Immunogenicity of bioactive magnetic nanoparticles: natural and acquired antibodies

Uniform magnetic nanoparticles (MNP) were prepared by nucleation followed by controlled growth of maghemite thin films onto porcine gelatin nuclei. The formed gelatin containing MNP (Gel-MNP) were then coated with dextran (Gel-MNP-Dex) followed by human serum albumin (Gel-MNP-Dex-HSA). Since these MNP are designated for clinical applications, studies concerning the immunogenicity of their antigenic components (porcine gelatin, dextran, and HSA) have been performed in BALB-C mice. These studies demonstrated that plasma of nonimmunized mice already contains basal levels of natural antibodies against all of these antigenic components. This work also demonstrated that the conjugated gelatin is a weak immunogen: Intraperitoneal injection of the various MNP (Gel-MNP, Gel-MNP-Dex dispersed in PBS emulsified with Incomplete Freund's Adjuvant (IFA) mineral oil and Gel-MNP-Dex-HSA dispersed in PBS) did not increase significantly the acquired anti-gelatin antibody titers. Exceptional behavior was observed following immunization with Gel-MNP-Dex-HSA dispersed in PBS emulsified with IFA, which exhibited an adjuvant effect and turned gelatin into a stronger immunogen. In contrast to gelatin, the conjugated HSA and dextran were found to be strong immunogens. The possibility that the various MNP will not induce an autoimmune response as a result of their clinical use is discussed in the contest of the protective role of the natural antibodies.     

Cop9 signalosome subunit 8 (CSN8) is essential for Drosophila development

The COP9 signalosome (CSN) is a multisubunit regulator highly conserved in evolution. We show here that CSN subunit 8 (CSN8) is essential for Drosophila development. CSN8 is maternally contributed and present throughout development. Null mutants generated in this study are larval lethal, showing phenotypes associated with mutations in either CSN4 (molting defects) or CSN5 (melanotic tumors). Analysis of mitotic and germ-line csn8^null clones revealed the requirement of CSN8 for multiple developmental processes. The germ-line clones arrested at mid-oogenesis, while the mitotic clones led to deformed adult eyes or wings. CSN8 is present exclusively as part of the CSN holo-complex, and lack of CSN8 in the mutants leads to CSN instability. Consistent with this, Cullin deneddylation is impaired in the csn8^null mutants.     

Clinical implications of UGT1A1*28 genotype testing in colorectal cancer patients

BACKGROUND:

Metastatic colorectal cancer is frequently treated with irinotecan, a topoisomerase‐I inhibitor. The UGT1A1 gene encodes for an enzyme that metabolizes irinotecan, and its genetic variants were shown to be associated with increased drug toxicity. We evaluated clinical outcomes associated with the UGT1A1*28 variant.

METHODS:

The study included 329 colorectal cancer patients from the Israeli population‐based Molecular Epidemiology of Colorectal Cancer study who were treated with a chemotherapy regimen that included irinotecan. Patients with metastases or disease recurrence were followed up for a median period of 2 years after occurrence of the event. Study end points were appearance of grade 3‐4 hematological and gastroenterological toxicity, hospitalization due to toxic events (mostly neutropenia, fever, diarrhea, or vomiting), length of hospitalization, and overall survival. UGT1A1*28 was genotyped from peripheral blood DNA by fragment analysis and reported as number of TATA sequence repeats in the promoter of the gene.

RESULTS:

The 7/7 variant of UGT1A1*28 was detected in 11.9% of the 329 participants. Grade 3‐4 hematological toxicity was significantly higher in 7/7 carriers compared with 6/7 and 6/6 carriers (48.0%,10.2%, and 7.7% respectively; P < .001), as was the risk of toxicity‐related hospitalization (45.8%, 25.3%, and 14.4% respectively; P = .001). Both short‐term death within 2 months of treatment start (12.8%, 5.2%, and 2.9%, respectively) and median overall survival (1.6, 2.0, and 2.4 years, respectively; P = .01) were significantly worse in the 7/7 carriers. The age/stage‐adjusted hazard ratio for patients with the 7/7 genotype compared with 6/6 was 1.7 (95% confidence interval, 1.1‐2.3).

CONCLUSIONS:

The UGT1A1*28 7/7 genotype is strongly associated with severe hematological toxicity and higher hospitalization rate and predicts lower survival of colorectal cancer in users of irinotecan. Cancer 2011. © 2011 American Cancer Society.     

