Characterization of Research Mentorship During Medical School for Future Radiation Oncology Trainees.

Purpose: Medical student access to radiation oncology (RO) research opportunities is important for stimulating interest in the specialty. The purpose of this study was to assess the publication record during medical school of students who ultimately matched in RO, to characterize the source(s) of their RO mentorship relative to other specialties. Methods and Materials: We performed web-based searches to identify manuscripts published during medical school (defined as being published from January 2016 to December 2019) for all RO residents with postgraduate year 2 status in 2020 to 2021. Students with a PhD degree and international graduates were excluded. Characteristics of these publications, the student, and the primary mentor, were assessed. Results: A total of 435 publications were authored by the 148 included residents. In total, 115 (78%) attended a medical school with an affiliated RO residency program. The median number of publications per student was 2 (interquartile range, 1-4), and students' median byline author position was 2 (interquartile range, 1-4). In total, 351 publications (80.7%) were on a cancer-related topic, with 234 (53.8%) published in oncology-oriented journal, and 96 (22.0%) published in RO-oriented journals. There were 294 unique mentors, with 70 mentors (24%) on 2 or more student publications. Most mentors (n = 187, 64%) shared the same institution as the student. Mentors were most commonly radiation oncologists/radiation biologists/medical physicists (n = 153, 52.6%), surgical subspecialists (n = 53, 21%), and medical oncologists (n = 18, 6.2%). Students working with primary RO mentors were more likely to publish in an oncology-oriented journal (79.1% vs 18.2%, P < .01) or RO-oriented journal (36.2% vs 2.2%, P < .01), compared with students working with non-RO mentors, respectively. A higher percentage of publications with RO mentors occurred in the last 2 years of medical school compared with the first 2 years (64.0% vs 40.9%, respectively, P < .01). Conclusions: Approximately one-half of student publications among future RO residents are published in nononcology journals, and result from mentoring relationships with non-RO physicians.

Assessment of Medical Student Research Mentorship in Radiation Oncology.

Purpose: Mentored medical student (MS) research opportunities in radiation oncology (RO) provide in-depth exposure to the specialty and may promote greater interest in a career in RO. Many radiation oncologists conduct research; however, the extent to which they directly engage MSs in their research is unknown. The purpose of this study was to characterize MS authorship in American Society for Radiation Oncology (ASTRO) journals. Methods and Materials: The byline and abstract of all scientific articles (ie, clinical, basic science, training/education) and case reports published from 2019 to 2021 in the International Journal of Radiation Oncology, Biology, and Physics; Practical Radiation Oncology; and Advances in Radiation Oncology were reviewed. Characteristics of MSs and senior authors are reported. Results: A total of 105 of 1785 articles (5.8%) included an MS author, among which 72 (68.6%) were clinical, 13 training/education (12.4%), 12 case reports (11.4%), and 8 basic science (7.6%). MS authors were more common for publications in Advances in Radiation Oncology (9.0%) than Practical Radiation Oncology (6.4%) or the International Journal of Radiation Oncology, Biology, and Physics (4.2%; P = .002). There were 125 unique MS authors from 72 institutions, among which 40 were first author (32.0%), 28 second author (22.4%), and 57 third (or higher) author (45.6%). There were 88 unique senior authors from 55 institutions, among which 10 (11.3%) were on 2 or more MS publications, and 57 (64.7%) shared the same institution as the MS. The median number of articles per mentor institution was 1 (interquartile range, 1-2), and the mentor institutions in the upper quartile in terms of number of MS publications accounted for 53 (50.5%) of all MS publications. Conclusions: Few publications in American Society for Radiation Oncology journals include MS authors with mentorship disproportionately from a small number of academic faculty at select institutions. These findings suggest that there is great potential for radiation oncologists to proactively engage more students in their work.

Cutaneous angiosarcoma: A review of current evidence for treatment with checkpoint inhibitors.

Cutaneous angiosarcoma (cAS) is a rare and aggressive subtype of soft tissue sarcoma with poor prognosis and suboptimal treatment options. Clinical presentation is variable, but cAS often arises from the head and neck. The most widely accepted current approach, surgical excision with adjuvant radiotherapy, is associated with high recurrence rates and can leave patients with profound disfigurement. Chemotherapy and targeted therapy alternatives have had limited success. Thus, there is a significant unmet need to address the absence of durable treatments for advanced and metastatic cAS. Like melanoma and cutaneous squamous cell carcinoma, tumor types with known response to immunotherapy, cAS harbors immune biomarkers, such as tumor mutational burden high (TMB-H), PD-L1 positivity, ultraviolet signature expression, and tertiary lymphoid structures. While data on the use and efficacy of immunotherapy in cAS is limited, the biomarkers suggest a promising advancement in future treatment options. This review aims to summarize and discuss current data from case reports, case series, retrospective studies and clinical trials regarding immunotherapy treatment and outcomes for cAS.

A phase 1b single-arm trial of intratumoral oncolytic virus V937 in combination with pembrolizumab in patients with advanced melanoma: results from the CAPRA study.

