Aliment Pharmacol Ther 2011; 34: 205–213
Summary
Background Standard of practice involves using transarterial therapy for multifocal hepatocellular carcinoma (HCC) alone and sorafenib only for more ...advanced HCC, but the sorafenib and transarterial therapy combination may provide greater efficacy.
Aim To evaluate the safety and efficacy of concurrent sorafenib and transarterial therapy in HCC.
Methods Consecutive cases of HCC were treated with sorafenib and transarterial therapy, receiving sorafenib 2 to 4 weeks before transarterial therapy. Baseline clinical parameters, adverse events (AEs) and survival were collected.
Results A total of 47 patients received sorafenib and transarterial therapy. The majority of the patients were male (70%) with HCV (60%), median age of 60 years, good performance status (0–1), stable cirrhosis (Child: A 72%; B 28%), unresectable tumour (stage: B 81%; C 19%) and median AFP of 24 ng/mL. Median follow‐up was 12 months and median time on sorafenib was 6 months. LC Bead TACE was used with a median frequency of 3. The majority of the patients (89%) experienced AEs. The most common AEs were fatigue (51%), hand‐foot skin reaction (51%) and diarrhoea (43%). Grade 3 and 4 AEs included fatigue (13%) and hand‐foot skin reaction (26%). Most patients required a dose reduction (66%). The main AE related to transarterial therapy was post‐TACE syndrome (23%). The disease control rate was 68% at 6 months. Overall median survival rate was 18.5 months (95% CI 16.1–20.9 months).
Conclusion Concurrent sorafenib and transarterial therapy is overall safe with no unexpected side effects and encouraging efficacy that warrants further study.
The uncoupling protein, thermogenin Palou, Andreu; Picó, Catalina; Bonet, M.Luisa ...
The international journal of biochemistry & cell biology,
01/1998, Letnik:
30, Številka:
1
Journal Article
Recenzirano
The uncoupling protein (UCP) or thermogenin is a 33
kDa inner-membrane mitochondrial protein exclusive to brown adipocytes in mammals that functions as a proton transporter, allowing the dissipation ...as heat of the proton gradient generated by the respiratory chain and thereby uncoupling oxidative phosphorylation. Thermogenesis (heat production) in brown adipose tissue, which is activated in response to cold exposure or chronic overeating, depends largely on UCP activity. Norepinephrine, released from sympathetic terminals and acting via
β-adrenoceptors and cAMP, is the main positive regulator of both UCP synthesis and activity. Brown fat thermogenesis plays a critical role in thermoregulation and in overall energy balance, at least in rodents. Manipulation of thermogenesis, whether through UCP or through analogous uncoupling proteins, could be an effective strategy against obesity.
The effects of acute and chronic acclimation to cold on uncoupling protein 1 (UCP1) levels, as well as on GDP-binding to mitochondria, cytochrome c oxidase activity and mitochondrial protein ...concentration in brown adipose tissue (BAT) of intact male and female rats have been analyzed. Results reveal that females rats are more sensitive to cold because their threshold temperature for the thermogenic response is set at a higher value (around 22 degreesC) than that of males (around 18 degreesC), hence leading to differences in BAT UCP1 levels between the sexes at different environmental temperatures. In vitro experiments showed that steroid hormones, beta-estradiol, estrone and progesterone, can reduce norepinephrine-induced UCP1 synthesis in brown adipocytes differentiated in primary culture. Thus the different sex-associated response of cold-induced thermogenesis in rats does not appear to be explained by a direct action of sex steroids upon the adipocyte, implying that other factors in the thermogenic regulatory system must be involved.
Noradrenaline-dependent brown adipose tissue (BAT) thermogenesis is activated by the cold and excess energy intake, largely depends on the activity of the uncoupling protein 1 (UCP1), and is mediated ...mainly through the beta3-adrenoceptor (beta3-AR). We investigated the expression of ucp2, a gene that encodes a putative UCP1-like uncoupling protein, along with that of ucp1 and beta3-ar, in the interscapular BAT (IBAT) of male and female rats chronically fed a cafeteria diet. After 3 months on this diet, male rats attained a 34% excess body mass and showed IBAT hypertrophy and increased IBAT thermogenic potential, in terms of both UCP1 and UCP2 mRNA expression (both by 1.6-fold), UCP1 protein expression (by 1.75-fold) and GDP binding to IBAT mitochondria (by 2.2-fold); female rats attained a larger excess body weight (50%) and their IBAT, although hypertrophied, showed no signs of increased thermogenic potential per gram of tissue. Interestingly, the IBAT of female rats was already activated compared to males. Treatment of mouse brown adipocytes in primary culture with noradrenaline also triggered a dose-dependent increase of the levels of UCP1 mRNA and UCP2 mRNA. Retroregulatory down-regulation of the beta3-AR mRNA levels was found in the two models used. The results support a physiological role for UCP2, along with UCP1, in rodent BAT thermogenesis.
Obesity could well become the most common health problem of the 21st century. There are more opportunities to consume large quantities of food: big portions of tasty, varied food, at reasonable ...prices, are available everywhere. Moreover, our bodies are better adapted to combat weight loss than to combat weight gain, since for thousands of years our species evolved in circumstances where nutrients were in short supply. The response of each individual to diet and other environmental factors varies considerably, depending on the characteristics of his/her body weight control mechanisms. The differentiating element in the future, especially as regards the dietary and pharmacological control of obesity, will be knowledge of an individual's possible response depending on his/her genetic background. Obesity can occur as a result of genetic or acquired changes in three main types of biochemical processes, which are the main focus of this review: a)feeding control, which determines the sensations of satiety and hunger through processes that depend on an interplay between internal signals (notably leptin) and environmental factors; b) energy efficiency, in particular the activation of thermogenesis mediated by uncoupling proteins (UCPs) that makes it possible to dissipate part of the energy contained in food as heat instead of accumulating it as fat, and c) adipogenesis, the process by which cells specialised in fat storage (adipocytes) are formed, which is controlled by an interplay of transcription factors, including members of the C/EBP, PPARgamma and ADD families. The knowledge of a growing number of genes and molecules implicated in these three types of processes and of their metabolic relationships is leading toward a molecular understanding of the body weight regulatory system, and is paving the way for new methods of obesity control, especially pharmacological but also nutritional and possibly involving genetic intervention.
