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1.  The oxysterol–CXCR2 axis plays a key role in the recruitment of tumor-promoting neutrophils 
The Journal of Experimental Medicine  2013;210(9):1711-1728.
Tumor-derived oxysterols recruit protumor neutrophils in an LXR-independent, CXCR2-dependent manner, thus favoring tumor growth by promoting neoangiogenesis and immunosuppression.
Tumor-infiltrating immune cells can be conditioned by molecules released within the microenvironment to thwart antitumor immune responses, thereby facilitating tumor growth. Among immune cells, neutrophils play an important protumorigenic role by favoring neoangiogenesis and/or by suppressing antitumor immune responses. Tumor-derived oxysterols have recently been shown to favor tumor growth by inhibiting dendritic cell migration toward lymphoid organs. We report that tumor-derived oxysterols recruit protumor neutrophils in a liver X receptor (LXR)–independent, CXCR2-dependent manner, thus favoring tumor growth by promoting neoangiogenesis and immunosuppression. We demonstrate that interfering with the oxysterol–CXCR2 axis delays tumor growth and prolongs the overall survival of tumor-bearing mice. These results identify an unanticipated protumor function of the oxysterol–CXCR2 axis and a possible target for cancer therapy.
PMCID: PMC3754872  PMID: 23897983
2.  Oxysterols recruit tumor-supporting neutrophils within the tumor microenvironment 
Oncoimmunology  2013;2(11):e26469.
By binding to the liver X receptor (LXR), oxysterols inhibit the expression of chemokine (C-C motif) receptor 7 (CCR7), hence impairing the migration of dendritic cells to secondary lymphoid organs and inhibiting antitumor immune responses. We have recently identified a new tumor-supporting activity of oxysterols, which recruit neutrophils within tumor microenvironment by a chemokine (C-X-C motif) receptor 2 (CXCR2)-dependent, LXR-independent mechanism.
PMCID: PMC3897566  PMID: 24490125
CXCR2; immune evasion; microenvironment; oxysterols; tumor-infiltrating neutrophils
3.  Comprehensive Genomic Characterization of Cutaneous Malignant Melanoma Cell Lines Derived from Metastatic Lesions by Whole-Exome Sequencing and SNP Array Profiling 
PLoS ONE  2013;8(5):e63597.
Cutaneous malignant melanoma is the most fatal skin cancer and although improved comprehension of its pathogenic pathways allowed to realize some effective molecular targeted therapies, novel targets and drugs are still needed. Aiming to add genetic information potentially useful for novel targets discovery, we performed an extensive genomic characterization by whole-exome sequencing and SNP array profiling of six cutaneous melanoma cell lines derived from metastatic patients. We obtained a total of 3,325 novel coding single nucleotide variants, including 2,172 non-synonymous variants. We catalogued the coding mutations according to Sanger COSMIC database and to a manually curated list including genes involved in melanoma pathways identified by mining recent literature. Besides confirming the presence of known melanoma driver mutations (BRAFV600E, NRASQ61R), we identified novel mutated genes involved in signalling pathways crucial for melanoma pathogenesis and already addressed by current targeted therapies (such as MAPK and glutamate pathways). We also identified mutations in four genes (MUC19, PAICS, RBMXL1, KIF23) never reported in melanoma, which might deserve further investigations. All data are available to the entire research community in our Melanoma Exome Database (at In summary, these cell lines are valuable biological tools to improve the genetic comprehension of this complex cancer disease and to study functional relevance of individual mutational events, and these findings could provide insights potentially useful for identification of novel therapeutic targets for cutaneous malignant melanoma.
PMCID: PMC3660556  PMID: 23704925
4.  Childhood obesity, overweight and underweight: a study in primary schools in Milan 
Eating and Weight Disorders  2013;18(2):183-191.
The study aims to assess the prevalence of obesity, overweight and underweight in children enrolled in government primary schools (6–11 years of age) in the city of Milan, Italy.
