Immunotherapy with low-dose recombinant interleukin 2 after high-dose chemotherapy and autologous stem cell transplantation in neuroblastoma.

The purpose of this study was to evaluate in a phase I-II trial whether low doses of recombinant human interleukin 2 (rHuIL-2) over a prolonged period of time are safe and effective in eradicating or controlling minimal residual disease in children with neuroblastoma given high-dose chemotherapy (HDCT) and autologous stem cell transplantation (ASCT). From January 1992 to July 1996, 17 consecutive patients, with either stage IV or relapsed neuroblastoma, were enrolled. Patients received rHuIL-2 after a median time interval (min-max) of 105 days (56-153) after HDCT and ASCT. The protocol consisted of 2 'priming' courses of rHuIL-2 at escalating doses administered intravenously at 72-h intervals, followed by 'maintenance' with 11 monthly and six bimonthly boosting 5-day courses administered subcutaneously on an outpatient basis. At April 1997, 7 out of the 17 patients had completed the treatment schedule, four had discontinued treatment because of toxicity and four because of relapse; the remaining two patients are still on treatment, having completed 15 courses. Expansion of T lymphocytes, together with an increase in both natural killer cells and in activated T lymphocytes was evidenced. After a median (min-max) follow-up time of 30 (16-64) months, 12 out of 17 patients are alive and well. Two patients relapsed and died 14 and 35 months after transplant. Three patients are alive after having relapsed at 41, 21 and 13 months. The actuarial 2-year event-free survival and overall survival are 67% and 92% respectively. Intermittent administration of low doses of rHuIL-2 given for a long period of time is well tolerated and seems capable of controlling minimal residual disease after HDCT and ASCT in children with high-risk neuroblastoma

Drosophila Lethal Giant Larvae Neoplastic Mutant as a Genetic Tool for Cancer Modeling

Drosophila lethal giant larvae (lgl) is a tumour suppressor gene whose function in establishing apical-basal cell polarity as well as in exerting proliferation control in epithelial tissues is conserved between flies and mammals. Individuals bearing lgl null mutations show a gradual loss of tissue architecture and an extended larval life in which cell proliferation never ceases and no differentiation occurs, resulting in prepupal lethality. When tissues from those individuals are transplanted into adult normal recipients, a subset of cells, possibly the cancer stem units, are again able to proliferate and give rise to metastases which migrate to distant sites killing the host. This phenotype closely resembles that of mammalian epithelial cancers, in which loss of cell polarity is one of the hallmarks of a malignant, metastatic behaviour associated with poor prognosis. Lgl protein shares with its human counterpart Human giant larvae-1 (Hugl-1) significant stretches of sequence similarity that we demonstrated to translate into a complete functional conservation, pointing out a role in cell proliferation control and tumorigenesis also for the human homologue. The functional conservation and the power of fly genetics, that allows the researcher to manipulate the fly genome at a level of precision that exceeds that of any other multicellular genetic system, make this Drosophila mutant a very suitable model in which to investigate the mechanisms underlying epithelial tumour formation, progression and metastatisation. In this review, we will summarise the results obtained in these later years using this model for the study of cancer biology. Moreover, we will discuss how recent advances in developmental genetics techniques have succeeded in enhancing the similarities between fly and human tumorigenesis, giving Drosophila a pivotal role in the study of such a complex genetic disease

Childhood obesity and respiratory diseases: Which link?

