Formulation of curcumin-loaded solid lipid nanoparticles produced by fatty acids coacervation technique

Curcumin (CU) loaded solid lipid nanoparticles (SLNs) of fatty acids (FA) were prepared with a coacervation technique based on FA precipitation from their sodium salt micelles in the presence of polymeric non-ionic surfactants. Myristic, palmitic, stearic, and behenic acids, and different polymers with various molecular weights and hydrolysis grades were employed as lipid matrixes and stabilisers, respectively. Generally, spherical-shaped nanoparticles with mean diameters below 500?nm were obtained, and using only middle-high hydrolysis, grade-polymer SLNs with diameters lower than 300?nm were produced. CU encapsulation efficiency was in the range 28-81% and highly influenced by both FA and polymer type. Chitosan hydrochloride was added to FA SLN formulations to produce bioadhesive, positively charged nanoparticles. A CU-chitosan complex formation could be hypothesised by DSC analysis, UV-vis spectra and chitosan surface tension determination. A preliminary study on HCT-116 colon cancer cells was developed to evaluate the influence of CU-loaded FA SLNs on cell viability.     

Dexamethasone and Suramin Inhibit Cell Proliferation and Interleukin-6-Mediated Immunoglobulin Secretion in Human Lymphoid and Multiple Myeloma Cell Lines

Uncontrolled growth of neoplastic cells and unregulated production of immunoglobulin are major components of the morbidity and mortality of multiple myeloma. Suramin, a polysulfonated napthylurea, has antitumor activity in a number of malignancies, but also significant dose-related toxicity. Suramin has been reported to have major antiproliferative effects in a variety of lymphoid cell lines. Glucocorticoids have long been recognized to have activity in lymphoid malignancies and multiple myeloma while IL-6 has been reported to be an autocrine growth factor for multiple myeloma. This study examines growth inhibition and inhibition of IL-6-mediated secretion of immunoglobulin in human lymphoid and myeloma cell lines by dexamethasone and suramin. Dexamethasone and suramin show synergistic inhibition of cell proliferation at their IC^|0 concentrations. IL-6-mediated immunoglobulin secretion is also inhibited by both dexamethasone and suramin in an additive fashion. Both dexamethasone and suramin induce apoptosis of lymphoid cell lines, and suramin inhibits the binding of IL-6 to its receptor in a multiple myeloma cell line. These findings suggest that the synergistic growth inhibitory activities of dexamethasone and suramin may be related to induction of apoptosis by both agents and inhibition of IL-6-mediated autocrine growth stimulation and immunoglobulin production. These results indicate that the combination of low-dose suramin (in concentrations not associated with significant clinical toxicity) and dexamethasone merit further study in the treatment of myeloma or lymphoid malignancies.     

Transarterial chemoembolization plus sorafenib: a sequential therapeutic scheme for HCV-related intermediate-stage hepatocellular carcinoma: a randomized clinical trial

Background.

Recurrence of hepatocellular carcinoma (HCC) is a major problem after surgical or ablative treatments. The aim of this prospective, single-center, placebo-controlled, randomized, double-blind clinical study was to evaluate the effectiveness of transarterial chemoembolization (TACE) combined with sorafenib as a sequential treatment regimen in delaying time to progression (TTP) of intermediate-stage HCC in patients with chronic hepatitis C virus (HCV) infection.

Material and Methods.

Between October, 2007 and January, 2011, 80 HCV-infected patients with Barcelona Clinic Liver Cancer stage B HCC underwent the TACE procedure. All had Child-Pugh class A disease. They were randomized 1:1 to receive sorafenib at a dose of 400 mg twice daily or placebo. Endpoints were the TTP and the rates of adverse events and toxicity.

Results.

Sixty-two of 80 patients (77%), 31 in the sorafenib group and 31 in the control group, completed the study. The median TTP was 9.2 months in the sorafenib group and 4.9 months in the placebo group (hazard ratio, 2.5; 95% confidence interval, 1.66–7.56; p < .001). Metachronous, multicentric HCC progression occurred less frequently in sorafenib-treated patients (p < .05). Adverse reactions to sorafenib caused withdrawal from the study of 9 (22%) patients.

Conclusion.

A conventional TACE procedure followed by sorafenib treatment resulted in a significantly longer TTP in patients with intermediate-stage HCV-related HCC, with no unexpected side effects.     

Estrogen receptor beta as a novel target of androgen receptor action in breast cancer cell lines

Introduction

The two isoforms of estrogen receptor (ER) alpha and beta play opposite roles in regulating proliferation and differentiation of breast cancers, with ER-alpha mediating mitogenic effects and ER-beta acting as a tumor suppressor. Emerging data have reported that androgen receptor (AR) activation inhibits ER-positive breast cancer progression mainly by antagonizing ER-alpha signaling. However, to date no studies have specifically evaluated a potential involvement of ER-beta in the inhibitory effects of androgens.

Methods

ER-beta expression was examined in human breast cancer cell lines using real-time PCR, Western blotting and small interfering RNA (siRNA) assays. Mutagenesis studies, electromobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP) analysis were performed to assess the effects of mibolerone/AR on ER-beta promoter activity and binding.

Results

In this study, we demonstrate that mibolerone, a synthetic androgen ligand, up-regulates ER-beta mRNA and protein levels in ER-positive breast cancer cells. Transient transfection experiments, using a vector containing the human ER-beta promoter region, show that mibolerone increases basal ER-beta promoter activity. Site-directed mutagenesis and deletion analysis reveal that an androgen response element (ARE), TGTTCT motif located at positions −383 and −377, is critical for mibolerone-induced ER-beta up-regulation in breast cancer cells. This occurs through an increased recruitment of AR to the ARE site within the ER-beta promoter region, along with an enhanced occupancy of RNA polymerase II. Finally, silencing of ER-beta gene expression by RNA interference is able to partially reverse the effects of mibolerone on cell proliferation, p21 and cyclin D1 expression.