One hundred and nine schools were randomly selected for the study. A cross-sectional study was conducted between March and June 2008. A survey was conducted using 16,588 questionnaires completed by parents. Anthropometric data (reported) of both parents and children and information on levels of physical activity and time children spent watching television (TV) were obtained.
In the total sample, parents are predominantly (75.0 %) of normal weight (M: 55.2 %; F: 79.1 %), 16.8 % are overweight (M: 36.9 %; F: 12.6 %), 4.0 % are obese (M: 6.6 %; F: 3.5 %) and 4.2 % are underweight (M: 1.3 %; F: 4.8 %). Among children, 68.7 % are of normal weight (M: 68.2 %; F: 69.2 %), 14.7 % are overweight (M: 15.3 %; F: 14.2 %), 4 % are obese (M: 4.5 %; F: 3.4 %), 11.8 % are underweight (M: 11.2 %; F: 12.5 %) and 0.8 % are severely thin (M: 0.9 %; F: 0.7 %). Children practice physical activity once or twice/week (48.3 %), three to four times/week (38.9 %) or five to seven times/week (8.9 %), while 3.9 % of children do not do any exercise. Most children (85.3 %) watch TV from 30 min to 2 h/day.
Contrary to the reported national average, the study shows the presence of only moderate levels of above-average weight and obesity among children. However, it remains important to monitor this phenomenon to raise awareness and to design programs of prevention throughout the country.
PMCID: PMC3664740  PMID: 23760847
Obesity; Overweight; Underweight; Children; Primary schools; Immigrants; Physical activity; TV watching
5.  Characterization of affective states by pupillary dynamics and autonomic correlates 
With the recent advent of new recording devices and an easier access to signal processing tools, researchers are increasingly exploring and studying the Pupil Dilation (PD) signal. Recently, numerous studies pointed out the relations between PD dynamics and psychophysiological states. Although it is well known that PD is controlled by the Autonomic Nervous System (ANS), and ANS responses are related to emotional events/stimuli, the relationship between emotional states and PD is still an open issue. The aim of this study is to define the statistical properties of the PD signal, to understand its relation with ANS correlates such as Heart Rate Variability (HRV) and respiration (RESP), and to explore if PD could provide information for the evaluation of the psychophysiological response of ANS to affective triggering events. ECG, RESP, and PD data from 13 normal subjects were recorded during a memory recall paradigm, and processed with spectral and cross-spectral analysis. Our results demonstrate that variability indices extracted from fast PD oscillations, not observable through standard cardiorespiratory identification in the frequency domain, would be able to discern psychophysiological responses elicited by basic emotional stimuli. A strong linear coupling was found between the variables, due to the influence of RESP on both PD and HRV within the High Frequency (HF) band, from 0.15 to 0.45 Hz. Most importantly, our results point at PD features as possible candidates for characterizing basic emotional stimuli.
PMCID: PMC3818468  PMID: 24223553
pupil dilation (PD); heart rate variability (HRV); autonomic nervous system (ANS); emotions; reconstruction; spectral analysis; very high frequencies; coherence analysis
6.  A genome wide association study for backfat thickness in Italian Large White pigs highlights new regions affecting fat deposition including neuronal genes 
BMC Genomics  2012;13:583.
Carcass fatness is an important trait in most pig breeding programs. Following market requests, breeding plans for fresh pork consumption are usually designed to reduce carcass fat content and increase lean meat deposition. However, the Italian pig industry is mainly devoted to the production of Protected Designation of Origin dry cured hams: pigs are slaughtered at around 160 kg of live weight and the breeding goal aims at maintaining fat coverage, measured as backfat thickness to avoid excessive desiccation of the hams. This objective has shaped the genetic pool of Italian heavy pig breeds for a few decades. In this study we applied a selective genotyping approach within a population of ~ 12,000 performance tested Italian Large White pigs. Within this population, we selectively genotyped 304 pigs with extreme and divergent backfat thickness estimated breeding value by the Illumina PorcineSNP60 BeadChip and performed a genome wide association study to identify loci associated to this trait.