Prevalence of childhood obesity is progressively increasing, reaching worldwide levels of 5.6% in girls and of 7.8% in boys. Several evidences showed that obesity is a major preventable risk factor and disease modifier of some respiratory conditions such as asthma and Obstructive Sleep Apnea Syndrome (OSAS). Co-occurrence of asthma and obesity may be due to common pathogenetic factors including exposure to air pollutants and tobacco smoking, Western diet, and low Vitamin D levels. Lung growth and dysanapsis phenomenon in asthmatic obese children play a role in impaired respiratory function which appears to be different than in adults. Genes involved in both asthma and obesity have been identified, though a gene-by-environment interaction has not been properly investigated yet. The identification of modifiable environmental factors influencing gene expression through epigenetic mechanisms may change the natural history of both diseases. Another important pediatric respiratory condition associated with obesity is Sleep-Disordered Breathing (SDB), especially Obstructive Sleep Apnea Syndrome (OSAS). OSAS and obesity are linked by a bidirectional causality, where the effects of one affect the other. The factors most involved in the association between OSAS and obesity are oxidative stress, systemic inflammation, and gut microbiota. In OSAS pathogenesis, obesity’s role appears to be mainly due to mechanical factors leading to an increase of respiratory work at night-time. However, a causal link between obesity-related inflammatory state and OSAS pathogenesis still needs to be properly confirmed. To prevent obesity and its complications, family education and precocious lifestyle changes are critical. A healthy diet may lead to an improved quality of life in obese children suffering from respiratory diseases. The present review aimed to investigate the links between obesity, asthma and OSAS, focusing on the available evidence and looking for future research fields

A novel PIEZO1 mutation in a patient with dehydrated hereditary stomatocytosis: A case report and a brief review of literature

open7noThis work was supported by EHA Junior Research Grant to Immacolata Andolfo (3978026), and by Bando Star Linea 1 - JUNIOR PRINCIPAL INVESTIGATOR GRANTS - COINOR, Università degli Studi di Napoli Federico II to Roberta Russo.Background: Dehydrated hereditary stomatocytosis (DHS) or hereditary xerocytosis is a rare, autosomal dominant hemolytic anemia characterized by macrocytosis, presence of stomatocytes and dehydration of red blood cells (RBCs). The dehydration is caused by a defect in cellular cation content. The most frequent expression of the pathology is hemolytic well-compensated anemia with high reticulocyte count, a tendency to macrocytosis, increased mean corpuscular hemoglobin concentration (MCHC) and mild jaundice. We here describe a new mutation of PIEZO1 gene, the most frequent mutated gene in DHS, in a family affected by hereditary hemolytic anemia. Case presentation: We describe the case of a 12-years-old girl with well-compensated chronic hemolysis, increased MCHC and a father who had the same hematological characteristics. After excluding secondary causes of chronic hemolysis and enzymatic defects of the RBCs, microscopic observation of the peripheral blood smear, tests of RBC lysis, ektacytometry, SDS-PAGE and in last instance genetic analysis has been performed. This complex diagnostic workup identified a new variant in the PIEZO1 gene, never described in literature, causative of DHS. This pathogenetic variant was also detected in the father. Conclusions: This case report highlights the importance of a correct and exhaustive diagnostic-workup in patients with clinical suspicious for hemolytic anemia in order to make a differential diagnosis. This is relevant for the management of these patients because splenectomy is contraindicated in DHS due to high thrombotic risk.openZama D.; Giulietti G.; Muratore E.; Andolfo I.; Russo R.; Iolascon A.; Pession A.Zama D.; Giulietti G.; Muratore E.; Andolfo I.; Russo R.; Iolascon A.; Pession A

The predictive role of biomarkers and genetics in childhood asthma exacerbations

Asthma exacerbations are associated with significant childhood morbidity and mortality. Recurrent asthma attacks contribute to progressive loss of lung function and can sometimes be fatal or near‐fatal, even in mild asthma. Exacerbation prevention becomes a primary target in the management of all asthmatic patients. Our work reviews current advances on exacerbation predictive factors, focusing on the role of non‐invasive biomarkers and genetics in order to identify subjects at higher risk of asthma attacks. Easy‐to‐perform tests are necessary in children; therefore, interest has increased on samples like exhaled breath condensate, urine and saliva. The variability of biomarker levels suggests the use of seriate measurements and composite markers. Genetic predisposition to childhood asthma onset has been largely investigated. Recent studies highlighted the influence of single nucleotide polymorphisms even on exacerbation susceptibility, through involvement of both intrinsic mechanisms and gene‐environment interaction. The role of molecular and genetic aspects in exacerbation prediction supports an individual‐shaped approach, in which follow‐up planning and therapy optimization take into account not only the severity degree, but also the risk of recurrent exacerbations. Further efforts should be made to improve and validate the application of biomarkers and genomics in clinical settings

