Immune surveillance properties of human NK cell-derived exosomes

Exosomes are nanovesicles released by normal and tumor cells, which are detectable in cell culture supernatant and human biological fluids, such as plasma. Functions of exosomes released by "normal" cells are not well understood. In fact, several studies have been carried out on exosomes derived from hematopoietic cells, but very little is known about NK cell exosomes, despite the importance of these cells in innate and adaptive immunity. In this paper, we report that resting and activated NK cells, freshly isolated from blood of healthy donors, release exosomes expressing typical protein markers of NK cells and containing killer proteins (i.e., Fas ligand and perforin molecules). These nanovesicles display cytotoxic activity against several tumor cell lines and activated, but not resting, immune cells. We also show that NK-derived exosomes undergo uptake by tumor target cells but not by resting PBMC. Exosomes purified from plasma of healthy donors express NK cell markers, including CD56(+) and perforin, and exert cytotoxic activity against different human tumor target cells and activated immune cells as well. The results of this study propose an important role of NK cell-derived exosomes in immune surveillance and homeostasis. Moreover, this study supports the use of exosomes as an almost perfect example of biomimetic nanovesicles possibly useful in future therapeutic approaches against various diseases, including tumors.     

Exploring interaction of beta-amyloid segment (25-35) with membrane models through paramagnetic probes.

The accumulation of beta-amyloid peptides into senile plaques is one of the hallmarks of Alzheimer's disease (AD). There is mounting evidence that the lipid matrix of neuronal cell membranes plays an important role in the beta-sheet oligomerization process of beta-amyloid. Abeta(25-35), the sequence of which is GSNKGAIIGLM, is a highly toxic segment of amyloid beta (Abeta)-peptides, which forms fibrillary aggregates. In the present work, two spin-labelled Abeta(25-35) analogues containing the nitroxide group of the amino acid TOAC (2,2,6,6-tetramethylpiperidine-1-oxyl-4-amino-4-carboxylic acid) as a paramagnetic probe at the N- or the C-terminus of the peptide sequence, respectively, were synthesized in order to investigate the peptide-membrane interaction. The orientation and associated changes of the peptide conformation in the presence of different artificial membrane models (micelles, liposomes) were evaluated by electron paramagnetic resonance and circular dichroism techniques. The results of this study allowed us to propose a model in which the C-terminal portion of the peptide is highly associated to the membrane, while the N-terminal part extends into the aqueous phase with occasional contacts with the lipid head-group region. Interestingly, the interaction of the C-terminal portion of the peptide is particularly enhanced in the presence of sodium dodecyl sulfate (SDS) molecules.     

Detection of Treponema denticola in root canal systems in primary and secondary endodontic infections. A correlation with clinical symptoms

AIM: The aim of the study was to investigate the presence of Treponema denticola in primary and secondary root-infected canal systems with periapical pathology and correlations with clinical signs and symptoms. METHODOLOGY: Endodontic samples were obtained from canals of 102 teeth: 79 had primary endodontic disease and 23 secondary endodontic disease. For each tooth, clinical data including symptoms and X-ray appearance were examined. The presence of T. denticola biological samples from the root canal space was detected by a PCR assay. RESULTS: T. denticola was detected in 24 out of the 79 teeth with primary infection and in 8 out of the 23 teeth with secondary infection. Teeth with specific clinical symptoms were frequently associated with T. denticola presence inside the root canal system. CONCLUSIONS: The presence of T. denticola in root canal system in association with specific clinical signs and symptoms of endodontic disease strongly suggests that this spirochete might play a critical role in the pathogenesis of the acute infection and rapid bone tissue alterations in both primary and secondary endodontic infections.     

Why we should take care of the competing risk bias in survival analysis: A phase II trial on the toxicity profile of radiotherapy for prostate cancer

AimThe aim of the present study is to evaluate and quantify the bias of competing risks in an Italian oncologic cohort comparing results from different statistical analysis methods.BackgroundCompeting risks are very common in randomized clinical trials and observational studies, in particular oncology and radiotherapy ones, and their inappropriate management causes results distortions widely present in clinical scientific articles.Materials and methodsThis is a single-institution phase II trial including 41 patients affected by prostate cancer and undergoing radiotherapy (IMRT-SIB) at the University Hospital of Udine.Different outcomes were considered: late toxicities, relapse, death.Death in the absence of relapse or late toxicity was considered as a competing event.ResultsThe Kaplan Meier method, compared to cumulative incidence function method, overestimated the probability of the event of interest (toxicity and biochemical relapse) and of the competing event (death without toxicity/relapse) by 9.36%. The log-rank test, compared to Gray's test, overestimated the probability of the event of interest by 5.26%.The Hazard Ratio's and cause specific hazard's Cox regression are not directly comparable to subdistribution hazard's Fine and Gray's modified Cox regression; nonetheless, the FG model, the best choice for prognostic studies with competing risks, found significant associations not emerging with Cox regression.ConclusionsThis study confirms that using inappropriate statistical methods produces a 10% overestimation in results, as described in the literature, and highlights the importance of taking into account the competing risks bias.     

