Combinatorial Intracellular Delivery Screening of Anticancer Drugs

Conventional drug solubilization strategies limit the understanding of the full potential of poorly water-soluble drugs during drug screening. Here, we propose a screening approach in which poorly water-soluble drugs are entrapped in poly(2-(methacryloyloxyethyl phosphorylcholine)-poly(2-(diisopropylaminoethyl methacryate) (PMPC–PDPA) polymersomes (POs) to enhance drug solubility and facilitate intracellular delivery. By using a human pediatric glioma cell model, we demonstrated that PMPC–PDPA POs mediated intracellular delivery of cytotoxic and epigenetic drugs by receptor-mediated endocytosis. Additionally, when delivered in combination, drug-loaded PMPC–PDPA POs triggered both an enhanced drug efficacy and synergy compared to that of a conventional combinatorial screening. Hence, our comprehensive synergy analysis illustrates that our screening methodology, in which PMPC–PDPA POs are used for intracellular codelivery of drugs, allows us to identify potent synergistic profiles of anticancer drugs

Blood group does not appear to affect longevity a pilot study in centenarians from Western Sicily

Centenarians are the best example of extreme human longevity, and they represent a selected population in which the appearance of major age-related diseases, such as cancer, and cardiovascular diseases among others, has been consistently delayed or escaped. The study of the long-lived individual genetic profile has the purpose to possibly identify the genes and the allelic variations influencing extended life expectancy, hence considering them as biomarkers of age-related diseases onset and development. The present study shows no significant differences between allelic variations of ABO blood groups among a group of centenarians from Western Sicily

A classical phenotype of Anderson-Fabry disease in a female patient with intronic mutations of the GLA gene: a case report

Background: Fabry disease (FD) is a hereditary metabolic disorder caused by the partial or total inactivation of a lysosomal hydrolase, the enzyme α-galactosidase A (GLA). This inactivation is responsible for the storage of undegraded glycosphingolipids in the lysosomes with subsequent cellular and microvascular dysfunction. The incidence of disease is estimated at 1:40,000 in the general population, although neonatal screening initiatives have found an unexpectedly high prevalence of genetic alterations, up to 1:3,100, in newborns in Italy, and have identified a surprisingly high frequency of newborn males with genetic alterations (about 1:1,500) in Taiwan. Case presentation: We describe the case of a 40-year-old female patient who presented with transient ischemic attack (TIA), discomfort in her hands, intolerance to cold and heat, severe angina and palpitations, chronic kidney disease. Clinical, biochemical and molecular studies were performed. Conclusions: Reported symptoms, peculiar findings in a renal biopsy – the evidence of occasional lamellar inclusions in podocytes and mesangial cells – and left ventricular (LV) hypertrophy, which are considered to be specific features of FD, as well as molecular evaluations, suggested the diagnosis of a classical form of FD. We detected four mutations in the GLA gene of the patient: -10C>T (g.1170C>T), c.370-77_-81del (g.7188-7192del5), c.640-16A>G (g.10115A>G), c.1000-22C>T (g.10956C>T). These mutations, located in promoter and intronic regulatory regions, have been observed in several patients with manifestations of FD. In our patient clinical picture showed a multisystemic involvement with early onset of symptoms, thus suggesting that these intronic mutations can be found even in patients with classical form of FD

Asymptotic expansions of the solutions of the Cauchy problem for nonlinear parabolic equations

Let $u$ be a solution of the Cauchy problem for the nonlinear parabolic equation $$\partial_t u=\Delta u+F(x,t,u,\nabla u) \quad in \quad{\bf R}^N\times(0,\infty), \quad u(x,0)=\varphi(x)\quad in \quad{\bf R}^N,$$ and assume that the solution $u$ behaves like the Gauss kernel as $t\to\infty$. In this paper, under suitable assumptions of the reaction term $F$ and the initial function $\varphi$, we establish the method of obtaining higher order asymptotic expansions of the solution $u$ as $t\to\infty$. This paper is a generalization of our previous paper, and our arguments are applicable to the large class of nonlinear parabolic equations

Hypoallergenic fragment of Par j 2 increases functional expression of Toll-like receptors in atopic children

Parietaria judaica (Par j) is one of the main causes of allergy in the Mediterranean countries. The activation of Toll-like receptor 4 (TLR4) by lipopolysaccharide (LPS) inhibits nasal inflammation of atopic children

Assignment of disulphide bridges in Par j 2.0101, a major allergen of Parietaria judaica pollen.

