Effect of dietary supplementation with ultramicronized palmitoylethanolamide in maintaining remission in cats with nonflea hypersensitivity dermatitis: a double-blind, multicentre, randomized, placebo-controlled study

Background Feline nonflea hypersensitivity dermatitis (NFHD) is a frequent cause of over-grooming, scratching and skin lesions. Multimodal therapy often is necessary. Hypothesis/Objectives To investigate the efficacy of ultramicronized palmitoylethanolamide (PEA-um) in maintaining methylprednisolone-induced remission in NFHD cats. Animals Fifty-seven NFHD cats with nonseasonal pruritus were enrolled originally, of which 25 completed all study requirements to be eligible for analysis. Methods and materials Cats were randomly assigned to PEA-um (15 mg/kg per os, once daily; n = 29) or placebo (n = 28) while receiving a 28 day tapering methylprednisolone course. Cats responding favourably to methylprednisolone were then administered only PEA-um (n = 21) or placebo (n = 23) for another eight weeks, followed by a four week long treatment-free period. Cats were maintained in the study until relapse or study end, whichever came first. Primary outcome was time to relapse. Secondary outcomes were pruritus Visual Analog Scale (pVAS), SCORing Feline Allergic Dermatitis scale (SCORFAD) and owner Global Assessment Score (GAS). Results Mean relapse time was 40.5 days (+/- 7.8 SE) in PEA-um treated cats (n = 13) and 22.2 days (+/- 3.7 SE) for placebo (n = 12; P = 0.04). On Day 28, the severity of pruritus was lower in the PEA-um treated cats compared to placebo (P = 0.03). Mean worsening of pruritus at the final study day was lower in the PEA-um group compared to placebo (P = 0.04), whereas SCORFAD was not different between groups. Mean owner GAS at the final study day was better in the PEA-um than the placebo-treated group (P = 0.05). Conclusion and clinical importance Ultramicronized palmitoylethanolamide could represent an effective and safe option to delay relapse in NFHD cats

Five recurrent BRCA1/2 mutations are responsible for cancer predisposition in the majority of Slovenian breast cancer families

<p>Abstract</p> <p>Background</p> <p>Both recurrent and population specific mutations have been found in different areas of the world and more specifically in ethnically defined or isolated populations. The population of Slovenia has over several centuries undergone limited mixing with surrounding populations.</p> <p>The current study was aimed at establishing the mutation spectrum of <it>BRCA1/2 </it>in the Slovenian breast/ovarian cancer families taking advantage of a complete cancer registration database. A second objective was to determine the cancer phenotype of these families.</p> <p>Methods</p> <p>The original population database was composed of cancer patients from the Institute of Oncology Ljubljana in Slovenia which also includes current follow-up status on these patients. The inclusion criteria for the <it>BRCA1/2 </it>screening were: (i) probands with at least two first degree relatives with breast and ovarian cancer; (ii) probands with only two first degree relatives of breast cancer where one must be diagnosed less than 50 years of age; and (iii) individual patients with breast and ovarian cancer, bilateral breast cancer, breast cancer diagnosed before the age of 40 and male breast cancer without any other cancer in the family.</p> <p>Results</p> <p>Probands from 150 different families met the inclusion criteria for mutation analysis of which 145 consented to testing. A <it>BRCA1/2 </it>mutation was found in 56 (39%). Two novel large deletions covering consecutive exons of <it>BRCA1 </it>were found. Five highly recurrent specific mutations were identified (1806C>T, 300T>G, 300T>A, 5382insC in the <it>BRCA1 </it>gene and IVS16-2A>G in the <it>BRCA2 </it>gene). The IVS16-2A>G in the <it>BRCA2 </it>gene appears to be a unique founder mutation in the Slovenian population. A practical implication is that only 4 PCR fragments can be used in a first screen and reveal the cancer predisposing mutation in 67% of the <it>BRCA1/2 </it>positive families. We also observed an exceptionally high frequency of 4 different pathogenic missense mutations, all affecting one of the cryptic cysteine residues of the <it>BRCA1 </it>Ring Finger domain.</p> <p>Conclusion</p> <p>A high mutation detection rate and the frequent occurrence of a limited array of recurring mutations facilitate <it>BRCA1/2 </it>mutation screening in Slovenian families.</p

