A Different Trend of Heat Shock Proteins 90 mRNA and Protein Inhepatocellular Carcinoma Cell Line-Secreted Extracellular Vesicles

Primary Hepatocellular Carcinoma (HCC) does not usually show any symptoms at the early stage and the use of biomarkers is necessary to aid in diagnosis. Recently Extracellular Vesicles (EVs), submicron membrane- bound structures secreted from different cell types containing a wide variety of bioactive molecules, have increased the attention in many cancers, including HCC, becoming an auspicious candidate as biomarkers and therapy in the scenario of limited diagnostic and treatment option. Many indications have shown that heat shock proteins (Hsps) are important modulators in treatment resistance and invasion of HCC becoming attractive therapeutic targets. In particular, Hsp90α/β isoforms have been found to play critical roles in regulating the proliferation, apoptosis, and metastasis of tumor cells, suggesting for these proteins a role as targets for modern anticancer therapies. The study aimedto verify the presence of Hsp90α/β in EVs secreted by an HCC tumor cell line (HepG2) and by a non-tumorigenic hepatocyte cell line (WRL68), both at protein and mRNA levels, and to analyze their expression variations. The result showed that Hsp90s are transported by the EVs as protein but not at the mRNA level. To build new therapeutic targets using EVs or other organelles as performed on exosomes in recent studies, it is essential to evaluate the action at the pre or post-transcriptional level given their different behavior in transporting proteins or mRNA

Alternative methods of follow up in breast cancer: a systematic review of the literature

Regular clinical follow up after breast cancer is a common practice. Evidence from retrospective reviews casts doubt on the efficacy of this practice and the various guidelines for follow up show little concordance. Our aim was to investigate what alternative follow-up methods (including reduced frequency of visits) have been subjected to controlled trial and to establish what evidence exists from controlled trials to advise the guidelines. The study involved systematic review of the literature using MEDLINE, Embase, CancerLit, Web of Sciences and EBM reviews as data sources. Methods included reviewing all randomised controlled trials comparing different follow-up frequencies or comparing an alternative method with clinical follow up after breast cancer. All outcome measures addressed in the trials were analysed. Two trials compared frequency of traditional follow up. Five trials assessed alternative methods. All were of inadequate power or duration to establish ideal frequency of clinic visits or safety of alternative follow-up methods. Alternative follow up had no detrimental effect on satisfaction or outcome. Few trials have been conducted, all of which are underpowered to establish safety of reducing or replacing clinic visits. Alternative methods of follow up are acceptable to patients and may be associated with other benefits. Larger trials are required

Changing pattern of the detection of locoregional relapse in breast cancer: the Edinburgh experience

The guidelines for follow-up of breast cancer patients concentrate on the first 3–5 years, with either reduced frequency of visits or discharge after this. They also recommend mammography, but no evidence exists to inform frequency. We analyse treatable relapses in our unit from 1312 patients with early stage breast cancer treated by breast conserving surgery (BCS) and postoperative radiotherapy between 1991 and 1998 to assess appropriateness of the guidelines. A total of 110 treatable relapses were analysed. Treatable relapse developed at 1–1.5% per year throughout follow-up. Forty-eight relapses were in ipsilateral breast, 25 ipsilateral axilla, 35 contralateral breast, 2 both breasts simultaneously. Thirty-seven relapses (33.5%) were symptomatic, 56 (51%) mammographically detected, 15 (13.5%) clinically detected, 2 (2%) diagnosed incidentally. Mammography detected 5.37 relapses per 1000 mammograms. Patients with symptomatic or mammographically detected ipsilateral breast relapse had significantly longer survival from original diagnosis (P=0.0002) and from recurrence (P=0.0014) compared with clinically detected. Treatable relapse occurs at a constant rate for at least 10 years. Clinical examination detects a minority (13.5%). Relapse diagnosed clinically is associated with poorer outcome. Long-term follow-up based on regular mammography is warranted for all patients treated by BCS

Glycoinositolphospholipids from Leishmania braziliensis and L. infantum: Modulation of Innate Immune System and Variations in Carbohydrate Structure

