EZH2, HIF-1, and their inhibitors: An overview on pediatric cancers

During the past decades, several discoveries have established the role of epigenetic modifications and cellularmicroenvironment in tumor growth and progression. One of the main representatives concerning epigenetic modification is the polycomb group (PcG). It is composed of different highly conserved epigenetic effector proteins preserving, through several post-translational modifications of histones, the silenced state of the genes implicated in a wide range of central biological events such as development, stem cell formation, and tumor progression. Proteins of the PcG can be divided in polycomb repressive complexes (PRCs): PRC1 and PRC2. In particular, enhancer of zeste homolog 2 (EZH2), the catalytic core subunit of PRC2, acts as an epigenetic silencer ofmany tumor suppressor genes through the trimethylation of lysine 27 on histone H3, an essential binding site for DNA methyl transferases and histone deacetylases. A growing number of data suggests that overexpression of EZH2 associates with progression and poor outcome in a large number of cancer cases. Hypoxia inducible factor (HIF) is an important transcription factor involved in modulating cellular response to the microenvironment by promoting and regulating tumor development such as angiogenesis, inflammation, metabolic reprogramming, invasion, and metastatic fate. The HIF complex is represented by different subunits (α and β) acting together and promoting the expression of vascular endothelial growth factor (VEGF), hexokinase II (HKII), receptor for advanced glycation end products (RAGE), carbonic anhydrase (CA), etc., after binding to the hypoxia-response element (HRE) binding site on the DNA. In this review, we will try to connect these two players by detailing the following: (i) the activity and influence of these two important regulators of cancer progression in particular for what concerns pediatric tumors, (ii) the possible correlation between them, and (iii) the feasibility and efficiency to contrast them using several inhibitors

Beyond islet trasplantation in diabetes cell terapy:from embryonic stem cells to transdifferentation of adult cells

Exogenous insulin is, at the moment, the therapy of choice of diabetes, but does not allow tight regulation of glucose leading to long-term complications. Recently, pancreatic islet transplantation to reconstitute insulin-producing cells, has emerged as an alternative promising therapeutic approach. Unfortunately, the number of donor islets is too low compared with the high number of patients needing a transplantation leading to a search for renewable sources of high-quality -cells. This review, summarizes more recent promising approaches to the generation of new -cells from embryonic stem cells for transdifferentiation of adult cells, particularly a critical examination of the seminal work by Lumelsky et al

Cell Therapy in Type 1 Diabetes

The incidence of diabetes mellitus has grown exponentially in the last few years. Etiopathogenesis of diabetes implies a ?-cells damage in the islet of Langerhans, either through an autoimmune reaction present in type 1 diabetic patients or through altered function within these cells that affect their ability to secrete a properly functioning insulin hormone, in patients suffering from type 2 diabetes. Exogenous insulin supply is, at the moment, the therapy of choice of the disease but it does not allow tight control of glucose regulation, leading to long-term complications. Over the past few decades, pancreas or pancreas-kidney organ transplantation has been the most effective treatment for severe diabetic patients. Recently, an alternative promising therapeutic approach, consisting of successful pancreatic islet transplantation to reconstitute the insulin producing ? cells, has also emerged. Unfortunately the number of donor islets is too low compared to high number of patients needing a transplant, so the search for new renewable sources of high-quality ?-cells becomes highly topical. In this review, starting from the description of state of art of islet transplantation, we summarize the more recent promising approaches to the generation of new ?-cells giving a big enfacy to adult stem/progenitor cells

Dissecting the different biological effects of oncogenic Ras isoforms in cancer cell lines: could stimulation of oxidative stress be the one more weapon of H-Ras? Regulation of oxidative stress and Ras biological effects