We identified 4 single nucleotide polymorphisms with P≤5.0E-07 and additional 119 ones with 5.0E-07
Further investigations are needed to evaluate the effects of the identified single nucleotide polymorphisms associated with backfat thickness on other traits as a pre-requisite for practical applications in breeding programs. Reported results could improve our understanding of the biology of fat metabolism and deposition that could also be relevant for other mammalian species including humans, confirming the role of neuronal genes on obesity.
PMCID: PMC3499287  PMID: 23153328
GWA; Backfat; Fatness; Obesity; Heavy pig
Sudden cardiac death (SCD) is common in patients with Emery-Dreifuss muscular dystrophy (EDMD) and is attributed to the development of life-threatening arrhythmias that occur in the presence of normal left ventricular systolic function. Heterogeneity of ventricular repolarization is considered to provide an electrophysiological substrate for malignant arrhythmias. QTc dispersion (QTc-D) and JTc dispersion (JTc-D) are electrocardiographic parameters indicative of heterogeneity of ventricular repolarization. The aim of our study was to evaluate the heterogeneity of ventricular repolarization in patients with Emery-Dreifuss muscular dystrophy with preserved systolic and diastolic cardiac function
The study involved 36 EDMD patients (age 20±12, 26 M) and 36 healthy subjects used as controls, matched for age and sex. Heart rate, QRS duration, maximum and minimum QT and JT interval, QTc-D and JTc-D measurements were performed.
Compared to the healthy control group, the EDMD group presented increased values of QTc-D (82.7±44.2 vs. 53.1±13.7; P=0,003) and JTc-D (73.6±32.3 vs. 60.4±11.1 ms; P=0.001). No correlation between QTc dispersion and ejection fraction (R=0.2, P=0.3) was found.
Our study showed a significant increase of QTc-D and JTc-D in Emery-Dreifuss muscular dystrophy patients with preserved systolic and diastolic cardiac function.
PMCID: PMC3560603  PMID: 23111739
Emery-Dreifuss muscular dystrophy (EDMD); sudden cardiac death (SCD); ventricular repolarization; QTc dispersion; JTc dispersion
PLoS ONE  2012;7(10):e46928.
Neuroblastoma (NB), the most common solid extracranial cancer of childhood, displays a remarkable low expression of Major Histocompatibility Complex class I (MHC-I) and Antigen Processing Machinery (APM) molecules, including Endoplasmic Reticulum (ER) Aminopeptidases, and poorly presents tumor antigens to Cytotoxic T Lymphocytes (CTL). We have previously shown that this is due to low expression of the transcription factor NF-kB p65. Herein, we show that not only NF-kB p65, but also the Interferon Regulatory Factor 1 (IRF1) and certain APM components are low in a subset of NB cell lines with aggressive features. Whereas single transfection with either IRF1, or NF-kB p65 is ineffective, co-transfection results in strong synergy and substantial reversion of the MHC-I/APM-low phenotype in all NB cell lines tested. Accordingly, linked immunohistochemistry expression patterns between nuclear IRF1 and p65 on the one hand, and MHC-I on the other hand, were observed in vivo. Absence and presence of the three molecules neatly segregated between high-grade and low-grade NB, respectively. Finally, APM reconstitution by double IRF1/p65 transfection rendered a NB cell line susceptible to killing by anti MAGE-A3 CTLs, lytic efficiency comparable to those seen upon IFN-γ treatment. This is the first demonstration that a complex immune escape phenotype can be rescued by reconstitution of a limited number of master regulatory genes. These findings provide molecular insight into defective MHC-I expression in NB cells and provide the rational for T cell-based immunotherapy in NB variants refractory to conventional therapy.
PMCID: PMC3465322  PMID: 23071666
Acta Myologica  2012;31(2):139-143.
Atrial Preference Pacing (APP) is a pacemaker (PM) algorithm that works by increasing the atrial pacing rate to achieve continuous suppression of a spontaneous atrial rhythm and prevent supraventricular tachyarrhythmias. We have previously shown that atrial preference pacing may significantly reduce the number and the duration of AF episodes in myotonic dystrophy type 1 (DM1) patients who are paced for standard indications.