Par j 2.0101, a major allergen of the Parietaria judaica pollen, was expressed in E. coli, purified to homogeneity and fully characterised both at the structural and the functional level. The recombinant rPar j 2.0101 protein showed an allergenic activity in histamine release, skin prick tests and capacity to bind IgE, almost identical to that of the native allergens purified from aqueous pollen extract. The complete pattern of S-S bridges of rPar j 2.0101 was determined by enzymatic digestion with endoproteinase Lys-C followed by mass spectrometric analysis of the resulting peptide mixtures. The eight cysteines occurring in the allergenic protein were found to be paired into the following four disulphides: Cys35-Cys83, Cys45-Cys6O, Cys61-Cys106 and Cys81-Cys121. This structural information probes Par j 2.0101 to attain a 3-D fold consistent with that of the non-specific lipid transfer protein (ns-LTP) family and it represents an effective molecular basis to develop modified antigens by selective site-directed mutagenesis for immunotherapy

Umbilical Cord Prolapse In Kaduna, Northern Nigeria: A Study Of Incidence

Prolapse of theumbilical cord is a live threatening obstetric emergency for the fetus-infant. To determine, the incidence of cord prolapse in the hospital. A-12½year retrospective study of all women who presented with cord prolapse in labour at a university teaching hospital. During the period therewere16633 deliveries and 34women presentedwith cord prolapse, giving an incidence of 2.0 per 1000 (1 in 504 deliveries). Highest incidence occurred in women of 35 years and above (5.0 per 1000); in the 25-29 years group 2.3 per 1000 and in those less than 20 years old 1.3 per 1000. The highest incidence of cord prolapse was in the para 5 and over, 2.4 per 1000; para 0, 2.0 per1000 and paras 1 4, 1.9 per 1000.The incidence of cord prolapse in the unregisteredwomenwas 5.2 per 1000, and in the registered 1.5 per 1000. The highest incidence was in the Hausa/ Fulani ethnic group 3.4 per 1000; the Yoruba ethnic group, 2.1 per 1000 ; the Northernminority ethnic group , 2.0 per 1000; the Ibo ethnic group, 1.0 per 1000. No case of cord prolapse was recorded among women of Southern minority ethnic group. The incidence of cord prolapse among preterm births was, 62.7 per 1000, breech, 32.5 per 1000; shoulder, 133.3 per 1000 , twin births.16.8 per 1000 and cesarean births, 11.4 per 1000. Cord prolapse is an uncommon obstetric complication, the incidence of which is determined by the influence of various factors acting individually or in synergy. Keywords: Cord Prolapse, incidence,Kaduna,Nigeria. Nigerian Journal of Clinical Practice Vol. 11 (4) 2008: pp. 316-31

Misdiagnosis of familial Mediterranean fever in patients with Anderson-Fabry disease

Fabry disease (FD) is an underdiagnosed pathology due to its symptomatology that overlaps with various systemic and rheumatic disorders, including familial Mediterranean fever (FMF). We examined the Mediterranean fever (MEFV) and α-galactosidase A (GLA) genes, whose mutations are responsible for FMF and FD, respectively, in 42 unrelated patients diagnosed with FMF, which revealed significant ambiguity regarding some of the symptoms which are also present in FD. The objective of this study was to determine the spectrum of mutations present in these genes, in order to identify cases of mistaken diagnosis of FMF and/or missed diagnosis of FD. Ten out of 42 patients had one mutation in homozygosis or two different mutations in heterozygosis in the MEFV gene; 20/42 had a single heterozygous mutation, and 12/42 did not have genetic alterations in MEFV. The analysis of the GLA gene conducted on all the samples revealed that three subjects, and some members of their families, had two different exonic mutations associated with FD. Family studies allowed us to identify eight other cases of FD, bringing the total undiagnosed subjects to 11/53. Analyzing the MEFV and GLA genes in patients with clinical diagnoses of FMF proved to be fundamentally important for the reduction of diagnostic errors