The phenomenon of the so-called "obesity pandemic" having arisen over the last decades has to be, in large part, attributed to changes of lifestyle and the associated changes in dietary habits and ...physical activity observed world-wide. The resulting interference in energy homeostasis plays a central role in the development of obesity in a large proportion of the population worldwide. In this article, current knowledge about central biological mechanisms of energy intake, energy storage, and energy expenditure is summarized. This includes, for example, the feeling of hunger/satiety, lipid turnover with the two components of lipolysis and lipogenesis, adipogenesis, as well as energy-consuming processes like (adaptive) thermogenesis, resting metabolic rate, and physical activity energy expenditure. Based on examples, the possible influence of genetic polymorphisms contributing to the development of adiposity are illustrated.
Summary
Background
Sorafenib is currently the only approved systemic therapy shown to have efficacy in the treatment of advanced hepatocellular carcinoma (HCC). Recent studies suggest that hepatitis ...C (HCV)‐related HCC patients derive more clinical benefit from sorafenib than other subgroups, but the mechanism for this effect is unknown. In vitro data suggest that sorafenib may exert anti‐viral properties, and thus our aim in this study was to evaluate potential anti‐viral activity of sorafenib in patients with HCV‐related HCC.
Aim
To evaluate potential anti‐viral activity of sorafenib in patients with HCV‐related HCC.
Methods
We prospectively enrolled patients with HCV‐related HCC treated with sorafenib for up to 6 months. Baseline clinical, viral and oncologic data were collected. Patients' HCV viral loads were obtained at various time points, and compared with their baseline viral levels. No patients received any known anti‐viral therapy during this time.
Results
Thirty‐three patients were identified with baseline and subsequent HCV levels available for analysis. Six patients completed 6 months of full dose sorafenib, and comparisons of their HCV viral loads showed no significant change at week 24 (difference of means = 0.3500, CI: −0.1799–0.8799, P = 0.150), or the interim time points. Similarly, the HCV viral loads of all patients who received sorafenib and the viral loads of those patients who had tumour response to sorafenib showed no significant changes at any time point.
Conclusion
Despite preclinical data and previous subgroup analyses suggesting that sorafenib has an anti‐viral effect against HCV, this study suggests that sorafenib lacks significant anti‐viral activity in HCV patients with HCC.
The effects of retinoic acid (RA) isomers (all-trans-RA and 9-cis-RA) on the appearance of uncoupling protein (UCP: thermogenin), the only unequivocal molecular marker of the brown adipocyte ...differentiated phenotype, have been investigated in primary cultures of brown adipocytes, in the brown adipocyte cell line H1B 1B and directly in intact mice. The results obtained with cultured cells indicate that retinoids function as inducers of the appearance of UCP and, at the same time, partially inhibit brown adipocyte cell proliferation. The two RA isomers displayed similar effectiveness as UCP inducers, their effect being comparable with that triggered by noradrenaline, so far considered to be the main modulator of UCP gene expression. The effectiveness of retinoids as UCP inducers was dependent on the stage of brown adipocyte differentiation, being maximal in confluent primary cells and in the medium-late differentiation stage of H1B 1B cells. Corroborating the results obtained in vitro we show that administration of all-trans-RA or 9-cis-RA to mice leads to an increase in their brown adipose tissue specific UCP content. 9-cis-RA treatment also prevented the loss of UCP on cold deacclimation. To our knowledge, this is the first report of a stimulatory effect of retinoid compounds on UCP induction in vivo.
Nanoparticulated iron oxide-hydroxide samples are synthetized in supercritical water in continuous regime. Freshly prepared iron(II) acetate solutions are used as precursors and experiments at ...different flow rates and reactor temperatures are carried out. Samples composition is determined by thermogravimetric and energy loss spectroscopy. The obtained powdered samples are structurally characterized through Rietveld refinements of X-ray diffraction data. They mainly consist of FeO1.5−z spinel-type phases, though minority oxyhydroxide and hematite phases are obtained at low temperatures and total flow rates.
Analysis by electron microscopy reveals mean particles sizes around 30 nm and roughly spherical morphology in most cases.
The electrochemical response, cycling performance and Coulombic efficiency are evaluated from discharge-charge and cycling experiments at different current densities. The obtained response seems to depend on the presence or absence of oxyhydroxide phases and on both microstructural homogeneity at nanoscale and relative concentration of supercritical water at the mixing point. The 7-3-200 electrode sample shows superior rate capability, with capacity values higher than graphite theoretical one, even at high rates (500 Ah kg−1 at 2C after 100 cycles). Besides, the capacity values are restored when returning to low rates, reaching 1200 Ah kg−1 at C/5 and 800 Ah kg−1 at C/2.
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•Nanoparticulated iron oxide-hydroxide anodes synthetized in supercritical water.•Samples mostly consist of FeO1.5−z spinel-type phases, mean particles sizes ca. 30 nm.•Optimal value 500 mAh g−1 at 2C after 100 cycles, 1200 mAh g−1 at C/5 when recovering.•The electrochemical response depends on homogeneity at the nanoscale.
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