycol-amine (PEG-amine), were synthesised and evaluated for their in vitro toxicity and ability to radiosensitise cells with 220 kV and 6 MV X-rays, using four cell lines representing normal and cancerous skin and breast tissues. Acute 3 h exposure of cells to AuNPs, bearing PEG-amine only or a 50:50 ratio of alpha-galactose derivative and PEG-amine resulted in selective uptake and toxicity towards cancer cells at unprecedentedly low nanomolar concentrations. Chemotoxicity was prevented by co-administration of N-acetyl cysteine antioxidant, or partially prevented by the caspase inhibitor Z-VAD-FMK. In addition to their intrinsic cancer-selective chemotoxicity, these AuNPs acted as radiosensitisers in combination with 220 kV or 6 MV X-rays. The ability of AuNPs bearing simple ligands to act as cancer-selective chemoradiosensitisers at low concentrations is a novel discovery that holds great promise in developing low-cost cancer nanotherapeutics.


Assuntos
Inibidores de Caspase/química , Inibidores de Caspase/farmacologia , Ouro/química , Nanopartículas Metálicas/química , Apoptose/efeitos dos fármacos , Linhagem Celular , Linhagem Celular Tumoral , Humanos , Espectroscopia de Ressonância Magnética , Microscopia Eletrônica de Transmissão
16.
PLoS One ; 11(8): e0161610, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27560685

RESUMO

The selective entry of nanoparticles into target tissues is the key factor which determines their tissue distribution. Entry is primarily controlled by microvascular endothelial cells, which have tissue-specific properties. This study investigated the cellular properties involved in selective transport of gold nanoparticles (<5 nm) coated with PEG-amine/galactose in two different human vascular endothelia. Kidney endothelium (ciGENC) showed higher uptake of these nanoparticles than brain endothelium (hCMEC/D3), reflecting their biodistribution in vivo. Nanoparticle uptake and subcellular localisation was quantified by transmission electron microscopy. The rate of internalisation was approximately 4x higher in kidney endothelium than brain endothelium. Vesicular endocytosis was approximately 4x greater than cytosolic uptake in both cell types, and endocytosis was blocked by metabolic inhibition, whereas cytosolic uptake was energy-independent. The cellular basis for the different rates of internalisation was investigated. Morphologically, both endothelia had similar profiles of vesicles and cell volumes. However, the rate of endocytosis was higher in kidney endothelium. Moreover, the glycocalyces of the endothelia differed, as determined by lectin-binding, and partial removal of the glycocalyx reduced nanoparticle uptake by kidney endothelium, but not brain endothelium. This study identifies tissue-specific properties of vascular endothelium that affects their interaction with nanoparticles and rate of transport.


Assuntos
Endotélio Vascular/efeitos dos fármacos , Ouro/química , Nanopartículas Metálicas/química , Animais , Transporte Biológico , Encéfalo/metabolismo , Citosol/metabolismo , Endocitose , Células Endoteliais/metabolismo , Humanos , Rim/metabolismo , Masculino , Microscopia Eletrônica de Transmissão , Polietilenoglicóis/química , Polissacarídeos/química , Ratos , Ratos Wistar , Distribuição Tecidual
17.
Nanomedicine (Lond) ; 11(6): 617-25, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26911484

RESUMO

AIM: To identify the localization of glucose-coated gold nanoparticles within cells of the brain after intravascular infusion which may point to the mechanism by which they cross the blood-brain barrier. MATERIALS & METHODS: Tissue distribution of the nanoparticles was measured by inductively-coupled-mass spectrometry and localization within the brain by histochemistry and electron microscopy. RESULTS & CONCLUSION: Nanoparticles were identified within neurons and glial cells more than 10 µm from the nearest microvessel within 10 min of intracarotid infusion. Their distribution indicated movement across the endothelial cytosol, and direct transfer between cells of the brain. The rapid movement of this class of nanoparticle (<5 nm) into the brain demonstrates their potential to carry therapeutic biomolecules or imaging reagents.