The essential role of the lipophosphoglycan (LPG) of Leishmania in innate immune response has been extensively reported. However, information about the role of the LPG-related glycoinositolphospholipids (GIPLs) is limited, especially with respect to the New World species of Leishmania. GIPLs are low molecular weight molecules covering the parasite surface and are similar to LPG in sharing a common lipid backbone and a glycan motif containing up to 7 sugars. Critical aspects of their structure and functions are still obscure in the interaction with the vertebrate host. In this study, we evaluated the role of those molecules in two medically important South American species Leishmania infantum and L. braziliensis, causative agents of visceral (VL) and cutaneous Leishmaniasis (CL), respectively. GIPLs derived from both species did not induce NO or TNF-α production by non-primed murine macrophages. Additionally, primed macrophages from mice (BALB/c, C57BL/6, TLR2−/− and TLR4−/−) exposed to GIPLs from both species, with exception to TNF-α, did not produce any of the cytokines analyzed (IL1-β, IL-2, IL-4, IL-5, IL-10, IL-12p40, IFN-γ) or p38 activation. GIPLs induced the production of TNF-α and NO by C57BL/6 mice, primarily via TLR4. Pre incubation of macrophages with GIPLs reduced significantly the amount of NO and IL-12 in the presence of IFN-γ or lipopolysaccharide (LPS), which was more pronounced with L. braziliensis GIPLs. This inhibition was reversed after PI-specific phospholipase C treatment. A structural analysis of the GIPLs showed that L. infantum has manose rich GIPLs, suggestive of type I and Hybrid GIPLs while L. braziliensis has galactose rich GIPLs, suggestive of Type II GIPLs. In conclusion, there are major differences in the structure and composition of GIPLs from L. braziliensis and L. infantum. Also, GIPLs are important inhibitory molecules during the interaction with macrophages

Effects of Aspirin on Endothelial Function and Hypertension

PURPOSE OF REVIEW: Endothelial dysfunction is intimately related to the development of various cardiovascular diseases, including hypertension, and is often used as a target for pharmacological treatment. The scope of this review is to assess effects of aspirin on endothelial function and their clinical implication in arterial hypertension. RECENT FINDINGS: Emerging data indicate the role of platelets in the development of vascular inflammation due to the release of proinflammatory mediators, for example, triggered largely by thromboxane. Vascular inflammation further promotes oxidative stress, diminished synthesis of vasodilators, proaggregatory and procoagulant state. These changes translate into vasoconstriction, impaired circulation and thrombotic complications. Aspirin inhibits thromboxane synthesis, abolishes platelets activation and acetylates enzymes switching them to the synthesis of anti-inflammatory substances. SUMMARY: Aspirin pleiotropic effects have not been fully elucidated yet. In secondary prevention studies, the decrease in cardiovascular events with aspirin outweighs bleeding risks, but this is not the case in primary prevention settings. Ongoing trials will provide more evidence on whether to expand the use of aspirin or stay within current recommendations

Inverse Association between Circulating Levels of Soluble Receptor for Advanced Glycation End-Products and Coronary Plaque Burden.

Aim: Low levels of soluble receptor for advanced glycation end-products (sRAGE) have been reported to be associated with coronary artery disease (CAD) and peripheral atherosclerosis. This study explored the relationship between circulating levels of sRAGE and the characteristics of coronary vessels detected by 64-slice computed tomography angiography (CTA).Methods: In this cross-sectional study we included 127 consecutive patients with CAD but without acute coronary syndrome. Quantitative volumetric analysis of the lumen and plaque burden of the vessel wall (soft and calcific components) was performed for the three major coronary vessels. Each component was expressed as a percentage of vessel volume and utilized in per-patient analysis. The patients were classified into two groups according to the presence of calcium volume: non-calcified plaque (NCP) group (calcium volume %=0) and calcified plaque (CP) group (calcium volume % >0).Results: In the NCP group, but not in the CP group, simple regression analysis revealed a negative association of total plaque burden % with sRAGE (β=-0.378, p=0.0019) and HDL cholesterol (β=-0.368, p=0.003) and a positive association with creatinine (β=0.258, p=0.041) and male gender (β=0.317, p=0.01). After adjusting for confounding factors, the total plaque burden % remained significantly associated only with sRAGE (β=-0.358, p=0.011).Conclusions: Circulating sRAGE levels are associated in an inverse manner with non-calcified plaque burden, suggesting that it may be related with early atherosclerosis and plaque progression