A different immunologic profile characterizes patients with HER-2-overexpressing and HER-2-negative locally advanced breast cancer: implications for immune-based therapies

INTRODUCTION: The clinical efficacy of trastuzumab and taxanes is at least partly related to their ability to mediate or promote antitumor immune responses. On these grounds, a careful analysis of basal immune profile may be capital to dissect the heterogeneity of clinical responses to these drugs in patients with locally advanced breast cancer undergoing neoadjuvant chemotherapy. METHODS: Blood samples were collected from 61 locally advanced breast cancers (36 HER2- and 25 HER2+) at diagnosis and from 23 healthy women. Immunophenotypic profiling of circulating and intratumor immune cells, including regulatory T (Treg) cells, was assessed by flow cytometry and immunohistochemistry, respectively. Serum levels of 10 different cytokines were assessed by multiplex immunoassays. CD8+ T cell responses to multiple tumor-associated antigens (TAA) were evaluated by IFN-γ-enzyme-linked immunosorbent spot (ELISPOT). The Student's t test for two tailed distributions and the Wilcoxon two-sample test were used for the statistical analysis of the data. RESULTS: The proportion of circulating immune effectors was similar in HER2+ patients and healthy donors, whereas higher percentages of natural killer and Treg cells and a lower CD4+/CD8+ T cell ratio (with a prevalence of naïve and central memory CD8+ T cells) were observed in HER2- cases. Higher numbers of circulating CD8+ T cells specific for several HLA-A*0201-restricted TAA-derived peptides were observed in HER2+ cases, together with a higher prevalence of intratumor CD8+ T cells. Serum cytokine profile of HER2+ patients was similar to that of controls, whereas HER2- cases showed significantly lower cytokine amounts compared to healthy women (IL-2, IL-8, IL-6) and HER2+ cases (IL-2, IL-1β, IL-8, IL-6, IL-10). CONCLUSIONS: Compared to HER2- cases, patients with HER2-overexpressing locally advanced breast cancer show a more limited tumor-related immune suppression. This may account for the clinical benefit achieved in this subset of patients with the use of drugs acting through, but also promoting, immune-mediated effects

NMR-based pharmacometabonomics: A new paradigm for personalised or precision medicine

Metabolic profiling by NMR spectroscopy or hyphenated mass spectrometry, known as metabonomics or metabolomics, is an important tool for systems-based approaches in biology and medicine. The experiments are typically done in a diagnostic fashion where changes in metabolite profiles are interpreted as a consequence of an intervention or event; be that a change in diet, the administration of a drug, physical exertion or the onset of a disease. By contrast, pharmacometabonomics takes a prognostic approach to metabolic profiling, in order to predict the effects of drug dosing before it occurs. Differences in pre-dose metabolite profiles between groups of subjects are used to predict post-dose differences in response to drug administration. Thus the paradigm is inverted and pharmacometabonomics is the metabolic equivalent of pharmacogenomics. Although the field is still in its infancy, it is expected that pharmacometabonomics, alongside pharmacogenomics, will assist with the delivery of personalised or precision medicine to patients, which is a critical goal of 21st century healthcare

Phenotypic features and genetic characterization of male breast cancer families: identification of two recurrent BRCA2 mutations in north-east of Italy