Assuntos
Encéfalo/metabolismo , Glucose/química , Glucose/farmacocinética , Ouro/química , Ouro/farmacocinética , Nanopartículas Metálicas/química , Animais , Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/ultraestrutura , Encéfalo/citologia , Encéfalo/ultraestrutura , Glucose/administração & dosagem , Ouro/administração & dosagem , Masculino , Nanopartículas Metálicas/administração & dosagem , Nanopartículas Metálicas/análise , Tamanho da Partícula , Ratos Wistar , Distribuição Tecidual
18.
Oecologia ; 44(2): 236-240, 1980 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28310562

RESUMO

The effects of altered tidal circulation on southern California salt marshes are investigated by comparing a well-flushed wetland and two modified wetlands which have reduced tidal flow. The Tijuana Estuary had continuous exchange of seawater but relatively low net aerial primary productivity (0.4-1.0 kg m-2yr-1) of vascular plants. Low productivity (0.6 kg m-2yr-1) was also found in the Flood Control Channel of the San Diego River, where tidal exchange was restricted to flow through a riprap dike. High productivity (1.2-2.9 kg m-2yr-1) in Los Penasquitos Lagoon was attributed to the influences of freshwater impounded behind a sand bar which blocked the mouth of the lagoon during much of the study period.It is hypothesized that elimination of tidal flow during the growing season increased primary productivity of vascular plants because freshwater runoff decreased soil salinity and because nutrients were retained within the marsh. However, we predict that sand bar obstruction can decrease productivity if below-average rainfall leads to hypersalinity of closed lagoons. Comprehensive evaluation of the effects of altered tidal circulation requires longterm study and examination of the total ecosystem.

19.
Appl Spectrosc ; 66(5): 595-9, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22524966

RESUMO

Near-infrared spectroscopy in diffuse reflection mode was used to evaluate the apparent viscosity of Para rubber field latex and concentrated latex over the wavelength range of 1100 to 2500 nm, using partial least square regression (PLSR). The model with ten principal components (PCs) developed using the raw spectra accurately predicted the apparent viscosity with correlation coefficient (r), standard error of prediction (SEP), and bias of 0.974, 8.6 cP, and -0.4 cP, respectively. The ratio of the SEP to the standard deviation (RPD) and the ratio of the SEP to the range (RER) for the prediction were 4.4 and 16.7, respectively. Therefore, the model can be used for measurement of the apparent viscosity of field latex and concentrated latex in quality assurance and process control in the factory.


Assuntos
Borracha/química , Espectroscopia de Luz Próxima ao Infravermelho/métodos , Hevea/química , Análise dos Mínimos Quadrados , Análise de Componente Principal , Viscosidade
20.
J Agric Food Chem ; 60(40): 9948-53, 2012 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-22963599

RESUMO

Livestock manure contains natural steroid hormones, with the most potent being 17ß-estradiol. The transport of steroid hormones from agricultural fields to adjacent water bodies can result in 17ß-estradiol environmental contamination impacting aquatic organisms. Sorption coefficients are useful input into models that estimate risk of water contamination. The feasibility of applying near-infrared spectroscopy (NIRS) for determining sorption coefficients of 17ß-estradiol in soil was investigated for two irregular undulating to hummocky terrain landscapes in Manitoba and Saskatchewan, Canada. A total of 609 soil samples in 140 soil profiles were collected from several horizons to a depth of 1 m. Air-dried and sieved (2 mm) soil samples were analyzed for soil organic carbon (SOC), soil pH, and soil texture. Sorption coefficients of 17ß-estradiol were determined by a batch equilibrium process. Spectral data were collected from soil samples (25 g) using two instruments, the 45VISNIR Zeiss Corona (wavelength range 700-1690 nm) and the Foss NIRSystems 6500 (wavelength range 1100-2500 nm). Regardless of the site and instrument, the predictive models were excellent for both SOC and 17ß-estradiol sorption coefficients. The data thus generated can be used as input parameters in fate models for efficient risk assessments and decision-making programs for environmental safety where soils are at risk of receiving inputs of 17ß-estradiol. Calibration results for soil pH were also adequate with Corona outperforming the Foss instrument. Soil texture predictions were relatively unsuccessful regardless of the instrument and site.


Assuntos
Estradiol/análise , Estradiol/química , Solo/química , Espectroscopia de Luz Próxima ao Infravermelho , Adsorção , Canadá , Concentração de Íons de Hidrogênio , Risco , Poluentes do Solo/análise , Poluição da Água
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