Cdx2 Polymorphism Affects the Activities of Vitamin D Receptor in Human Breast Cancer Cell Lines and Human Breast Carcinomas

Vitamin D plays a role in cancer development and acts through the vitamin D receptor (VDR). It regulates the action of hormone responsive genes and is involved in cell cycle regulation, differentiation and apoptosis. VDR is a critical component of the vitamin D pathway and different common single nucleotide polymorphisms have been identified. Cdx2 VDR polymorphism can play an important role in breast cancer, modulating the activity of VDR. The objective of this study is to assess the relationship between the Cdx2 VDR polymorphism and the activities of VDR in human breast cancer cell lines and carcinomas breast patients. Cdx2 VDR polymorphism and antiproliferative effects of vitamin D treatment were investigated in a panel of estrogen receptor-positive (MCF7 and T-47D) and estrogen receptor-negative (MDA-MB-231, SUM 159PT, SK-BR-3, BT549, MDA-MB-468, HCC1143, BT20 and HCC1954) human breast cancer cell lines. Furthermore, the potential relationship among Cdx2 VDR polymorphism and a number of biomarkers used in clinical management of breast cancer was assessed in an ad hoc set of breast cancer cases. Vitamin D treatment efficacy was found to be strongly dependent on the Cdx2 VDR status in ER-negative breast cancer cell lines tested. In our series of breast cancer cases, the results indicated that patients with variant homozygote AA were associated with bio-pathological characteristics typical of more aggressive tumours, such as ER negative, HER2 positive and G3. Our results may suggest a potential effect of Cdx2 VDR polymorphism on the efficacy of vitamin D treatment in aggressive breast cancer cells (estrogen receptor negative). These results suggest that Cdx2 polymorphism may be a potential biomarker for vitamin D treatment in breast cancer, independently of the VDR receptor expression.     

Cyphastrea kausti sp. n. (Cnidaria,Anthozoa, Scleractinia), a new species of reef coral from the Red Sea

A new scleractinian coral species, Cyphastrea kausti sp. n., is described from 13 specimens from the Red Sea. It is characterised by the presence of eight primary septa, unlike the other species of the genus, which have six, ten or 12 primary septa. The new species has morphological affinities with Cyphastrea microphthalma, from which it can be distinguished by the lower number of septa (on average eight instead of ten), and smaller calices and corallites. This species was observed in the northern and central Red Sea and appears to be absent from the southern Red Sea.     

Weather-Related Flood and Landslide Damage: A Risk Index for Italian Regions

The frequency of natural hazards has been increasing in the last decades in Europe and specifically in Mediterranean regions due to climate change. For example heavy precipitation events can lead to disasters through the interaction with exposed and vulnerable people and natural systems. It is therefore necessary a prevention planning to preserve human health and to reduce economic losses. Prevention should mainly be carried out with more adequate land management, also supported by the development of an appropriate risk prediction tool based on weather forecasts. The main aim of this study is to investigate the relationship between weather types (WTs) and the frequency of floods and landslides that have caused damage to properties, personal injuries, or deaths in the Italian regions over recent decades. In particular, a specific risk index (WT-FLARI) for each WT was developed at national and regional scale. This study has identified a specific risk index associated with each weather type, calibrated for each Italian region and applicable to both annual and seasonal levels. The risk index represents the seasonal and annual vulnerability of each Italian region and indicates that additional preventive actions are necessary for some regions. The results of this study represent a good starting point towards the development of a tool to support policy-makers, local authorities and health agencies in planning actions, mainly in the medium to long term, aimed at the weather damage reduction that represents an important issue of the World Meteorological Organization mission.     

Urinary proteomics for the study of genetic kidney diseases

Despite their low prevalence, genetic kidney diseases (GKD) still represent a serious health problem. They often lead to kidney failure and to the consequent need of dialysis or kidney transplant. To date, reliable diagnosis requires laborious genetic tests and/or a renal biopsy. Moreover, only scant and non-specific markers exist for prognostic purposes. Biomarkers assayed in an easily available and low-cost sample, such as urine, would be highly valuable. Urinary proteomics can provide clues related to their development through the identification of differentially expressed proteins codified by the affected genes, or other dis-regulated species, in total or fractionated urine, providing novel mechanistic insights. In this review, the authors summarize and discuss the results of the main proteomic investigations on GKD urine samples and in urinary extracellular vesicles.     

Copper retention by a strain ofBacillus

Summary A survey has been made of the copper accumulation by resting cells of bacteria selected as copper-resistant, isolated from activated sludges. The best selected strain, classified asBacillus, retained copper at up to 3.8% of its cell dry weight. These values were lower in the presence of glucose, unlike a type culture ofBacillus cereus, in which the retention of copper was higher when glucose was present. Possible reasons for these changes in uptake of both strains are suggested.     

Iron metabolism genes in Antarctic notothenioids: A review

Iron is an essential element for metabolic processes intrinsic to life, but the properties that make iron a necessity also make it potentially deleterious. To avoid harm, iron homeostasis is achieved through iron transport, storage and regulatory proteins. The functions of some of these molecules are well described, for example transferrin and ferritin, whereas the roles of others remain unclear. The past decade has seen the identification of new molecules involved in iron metabolism, such as divalent metal transporter-1, and hepcidin. The present review aims at surveying the studies carried out on some of the most important genes involved in transport and storage of iron in Antarctic Notothenioidei, a dominating fish group endowed of a number of striking adaptive characters, including reduced (or absence of) hematocrit. This unique peculiarity among vertebrates makes this fish group a suitable system to studying the relationship between hemoglobin and iron metabolism and to understanding the adaptive changes occurred in Antarctic fish metabolism during their evolution to avoid the deleterious effects of iron overload in the absence of hemoglobin. The results summarised here indicate that the loss of hemoglobin in the most specialized group of Antarctic notothenioids, belonging to the Channychthyidae family, is accompanied by remodulation of the iron metabolism.