Ras proteins are small GTPase functioning as molecular switches that, in response to particular extracellular signalling, as growth factors, activate a diverse array of intracellular effector cascades regulating cell proliferation, differentiation and apoptosis. Human tumours frequently express Ras proteins (Ha-, Ki-, N-Ras) activated by point mutations which contribute to malignant phenotype, including invasiveness and angiogenesis. Despite the common signalling pathways leading to similar cellular responses, studies clearly demonstrate unique roles of the Ras family members in normal and pathological conditions and the lack of functional redundancy seems to be explainable, at least in part, by the ability of Ras isoforms to localize in different microdomains to plasma membrane and intracellular organelles. This different intracellular compartmentalization could help Ras isoforms to contact different downstream effectors finally leading to different biological outcomes. Interestingly, it has also been shown that Ha- and Ki-Ras exert an opposite role in regulating intracellular redox status. In this regard we suggest that H-Ras specific induction of ROS (reactive oxygen species) production could be one of the main determinants of the invasive phenotype which characterize cancer cells harbouring H-Ras mutations. In our hypothesis then, while K-Ras (not able to promote oxidative stress) could mainly contribute to cancer progression and invasiveness through activation of MAPK and PI3K, H-Ras-mediated oxidative stress could play a unique role in modulation of intercellular contacts leading to a loss of cell adhesion and eventually also to a metastatic spread

Is secondary hyperparathyroidism-related myelofibrosis a negative prognostic factor for kidney transplant outcome?

Secondary hyperparathyroidism (HP) presenting with hypocalcemia and subsequent increased parathormone (PTH), is mainly identified in patients with chronic renal failure, which has been associated with variable degrees of bone marrow fibrosis. For suitable patients with end-stage renal disease (ESRD), kidney transplantation is recognized as the therapy of choice, being superior to dialysis in terms of quality of life and long-term mortality risk; in this regard interesting data show that increased time on dialysis prior to kidney transplantation is associated with decreased graft and patient survival. In our opinion an important and until now underestimated determinant of graft survival is the proper activity of bone marrow because of the emerging role of hematopoietic stem cells (HSC) in repair of ischemia/reperfusion (IR) damage. We postulate that in ESRD patients, who usually undergo long dialytic treatment, a myelofibrosis caused by an overt secondary HP could drastically decrease the HSC potential for IR damage repair after kidney transplant; this could irremediably lead to a delay in graft function with all related complicances. If the curative role of bone marrow-derived stem cells was confirmed by more data obtained in experimental animal models, it could be possible to try a cellular-based therapeutic approach in the management of ESRD patients which are in waiting list for a kidney transplant

Eight-point Compass Rose Underlay Technique in 72 Consecutive Elderly Patients with Large Incisional Hernia

SummaryBackgroundRepair of incisional hernia (IH) in the elderly is a challenge for the surgeon. Primary closure is preferable but is not always possible because of high recurrence rates of IH repaired without a prosthesis and/or possible respiratory and cardiovascular complications due to extreme tension of the margins. We report our experience with underlay mesh placement in elderly patients with large IH.MethodsA total of 72 patients from January 2003 to December 2009 underwent IH repair involving placement of an intraperitoneal Gore® DualMesh® prosthesis. The prosthesis was first anchored at eight points in a compass rose pattern using a Gore® suture passer and then firmly secured to the abdominal wall with a 360° internal crown running suture.ResultsTwo intraoperative intestinal tears occurred during debridement and were immediately sutured. Postoperative complications included seven seromas, four hematomas, and two infections, one of which was resolved with conservative treatment while one required prosthesis removal.ConclusionThis surgical procedure, like laparoscopic treatment, allows the surgeon to avoid dissection of the abdominal layer and improves prosthesis adhesion with reinforcement of the incisional area near the abdominal defect. The reduction in operation time is remarkable. Despite good results in terms of safety and minimal recurrence for laparoscopy in the management of IH, the use of minimally invasive techniques for large incisional wall defects, especially in elderly patients, is still controversial and practiced by few surgeons. This open technique avoids cardiopulmonary complications arising from pneumoperitoneum in the elderly