However, the role that APP therapies play in the prevention of AF in a long-term period remains still unclear. Aim of the present prospective study was to evaluate whether this beneficial effect is maintained for 24-months follow-up period.
To this aim, 50 patients with Myotonic Dystrophy type 1 who underwent dual-chamber PM implantation for first- and second- degree atrioventricular block, were consecutively enrolled and followed for 2 years. One month later the stabilization period, after the implantation, they were randomized to APP algorithm programmed OFF or ON for 6 months each, using a cross-over design, and remained in the same program for the second year. The results showed that while the number of AF episodes during active treatment (APP ON phases) was lower than that registered during no treatment (APP OFF phases), no statistically significant difference was found in AF episodes duration between the two phases. Furthermore, during the APP OFF and APP ON phases, the percentage of atrial pacing was 0 and 99%, respectively, while the percentage of ventricular pacing did not show differences statistically significant (11 vs. 9%, P = 0.2). Atrial premature beats were significantly higher during APP OFF phases than during APP ON phases. Lead parameters remained stable over time and there were no lead-related complications. Based on these 24-months follow-up data, we can conclude that, in DM1 patients who underwent dual-chamber PM implantation, APP is an efficacy algorithm for preventing paroxysmal AF even in long term periods.
PMCID: PMC3476853  PMID: 23097606
myotonic dystrophy; atrial preference pacing; atrial fibrillation
Acta Myologica  2012;31(2):154-155.
We report an improvement in symptoms of heart failure, a reduced left ventricular dysfunction and induced reverse remodelling in one patient with Myotonic Dystrophy type 1, showing an early onset ventricular dysfunction secondary to a complete left bundle branch block (LBBB) who underwent cardioverter defibrillator CRT (ICD- CRT) implantation.
PMCID: PMC3476859  PMID: 23097608
myotonic dystrophy; cardiac resynchronization therapy; sudden death
PLoS ONE  2011;6(9):e24729.
We have previously demonstrated that gene therapy can rescue the phenotype and extend lifespan in the delta-sarcoglycan deficient cardiomyopathic hamster. In patients with similar genetic defects, steroids have been largely used to slow down disease progression. Aim of our study was to evaluate the combined effects of steroid treatment and gene therapy on cardiac function. We injected the human delta-sarcoglycan cDNA by adeno-associated virus (AAV) 2/8 by a single intraperitoneal injection into BIO14.6 Syrian hamsters at ten days of age to rescue the phenotype. We then treated the hamsters with deflazacort. Treatment was administered to half of the hamsters that had received the AAV and the other hamsters without AAV, as well as to normal hamsters. Both horizontal and vertical activities were greatly enhanced by deflazacort in all groups. As in previous experiments, the AAV treatment alone was able to preserve the ejection fraction (70±7% EF). However, the EF value declined (52±14%) with a combination of AAV and deflazacort. This was similar with all the other groups of affected animals. We confirm that gene therapy improves cardiac function in the BIO14.6 hamsters. Our results suggest that deflazacort is ineffective and may also have a negative impact on the cardiomyopathy rescue, possibly by boosting motor activity. This is unexpected and may have significance in terms of the lifestyle recommendations for patients.
PMCID: PMC3170375  PMID: 21931833
Journal of Cancer  2011;2:329-330.
In this bi-institutional study, twenty-three stage IIIC-IV MAGE-A3+ melanoma patients were vaccinated with M3TK-GML biweekly at three dose levels, with a subsequent phase of vaccinations at the maximum dose level. Anti-MAGE-A3 and anti-TK T cells were assessed by in vitro assay and delayed-type hypersensitivity skin testing.
PMCID: PMC3119396  PMID: 21716850
MAGE-A3; Melanoma; Immunotherapy
Development of the posterior lateral line (PLL) system in zebrafish involves cell migration, proliferation and differentiation of mechanosensory cells. The PLL forms when cranial placodal cells delaminate and become a coherent, migratory primordium that traverses the length of the fish to form this sensory system. As it migrates, the primordium deposits groups of cells called neuromasts, the specialized organs that contain the mechanosensory hair cells. Therefore the primordium provides both a model for studying collective directional cell migration and the differentiation of sensory cells from multipotent progenitor cells.