Conclusions

Collectively, these data provide evidence for a novel mechanism by which activated AR, through an up-regulation of ER-beta gene expression, inhibits breast cancer cell growth.     

Diabetic nephropathy: Clinical and histological study in 22 patients

Summary Twenty-two patients with insulin-dependent diabetes mellitus and renal involvement were submitted to renal biopsy. Mean age was 42 years; 10 were males, 12 females. The mean interval between clinical manifestation of nephropathy and biopsy was about 2 years. At the time of biopsy, 4 groups were distinguished according to clinical conditions, depending on the presence or absence of nephrotic syndrome and renal failure. Renal lesions were semiquantitatively evaluated, a separate score being considered for glomerular and vascular lesions. Immunofluorescence most frequently showed a pattern of faint linear IgG deposits along glomerular basement membranes: Severity of histological lesions and pattern of urinary abnormalities were not correlated with the duration of diabetes or the patients’ age. Both glomerular and vascular lesions were correlated with the presence of renal failure, while no relationship with the pattern of urinary abnormalities was found. Fourteen patients were followed for more than one year after biopsy: 5 had normal renal function, 4 were in chronic renal insufficiency and 5 in end-stage renal failure (3 were in dialysis, 2 died). There was no correlation between the 3 above-mentioned types of evolution and glomerular histological findings. Nevertheless a higher score of vascular impairment at biopsy was observed among patients who subsequently were found to have a more unfavorable prognosis. Therefore renal biopsy, by providing information on the degree of renal vascular damage, may have some value in predicting the clinical course of diabetic nephropathy.     

Radiotherapy in low-grade glioma adult patients: a retrospective survival and neurocognitive toxicity analysis

Purpose

The treatment of low-grade glioma is still debated. Surgery is the first-line approach, and the correct timing of radiation therapy has not yet been defined since “early” radiation therapy improves relapse-free survival but not overall survival. Since a longer progression-free survival is desirable, the main issue related to radiotherapy is the incidence of late neurocognitive toxicity.

Materials and methods

Ninety-five patients with low-grade glioma were consecutively treated with early (within 3 months) or late (at disease progression) post-surgical radiation therapy. Clinical and therapeutic factors were entered into the analysis overall (OS) and progression-free (PFS) survival, and the distribution in two accrual periods identified based on the evolution of imaging procedures and radiotherapy techniques were compared. For 6/18 long survivors (LS) without evidence of disease, neurocognitive evaluation was obtained and the dose to the hippocampus region was retrospectively calculated.

Results

Univariate analysis of OS showed a statistically significant advantage for grade 1 and oligodendroglioma histology, better performance status [Karnofsky index (KI)], age <40 years, radical surgery, no steroid treatment; PFS was significantly related with younger age, better KI and “early” radiotherapy. Multivariate analysis of OS confirmed the significance of all variables except surgery; for PFS, only “early” radiotherapy and better KI retained significance. Memory impairment was evident in 4/6 of the LS tested; quality of life was good and executive functions were normal.

Conclusion

Radiotherapy remains an essential component in the treatment of low-grade glioma. Prospective studies are needed to evaluate the relative contributions of the disease itself and of surgery, radiation and chemotherapy to long-term neurocognitive damage.     

β-Carotene supplementation decreases placental transcription of LDL receptor-related protein 1 in wild-type mice and stimulates placental β-carotene uptake in marginally vitamin A-deficient mice

The human diet contains β-carotene as the most abundant precursor of vitamin A, an essential nutrient for embryogenesis. Our laboratory previously showed the importance of β-carotene metabolism via β-carotene-15,15'-oxygenase (CMOI) to support mouse embryonic development. However, the mechanisms regulating embryonic acquisition and utilization of β-carotene from the maternal circulation via placenta remain unknown. We used wild-type (WT) and Lrat(-/-)Rbp(-/-) (L(-/-)R(-/-)) mice, the latter being a model of marginal vitamin A deficiency. Pregnant dams, fed a nonpurified diet sufficient in vitamin A throughout life, were i.p. supplemented with β-carotene or vehicle at 13.5 d postcoitum (dpc). Effects of this acute maternal supplementation on retinoid and β-carotene metabolism in maternal (serum, liver) and developing tissues (placenta, yolk sac, embryo) were investigated at 14.5 dpc. We showed that, upon supplementation, placental β-carotene concentrations were greater in L(-/-)R(-/-) than in WT mice. However, the retinoid (retinol and retinyl ester) concentrations remained unchanged in placenta (and in all other tissues analyzed) of both genotypes upon β-carotene administration. We also showed that upon a single i.p. β-carotene supplementation, placental LDL receptor-related protein (Lrp1) mRNA expression was lower in WT mice, and embryonic CmoI mRNA expression was greater in L(-/-)R(-/-) mice. Together, these data suggest a potential role of LRP1 in mediating the uptake of β-carotene across the placenta and that even a marginally impaired maternal vitamin A status may influence uptake and utilization of β-carotene by the placenta and the embryo.     

Congenital lupus erythematosus: case report and review of the literature

Abstract: Congenital presentation of neonatal lupus erythematous is very rare. We describe an infant who had congenital neonatal lupus erythematosus with atrophic lesions on the face and scarring lesions on the trunk. All radiologic, virologic, and hematologic assays were normal. Skin biopsy specimen and immunofluorescence findings led us to suspect neonatal lupus, a diagnosis confirmed by positivity for anti‐Sjörgen syndrome and antinuclear antibodies both in the child and her mother. In this infant, skin manifestations represented the stable and irreversible outcome of an inflammatory stage that occurred during pregnancy.