RECURRENT RENAL CARCINOMA MIMICKING A GOITRE: A CASE REPORT

Although the thyroid is a high vascularised gland, it is not common terget of metastases from extraglandular cancer. We reported a case of a 70 year-old woman who underwnt total thyroidectomy for multinodular goitre. In the patient's clinical hystory a nephrectomy was carried out 2 years before due to unspecified causes. The histopathological examination of the thyiroid showed a pattern compatible with clear cell renal carcinoma metastasis. The patient's relatives revealed, when questioned again, that the nephrectomy was due to the presence of a clear renal cell carcinoma keep concealed to the patients. Thanks to a timely intervention, the mass was removed and a better survival was guaranted to the patient

THE MEDITERRANEAN DIET: A HISTORY OF HEALTH

The Mediterranean tradition offers a cousine rich in colors, aromas and memories, which support the taste and the spirit of those who live in harmony with nature. Everyone is talking about the Mediterranean diet, but few are those who do it properly, thus generating a lot of confusion in the reader. And so for some it coincides with the pizza, others identified it with the noodles with meat sauce, in a mixture of pseudo historical traditions and folklore that do not help to solve the question that is at the basis of any diet: combine and balance the food so as to satisfy the qualitative and quantitative needs of an individual and in a sense, preserves his health through the use of substances that help the body to perform normal vital functions. The purpose of our work is to demonstrate that the combination of taste and health is a goal that can be absolutely carried out by everybody, despite those who believe that only a generous caloric intake can guarantee the goodness of a dish and the satisfaction of the consumers. That should not be an absolute novelty, since the sound traditions of the Mediterranean cuisine we have used for some time in a wide variety of tasty gastronomic choices, from inviting colors and strong scents and absolutely in line with health

LONG-TERM RESULTS AFTER ENDOSCOPIC DILATION OF POST-OPERATIVE COLO-COLONIC ANASTOMOTIC STENOSES. OUR EXPERIENCE IN 42 PATIENTS.

The aim of this study is to evaluate long-term complications and patient's quality of life after the endoscopic treatment of benign anastomotic colo-colonic strictures. From January 2000 to November 2008,, 42 patients who had undergone surgery for colorectal cancer were endoscopically treated for a postoperative symptomatic stricture. The dilation were performed using a 20-30 mm pneumatic dilator. The clinical results were classified in relation to the abdominal symptomatology reported by the patients, and were evaluated in the short-term (one-week) and long-term (mean follow-up.36 months)period. Results: 15 patients underwent a total of 22 dilating sessions; 9 patients had a single dilating session, 18 patients underwent 5 dilating sessions. Three bowel peforations at the site of dilation, 1 septic complications and a transient mucosal bleeding were registered. immediate symptomatic relief was achieved in all the cases; the symptoms caused by the strictures disappeared after the first session. Normal defecation was immediately restored after the treatment. satisfactory good long-term clinical results were achieved in thirty-seven patients (88%). Conclusion: This study confirms the assumption that dilation with balloon may be considered the first-line therapeutic approach safe and effective for symptomatic benign anastomotic strictures after colorectal resection surgery for adenocarcinoma. The treatment of benign anastomotic strictures by standard endoscopic dilation is an effective contribution against stricture-related gastrointestinal symptoms. The standard criterion used to define successful anastomoses (10-13 mm in diameter)is sufficient for an optimal result

Enteral nutrition: our experience with percutaneous endoscopic gastrostomy (PEG) and revision of literature

Enteral nutrition (EN), as parenteral nutrition (PN), can be used in cases of patients whose medical conditions prevent the intake of food by mouth; unlike PN, EN keeps the functionality of the digestive tract and it makes home management of patients easier. However, the experience and literature have documented a number of serious complications, fortunately rare, which depend on the methods used in EN realization. We report in this paper our experience in 44 cases of percutaneous endoscopic gastrostomy (PEG), concluding that it is a safe and complications-free procedure. We believe that a nutritional intervention is indicated when, improving nutritional status, patients can obtain a better quality of life and have an average life expectancy