Through the combined use of transgenic fish, Fluorescence Activated Cell Sorting and microarray analysis we identified a repertoire of key genes expressed in the migrating primordium and in differentiated neuromasts. We validated the specific expression in the primordium of a subset of the identified sequences by quantitative RT-PCR, and by in situ hybridization. We also show that interfering with the function of two genes, f11r and cd9b, defects in primordium migration are induced. Finally, pathway construction revealed functional relationships among the genes enriched in the migrating cell population.
Our results demonstrate that this is a robust approach to globally analyze tissue-specific expression and we predict that many of the genes identified in this study will show critical functions in developmental events involving collective cell migration and possibly in pathological situations such as tumor metastasis.
PMCID: PMC3016277  PMID: 21144052
Heart  2006;93(12):1591-1598.
Myocardial scintigraphy and/or conventional angiography (CA) are often performed before cardiac surgery in an attempt to identify unsuspected coronary artery disease which might result in significant cardiac morbidity and mortality. Multidetector CT coronary angiography (MDCTCA) has a recognised high negative predictive value and may provide a non‐invasive alternative in this subset of patients. The aim of this study was to evaluate the clinical value of MDCTCA as a preoperative screening test in candidates for non‐coronary cardiac surgery.
132 patients underwent MDCTCA (Somatom Sensation 16 Cardiac, Siemens) in the assessment of the cardiac risk profile before surgery. Coronary arteries were screened for ⩾50% stenosis. Patients without significant stenosis (Group 1) underwent surgery without any adjunctive screening tests while all patients with coronary lesions ⩾50% at MDCTCA (Group 2) underwent CA.
16 patients (12.1%) were excluded due to poor image quality. 72 patients without significant coronary stenosis at MDCTCA were submitted to surgery. 30 out of 36 patients with significant (⩾50%) coronary stenosis at MDCTCA and CA underwent adjunctive bypass surgery or coronary angioplasty. In 8 patients, MDCTCA overestimated the severity of the coronary lesions (>50% MDCTCA, <50% CA).
No severe cardiovascular perioperative events such as myocardial ischaemia, myocardial infarction or cardiac failure occurred in any patient in Group 1.
MDCTCA seems to be effective as a preoperative screening test prior to non‐coronary cardiac surgery. In this era of cost containment and optimal care of patients, MDCTCA is able to provide coronary vessel and ventricular function evaluation and may become the method of choice for the assessment of a cardiovascular risk profile prior to major surgery.
PMCID: PMC2095762  PMID: 17164488
BMC Genomics  2010;11:639.
The goat (Capra hircus) represents one of the most important farm animal species. It is reared in all continents with an estimated world population of about 800 million of animals. Despite its importance, studies on the goat genome are still in their infancy compared to those in other farm animal species. Comparative mapping between cattle and goat showed only a few rearrangements in agreement with the similarity of chromosome banding. We carried out a cross species cattle-goat array comparative genome hybridization (aCGH) experiment in order to identify copy number variations (CNVs) in the goat genome analysing animals of different breeds (Saanen, Camosciata delle Alpi, Girgentana, and Murciano-Granadina) using a tiling oligonucleotide array with ~385,000 probes designed on the bovine genome.
We identified a total of 161 CNVs (an average of 17.9 CNVs per goat), with the largest number in the Saanen breed and the lowest in the Camosciata delle Alpi goat. By aggregating overlapping CNVs identified in different animals we determined CNV regions (CNVRs): on the whole, we identified 127 CNVRs covering about 11.47 Mb of the virtual goat genome referred to the bovine genome (0.435% of the latter genome). These 127 CNVRs included 86 loss and 41 gain and ranged from about 24 kb to about 1.07 Mb with a mean and median equal to 90,292 bp and 49,530 bp, respectively. To evaluate whether the identified goat CNVRs overlap with those reported in the cattle genome, we compared our results with those obtained in four independent cattle experiments. Overlapping between goat and cattle CNVRs was highly significant (P < 0.0001) suggesting that several chromosome regions might contain recurrent interspecies CNVRs. Genes with environmental functions were over-represented in goat CNVRs as reported in other mammals.