Role of microRNAs in the main molecular pathways of hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the most common primary liver malignant neoplasia. HCC is characterized by a poor prognosis. The need to find new molecular markers for its diagnosis and prognosis has led to a progressive increase in the number of scientific studies on this topic. MicroRNAs (miRNAs) are small noncoding RNA that play a role in almost all main cellular pathways. miRNAs are involved in the regulation of expression of the major tumor-related genes in carcinogenesis, acting as oncogenes or tumor suppressor genes. The aim of this review was to identify papers published in 2017 investigating the role of miRNAs in HCC tumorigenesis. miRNAs were classified according to their role in the main molecular pathways involved in HCC tumorigenesis: (1) mTOR; (2) Wnt; (3) JAK/STAT; (4) apoptosis; and (5) MAPK. The role of miRNAs in prognosis/response prediction was taken into consideration. Bearing in mind that the analysis of miRNAs in serum and other body fluids would be crucial for clinical management, the role of circulating miRNAs in HCC patients was also investigated. The most represented miRNA-regulated pathway in HCC is mTOR, but apoptosis, Wnt, JAK/STAT or MAPK pathways are also influenced by miRNA expression levels. These miRNAs could thus be used in clinical practice as diagnostic, prognostic or therapeutic targets for HCC treatment

Prevalence of the single-nucleotide polymorphism rs11554137 (IDH1105GGT) in brain tumors of a cohort of Italian patients

IDH mutational status is required for proper diagnosis according to the WHO criteria revised in 2016. The single nucleotide polymorphism (SNP) rs11554137 (IDH1105GGT) at codon 105 of IDH1 has been reported in patients with several tumor types, including those with glioma. The aim of this study is to investigate the prevalence of IDH1105GGTin a cohort of brain tumors, and its association with clinicopathologic features and IDH1 and IDH2 missense mutations. Exon 4 of IDH1 and IDH2 was analyzed in a series of brain tumors classified according to current WHO criteria. DNA from control individuals was analyzed to infer the prevalence of IDH1105GGTin the reference population. Analysis was performed using next generation sequencing. IDH1105GGTwas three times more frequent in patients with tumors (44/293 cases, 15.0%) vs. population controls (6/109, 5.5%) (p = 0.0102). IDH1105GGTwas more frequent in grade III tumors (26.1%) compared to grade II (10.9%, p = 0.038) and grade IV tumors (13.7%, p = 0.041). IDH1105GGTwas more frequent in grade II and III tumors without an IDH tumor missense mutation (43.8%) than in those with (11.5%, p = 0.005). The IDH1105GGTSNP likely represents an important genetic marker, worthy of additional investigation to better understand the clinical and biological features of IDH-WT infiltrating gliomas

Perfluoroalkyl substances in human milk: A first survey in Italy

Due to their widespread diffusion, perfluoroalkyl substances (PFASs) have been frequently found in the environment and in several animal species. It has been demonstrated that they can easily reach also humans, mainly through diet. Being lactation a major route of elimination of these contaminants, their occurrence in human milk is of particular interest, especially considering that it generally represents the unique food source for newborns. Perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA), the two most important compounds of this family, have been frequently found in human milk at variable concentrations, but still limited data are available. The present study, the first conducted in Italy capable to detect these pollutants at ultra-trace levels by UPLC-MS/MS, confirmed the role of lactation as a relevant source of exposure for breastfed children. The measured concentrations ranged between 15 and 288 ng/L for PFOS and between 24 and 241 ng/L for PFOA. Moreover, mean concentrations and frequencies of both analytes resulted higher in milk samples provided by primiparous women, suggesting that the risk of intake might be higher for first-borns. Finally, comparing these results with previous data, PFOS gradual decrease over time since year 2000 was confirmed