Maternal complications associated with multiple cesarean deliveries

OBJECTIVE: The claim that a planned repeat cesarean delivery is safer than a trial of labor after cesarean may not be applicable to women who desire larger families. The aim of this study was to assess maternal complications after multiple cesarean deliveries. METHODS: The records of women who underwent two or more planned cesarean deliveries between 2000 and 2005 were reviewed. We compared maternal complications occurring in 277 women after three or more cesarean deliveries (multiple-cesarean group) with those occurring in 491 women after second cesarean delivery (second-cesarean group). RESULTS: Excessive blood loss (7.9% versus 3.3%; P < .005), difficult delivery of the neonate (5.1% versus 0.2%; P < .001), and dense adhesions (46.1% versus 25.6%; P < .001) were significantly more common in the multiple-cesarean group. Placenta accreta (1.4%) and hysterectomy (1.1%) were more common, but not significantly so, in the multiple-cesarean group. The proportion of women having any major complication was higher in the multiple-cesarean group, 8.7% versus 4.3% (P = .013), and increased with the delivery index number: 4.3%, 7.5%, and 12.5% for second, third, and fourth or more cesarean delivery, respectively (P for trend = .004). CONCLUSION: Multiple cesarean deliveries are associated with more difficult surgery and increased blood loss compared with a second planned cesarean delivery. The risk of major complications increases with cesarean delivery number. LEVEL OF EVIDENCE: II-2.     

Atrophy or hypertrophy in chronic renal ischemia: role of the IGF-I system

To examine the role of insulin-like growth factor–1 (IGF-1) in renal atrophy of rats with two-kidney, one-clip (2K1C), in which the clipped kidney atrophies, and in the one-kidney, one-clip (1K1C) model of renovascular hypertension, in which it hypertrophies, we studied levels of IGF-I, mRNA, and protein in 2K1C, 1K1C, and unilateral nephrectomy (NPX) in rats by solution-hybridization RNase protection, and radioimmunoassay, respectively, both cross-reactively and longitudinally at 3, 10, and 30 days after clipping. Three days after clipping, there were no differences in blood pressure or kidney size; however, 10 and 30 days postoperation, the clipped kidney shrank in the 2K1C model. The nonclipped 2K1C and the clipped 1K1C and unilateral nephrectomy kidneys increased in weight (P < .05. At day 3 the IGF-I levels were lower (557 ± 54, 335 ± 61 ng/g in control and clipped 2K1C, P < .05, v 1074 ± 186, 1109 ± 54, and 1154 ± 200 ng/g kidney, nonclipped 2K1C, 1K1C, and NPX, respectively). At 30 days the IGF-I levels were 300 ± 24 ng/g in control (P < .05) v clipped 2K1C, 160 ± 19, 218 ± 20 ng/g in nonclipped 2K1C and 406 ± 33 and 470 ± 34 ng/g in 1K1C and NPX, respectively (P < .05) v control and clipped 2K1C. Kidney mRNA was increased in the clipped 2K1C. In conclusion, the kidney that had higher IGF-I levels early in nonclipped 2K1C, 1K1C, and nephrectomy hypertrophied, and the kidney (clipped 2K1C) that failed to increase IGF-I atrophied. IGF-I levels are dissociated from the local mRNA message.     

The semaphorins: versatile regulators of tumour progression and tumour angiogenesis

The semaphorins and their receptors, the neuropilins and the plexins, were originally characterized as constituents of the complex regulatory system responsible for the guidance of axons during the development of the central nervous system. However, a growing body of evidence indicates that various semaphorins can either promote or inhibit tumour progression through the promotion or inhibition of processes such as tumour angiogenesis, tumour metastasis and tumour cell survival. This Review focuses on the emerging role of the semaphorins in cancer.     

Assessing goodness-of-fit of parametric regression models for lifetime data – graphical methods

Graphical methods are often used to check goodness-of-fit of models to data. It is common to plot residuals against a reference distribution so that when the model fits the data, the configuration should be close to a straight line. Since the resemblance to a straight line is often unclear, it has been suggested to add simulated envelopes within which the configuration is expected to lie. The implementation of this method for survival data analysis is not straightforward. In this paper we point out the difficulties which arise in constructing envelopes on residual plots for randomly censored data. Methods are suggested to deal with the problems and evaluated; they are illustrated by simulated data and on a follow-up study of myeloma.     

The Anticonvulsant Zonisamide Reduces Ethanol Self-Administration by Risky Drinkers

Objective: The purpose of this study is to examine the effects of zonisamide on ethanol self-administration and subjective effects in risky drinkers using a human laboratory paradigm. Method: We conducted a double-blind, placebo-controlled study of the effects of zonisamide 100 mg on ethanol self-administration and urge to drink in risky drinkers (N = 10) (). Result: During the second hour of a 2-hour self-administration session ethanol consumption was 50% lower in the zonisamide group as compared to the placebo group. Urge to drink was also significantly lower under the zonisamide condition. Conclusion: These results indicate that a single dose of zonisamide reduces urge to drink and the quantity of ethanol self-administered by risky drinkers during their second hour of access to alcohol. Scientific Significance: Zonisamide may help individuals drinking at risky levels reduce their intake of alcohol.