We describe a first map of goat CNVRs. This provides information on a comparative basis with the cattle genome by identifying putative recurrent interspecies CNVs between these two ruminant species. Several goat CNVs affect genes with important biological functions. Further studies are needed to evaluate the functional relevance of these CNVs and their effects on behavior, production, and disease resistance traits in goats.
PMCID: PMC3011854  PMID: 21083884
BMC Genetics  2010;11:59.
In the domestic rabbit (Oryctolagus cuniculus), classical genetic studies have identified five alleles at the Extension locus: ED (dominant black), ES (steel, weaker version of ED), E (wild type, normal extension of black), eJ(Japanese brindling, mosaic distribution of black and yellow) and e (non-extension of black, yellow/red with white belly). Sequencing almost the complete coding sequence (CDS) of the rabbit MC1R gene, we recently identified two in-frame deletions associated with dominant black (c.280_285del6; alleles ED or ES) and recessive red (c.304_333del30; allele e) coat colours. It remained to characterize the eJallele whose phenotypic effect is similar to the Orange and Sex-linked yellow loci of cat and Syrian hamster.
We sequenced the whole CDS in 25 rabbits of different coat colours including 10 Japanese and 10 Rhinelander (tricolour) rabbits and identified another 6 bp-in frame deletion flanked by a G > A transition in 5' (c.[124G>A;125_130del6]) that was present in all animals with Japanese brindling coat colour and pattern. These mutations eliminate two amino acids in the first transmembrane domain and, in addition, cause an amino acid substitution at position 44 of the wild type sequence. Genotyping 371 rabbits of 31 breeds with different coat colour this allele (eJ) was present in homozygous state in Japanese, Rhinelander and Dutch tricolour rabbits only (except one albino rabbit). Rabbits with eJ/eJ genotype were non fixed at the non-agouti mutation we previously identified in the ASIP gene. Segregation in F1 and F2 families confirmed the order of dominance already determined by classical genetic experiments with a possible dose effect evident comparing eJ/eJ and eJ/e animals. MC1R mRNA was expressed in black hair skin regions only.
The c.[124A;125_130del6] allele may be responsible for a MC1R variant determining eumelanin production in the black areas. However, the mechanism determining the presence of both red and black hairs in the same animal seems more complex. Expression analyses of the c.[124A;125_130del6] allele suggest that MC1R transcription may be regulated epigenetically in rabbits with the Japanese brindling phenotype. Further studies are needed to clarify this issue.
PMCID: PMC3236303  PMID: 20594318
BMC Genetics  2009;10:47.
Agouti and Extension loci control the relative amount of eumelanin and pheomelanin production in melanocytes that, in turn, affects pigmentation of skin and hair. The Extension locus encodes the melanocortin 1 receptor (MC1R) whose permanent activation, caused by functional mutations, results in black coat colour, whereas other inactivating mutations cause red coat colour in different mammals.
The whole coding region of the MC1R gene was sequenced in goats of six different breeds showing different coat colours (Girgentana, white cream with usually small red spots in the face; Maltese, white with black cheeks and ears; Derivata di Siria, solid red; Murciano-Granadina, solid black or solid brown; Camosciata delle Alpi, brown with black stripes; Saanen, white; F1 goats and the parental animals). Five single nucleotide polymorphisms (SNPs) were identified: one nonsense mutation (p.Q225X), three missense mutations (p.A81V, p.F250V, and p.C267W), and one silent mutation. The stop codon at position 225 should cause the production of a shorter MC1R protein whose functionality may be altered. These SNPs were investigated in a larger sample of animals belonging to the six breeds. The Girgentana breed was almost fixed for the p.225X allele. However, there was not complete association between the presence of red spots in the face and the presence of this allele in homozygous condition. The same allele was identified in the Derivata di Siria breed. However, its frequency was only 33%, despite the fact that these animals are completely red. The p.267W allele was present in all Murciano-Granadina black goats, whereas it was never identified in the brown ones. Moreover, the same substitution was present in almost all Maltese goats providing evidence of association between this mutation and black coat colour.