BACKGROUND: Breast cancer in men is an infrequent occurrence, accounting for ~1% of all breast tumors with an incidence of about 1:100,000. The relative rarity of male breast cancer (MBC) limits our understanding of the epidemiologic, genetic and clinical features of this tumor. METHODS: From 1997 to 2003, 10 MBC patients were referred to our Institute for genetic counselling and BRCA1/2 testing. Here we report on the genetic and phenotypic characterization of 10 families with MBC from the North East of Italy. In particular, we wished to assess the occurrence of specific cancer types in relatives of MBC probands in families with and without BRCA2 predisposing mutations. Moreover, families with recurrent BRCA2 mutations were also characterized by haplotype analysis using 5 BRCA2-linked dinucleotide repeat markers and 8 intragenic BRCA2 polymorphisms. RESULTS: Two pathogenic mutations in the BRCA2 gene were observed: the 9106C>T (Q2960X) and the IVS16-2A>G (splicing) mutations, each in 2 cases. A BRCA1 mutation of uncertain significance 4590C>G (P1491A) was also observed. In families with BRCA2 mutations, female breast cancer was more frequent in the first and second-degree relatives compared to the families with wild type BRCA1/2 (31.9% vs. 8.0% p = 0.001). Reconstruction of the chromosome phasing in three families and the analysis of three isolated cases with the IVS16-2A>G BRCA2 mutation identified the same haplotype associated with MBC, supporting the possibility that this founder mutation previously detected in Slovenian families is also present in the North East of our Country. Moreover, analysis of one family with the 9106C>T BRCA2 mutation allowed the identification of common haplotypes for both microsatellite and intragenic polymorphisms segregating with the mutation. Three isolated cases with the same mutation shared the same intragenic polymorphisms and three 5' microsatellite markers, but showed a different haplotype for 3' markers, which were common to all three cases. CONCLUSION: The 9106C>T and the IVS16-2A>G mutations constitute recurrent BRCA2 mutations in MBC cases from the North-East of Italy and may be associated with a founder effect. Knowledge of these two recurrent BRCA2 mutations predisposing to MBC may facilitate the analyses aimed at the identification of mutation carriers in our geographic area

The occurrence of germline BRCA1 and BRCA2 sequence alterations in Slovenian population

<p>Abstract</p> <p>Background</p> <p>The <it>BRCA1 </it>and <it>BRCA2 </it>mutation spectrum and mutation detection rates according to different family histories were investigated in 521 subjects from 322 unrelated Slovenian cancer families with breast and/or ovarian cancer.</p> <p>Methods</p> <p>The <it>BRCA1 </it>and <it>BRCA2 </it>genes were screened using DGGE, PTT, HRM, MLPA and direct sequencing.</p> <p>Results</p> <p>Eighteen different mutations were found in <it>BRCA1 </it>and 13 in <it>BRCA2 </it>gene. Mutations in one or other gene were found in 96 unrelated families. The mutation detection rates were the highest in the families with at least one breast and at least one ovarian cancer - 42% for <it>BRCA1 </it>and 8% for <it>BRCA2</it>. The mutation detection rate observed in the families with at least two breast cancers with disease onset before the age of 50 years and no ovarian cancer was 23% for <it>BRCA1 </it>and 13% for <it>BRCA2</it>. The mutation detection rate in the families with at least two breast cancers and only one with the disease onset before the age of 50 years was 11% for <it>BRCA1 </it>and 8% for <it>BRCA2</it>. In the families with at least two breast cancers, all of them with disease onset over the age of 50 years, the detection rate was 5% for <it>BRCA2 </it>and 0% for <it>BRCA1</it>.</p> <p>Conclusion</p> <p>Among the mutations detected in Slovenian population, 5 mutations in <it>BRCA1 </it>and 4 mutations in <it>BRCA2 </it>have not been described in other populations until now. The most frequent mutations in our population were c.181T > G, c.1687C > T, c.5266dupC and c.844_850dupTCATTAC in <it>BRCA1 </it>gene and c.7806-2A > G, c.5291C > G and c.3978insTGCT in <it>BRCA2 </it>gene (detected in 69% of <it>BRCA1 </it>and <it>BRCA2 </it>positive families).</p

Presentazione del sito neolitico tardo e dell’età del Rame di Monte Doc nelle Prealpi Trevigiane.

Monte Doc si presenta come sito di rilevante significato per l’archeologia del tardo Neolitico e dell’Eneolitico. L’abbondanza di manufatti e il loro stato di conservazione consentiranno di approfondire le conoscenze sulle attività artigianali, l’economia e il commercio delle comunità pastorali-agricole dell’Italia nord-orientale e soprattutto di tracciare i contorni dell’areale di diffusione di nuclei e manufatti litici, nonchè delle lame di pugnale e dei pezzi preformati. Il sito si configura attualmente come l’unico esempio di produzione artigianale bene conservato e indagato sistematicamente su vaste superfici dell’arco alpino italiano a nord del Po. La prosecuzione degli studi ed eventuali indagini di terreno a completamento dei lavori finora eseguiti consentiranno di verificare l’importanza strategica dei rilievi prealpini affacciati sulla pianura e sui suoi principali traffici commerciali