According to the results obtained in the investigated goat breeds, MC1R mutations may determine eumelanic and pheomelanic phenotypes. However, they are probably not the only factors. In particular, the surprising not complete association of the nonsense mutation (p.Q225X) with red coat colour raises a few hypotheses on the determination of pheomelanic phenotypes in goats that should be further investigated.
PMCID: PMC2748843  PMID: 19706191
The incidence of thoracic aortic aneurysms (TAAs) is increasing with the present rate of occurrence at 10.9 cases per 100,000 people per year. The estimated 5-year risk of rupture of a TAA with a diameter between 4 and 5.9 cm is 16%, but it rises to 31% for aneurysms ≥ 6 cm. Despite increasing awareness of the importance of early diagnosis and treatment options, there are no clear guidelines available at the time of writing. Nor is there any clear evidence for specific pharmacological treatment able to resolve or delay the disease progression. Endovascular treatment (EVT), proposed as an alternative to surgery, has been considered a therapeutic innovation, especially because it is minimally invasive, which allows treatment even in high surgical risk patients. Vascular imaging is crucial for patient selection, endoprosthesis choice, and planning of the treatment because not all aneurysms are suitable. Early and midterm results are encouraging, but long-term results are necessary to definitively assess reliability of stent-graft materials and improvement in patient survival. In the choice between surgical or endovascular repair of TAAs, many factors must be considered, including the clinical situation, comorbidities, anatomy, choice of equipment, and last, but not less important, experience of the clinical team.
PMCID: PMC3036420  PMID: 21326796
Thoracic aortic aneurysm; endovascular treatment and follow-up
As for a consolidated tradition, the 5th annual meeting of the Italian Network for Cancer Biotherapy took place in the Certosa of Pontignano, a Tuscan monastery, on September 20–22, 2007. The congress gathered more than 40 Italian leading groups representing academia, biotechnology and pharmaceutical industry. Aim of the meeting was to share new advances in cancer bio-immunotherapy and to promote their swift translation from pre-clinical research to clinical applications. Several topics were covered including: a) molecular and cellular mechanisms of tumor escape; b) therapeutic antibodies and recombinant constructs; c) clinical trials up-date and new programs; d) National Cooperative Networks and their potential interactions; e) old and new times in cancer immunology, an "amarcord". Here, we report the main issues discussed during the meeting.
PMCID: PMC2275223  PMID: 18269750
The Journal of Clinical Investigation  2007;117(10):3087-3096.
The exploitation of the physiologic processing and presenting machinery of DCs by in vivo loading of tumor-associated antigens may improve the immunogenic potential and clinical efficacy of DC-based cancer vaccines. Here we show that lymphocytes genetically modified to express self/tumor antigens, acting as antigen carriers, efficiently target DCs in vivo in tumor-bearing mice. The infusion of tyrosinase-related protein 2–transduced (TRP-2–transduced) lymphocytes induced the establishment of protective immunity and long-term memory in tumor-bearing mice. Analysis of the mechanism responsible for the induction of such an immune response allowed us to demonstrate that cross-presentation of the antigen mediated by the CD11c+CD8α+ DC subset had occurred. Furthermore, we demonstrated in vivo and in vitro that DCs had undergone activation upon phagocytosis of genetically modified lymphocytes, a process mediated by a cell-to-cell contact mechanism independent of CD40 triggering. Targeting and activation of secondary lymphoid organ–resident DCs endowed antigen-specific T cells with full effector functions, which ultimately increased tumor growth control and animal survival in a therapeutic tumor setting. We conclude that the use of transduced lymphocytes represents an efficient method for the in vivo loading of tumor-associated antigens on DCs.
PMCID: PMC1978420  PMID: 17885685
Heart International  2006;2(2):126.
The authors present a case of 36 year old male patient with idiopathic postural orthostatic tachycardia syndrome (POTS) diagnosed during head-up tilt testing. Power spectral analysis of heart rate variability (HRV) during the tilt test revealed that the ratio of low and high frequency powers (LF/HF) increased with the onset of orthostatic intolerance. This analysis confirmed in our patient a strong activation in sympathetic tone.
PMCID: PMC3184666  PMID: 21977261
Postural orthostatic tachycardia syndrome; POTS; Sympathovagal balance; Heart rate variability; HRV
Heart International  2006;2(1):27.
The aim of our study was to evaluate the effect of cardiac resyncronization therapy (CRT) on QT dispersion (QTd), JT dispersion (JTd) and transmural dispersion of re-polarization (TDR), markers of heterogeneity of ventricular repolarization in a study population with severe heart failure.
Methods and Results:
Fifty patients (43 male, 7 female, aged 60.2 ± 3.1 years) suffering from congestive heart failure (N = 39 NYHA class III; N = 11 NYHA class IV) as a result of coronary artery disease (N = 19) or of dilated cardiomyopathy (N = 31), sinus rhythm, QRS duration >130 ms (mean QRS duration >156 ± 21 ms), an ejection fraction < 35%, left ventricular end-diastolic diameter >55 mm, underwent permanent biventricular DDDR pacemaker implantation. A 12-lead standard electrocardiogram was performed at baseline, during right-, left-, and biventricular pacing and QTd, JTd and TDR were assessed. Biventricular pacing significantly reduced QTd (73.93 ± 19.4 ms during BiVP vs 91 ± 6.7 ms at sinus rhythm, p = 0.004), JTd (73.18 ± 17.16 ms during BiVP vs 100.72 ± 39.04 at baseline p = 0.003), TDR (93.16 ± 15.60 vs 101.55 ± 19.08 at baseline; p<0.004), as compared to sinus rhythm. Right ventricular endocardial pacing and left ventricular epicardial pacing both enhanced QTd (RVendoP 94 ± 51 ms, p<0.03; LVepiP 116 ±71 ms, p<0.02) and TDR (RVendoP 108.13 ± 19.94 ms; p<0.002; LVepiP 114.71 ± 26.1; p<0.05).There was no effect on JTd during right and left ventricular stimulation.
Biventricular pacing causes a statistically significant reduction of ventricular heterogeneity of ripolarization and has an electrophysiological antiarrhythmic influence on arrhythmogenic substrate of dilatative cardiomiopathy.
PMCID: PMC3184659  PMID: 21977248
Biventricular pacing; QT dispersion; JT dispersion; TDR; Heart failure
By stimulating human CD8+ T lymphocytes with autologous dendritic cells infected with an adenovirus encoding MAGE-3, we obtained a cytotoxic T lymphocyte (CTL) clone that recognized a new MAGE-3 antigenic peptide, AELVHFLLL, which is presented by HLA-B40. This peptide is also encoded by MAGE-12. The CTL clone recognized MAGE-3–expressing tumor cells only when they were first treated with IFN-γ. Since this treatment is known to induce the exchange of the three catalytic subunits of the proteasome to form the immunoproteasome, this result suggested that the processing of this MAGE-3 peptide required the immunoproteasome. Transfection experiments showed that the substitution of β5i (LMP7) for β5 is necessary and sufficient for producing the peptide, whereas a mutated form of β5i (LMP7) lacking the catalytically active site was ineffective. Mass spectrometric analyses of in vitro digestions of a long precursor peptide with either proteasome type showed that the immunoproteasome produced the antigenic peptide more efficiently, whereas the standard proteasome more efficiently introduced cleavages destroying the antigenic peptide. This is the first example of a tumor-specific antigen exclusively presented by tumor cells expressing the immunoproteasome.
PMCID: PMC2193621  PMID: 11854353
β5i; proteasome; mass spectrometry; tumor; HLA-B40

Results 1-23 (23)