BACKGROUND: CAPRA (NCT02565992) evaluated Coxsackievirus A21 (V937) + pembrolizumab for metastatic/unresectable stage IIIB-IV melanoma. METHODS: Patients received intratumoral V937 on days 1, 3, 5, and 8 (then every 3 weeks [Q3W]) and intravenous pembrolizumab 2 mg/kg Q3W from day 8. Primary endpoint was safety. RESULTS: Median time from first dose to data cutoff was 32.0 months. No dose-limiting toxicities occurred; 14% (5/36) of patients experienced grade 3‒5 treatment-related adverse events. Objective response rate was 47% (complete response, 22%). Among 17 responders, 14 (82%) had responses ≥ 6 months. Among 8 patients previously treated with immunotherapy, 3 responded (1 complete, 2 partial). Responses were associated with increased serum CXCL10 and CCL22, suggesting viral replication contributes to antitumor immunity. For responders versus nonresponders, there was no difference in baseline tumor PD-L1 expression, ICAM1 expression, or CD3+ infiltrates. Surprisingly, the baseline cell density of CD3+CD8- T cells in the tumor microenvironment was significantly lower in responders compared with nonresponders (P = 0.0179). CONCLUSIONS: These findings suggest responses to this combination may be seen even in patients without a typical "immune-active" microenvironment. TRIAL REGISTRATION NUMBER: NCT02565992.

A phase Ib dose-escalation study of troriluzole (BHV-4157), an oral glutamatergic signaling modulator, in combination with nivolumab in patients with advanced solid tumors.

BACKGROUND: Glutamate signaling activates MAPK and PI3K/AKT pathways in tumor cells. Treatment with riluzole, a glutamate release inhibitor, has been previously shown to be safe in melanoma patients and produced biologic effects, but did not lead to radiographic responses, possibly due to poor pharmacokinetic properties. Therefore, we conducted a phase Ib trial to determine the safety and tolerability of the combination of the riluzole prodrug troriluzole (BHV-4157, trigriluzole) and the PD-1 antibody nivolumab in patients with advanced solid tumors. METHODS: Patients with advanced or refractory solid tumors and measurable disease per RECIST 1.1 were treated with increasing doses of troriluzole using a semi-Bayesian modified toxicity probability interval dose escalation procedure. Troriluzole monotherapy was orally self-administered for a 14-day lead-in period followed by continuation of troriluzole in combination with nivolumab 240 mg IV every 2 weeks. Endpoints included safety, pharmacokinetics (PK) and efficacy. RESULTS: We enrolled 14 patients with advanced solid tumors (melanoma = 3, NSCLC = 3, renal cell carcinoma = 2, bladder/urothelial = 2, ovarian cancer = 1, adenoid cystic carcinoma = 1, pleural mesothelial = 1, head and neck cancer = 1). Eleven patients had cancer progression on prior therapy with PD-1 or PD-L1 agent. Patients received troriluzole total daily doses from 140 to 560 mg (divided). The most common treatment-related adverse events (TRAE) occurring in ≥ 5 patients (> 35%) were transaminitis and increased lipase. DLT (dose-limiting toxicity) occurred in 3 patients: (1) grade 3 anorexia, (2) grade 3 fatigue and, (3) grade 3 atrial fibrillation. Six patients were treated at the MTD (maximum tolerated dose). No subjects discontinued treatment due to AEs. One response occurred (7%), which was a partial response in a subject who had PD-1 refractory disease. The 6-month PFS rate was 21%. PK data showed that the prodrug troriluzole was efficiently cleaved into riluzole by 2-h post-dosing in all dose cohorts tested. CONCLUSION: The combination of troriluzole and nivolumab was safe and well-tolerated. The MTD of troriluzole was determined to be 420 mg total daily dose. The observed antitumor activity, primarily disease stabilization, is of interest in patients with PD-1 resistant tumors. Trial Registration ClinicalTrials.gov Identifier NCT03229278.

Chronic Immune-Related Adverse Events Following Adjuvant Anti-PD-1 Therapy for High-risk Resected Melanoma.

Importance: Agents targeting programmed cell death 1 (PD-1)/PD ligand 1 (PD-L1) improve long-term survival across many advanced cancers and are now used as adjuvant therapy for resected stage III and IV melanomas. The incidence and spectrum of chronic immune-related adverse events (irAEs) have not been well defined. Objective: To determine the incidence, time course, spectrum, and associations of chronic irAEs arising from adjuvant anti-PD-1 therapy. Design, Setting, and Participants: This retrospective multicenter cohort study was conducted between 2015 and 2020 across 8 academic medical centers in the United States and Australia. Patients with stage III to IV melanomas treated with anti-PD-1 in the adjuvant setting were included. Main Outcomes and Measures: Incidence, types, and time course of chronic irAEs (defined as irAEs persisting at least 12 weeks after therapy cessation). Results: Among 387 patients, the median (range) age was 63 (17-88) years, and 235 (60.7%) were male. Of these patients, 267 (69.0%) had any acute irAE, defined as those arising during treatment with anti-PD-1, including 52 (19.5%) with grades 3 through 5 events; 1 patient each had fatal myocarditis and neurotoxicity. Chronic irAEs, defined as those that persisted beyond 12 weeks of anti-PD-1 discontinuation, developed in 167 (43.2%) patients, of which most (n = 161; 96.4%) were mild (grade 1 or 2) and most persisted until last available follow-up (n = 143; 85.6%). Endocrinopathies (73 of 88; 83.0%), arthritis (22 of 45; 48.9%), xerostomia (9 of 17; 52.9%), neurotoxicities (11 of 15; 73.3%), and ocular events (5 of 8; 62.5%) were particularly likely to become chronic. In contrast, irAEs affecting visceral organs (liver, colon, lungs, kidneys) had much lower rates of becoming chronic irAEs; for example, colitis became chronic in 6 of 44 (13.6%) cases, of which 4 of 6 (66.7%) resolved with prolonged follow-up. Age, gender, time of onset, and need for steroids were not associated with the likelihood of chronicity of irAEs. Conclusion and Relevance: In this multicenter cohort study, chronic irAEs associated with anti-PD-1 therapy appear to be more common than previously recognized and frequently persisted even with prolonged follow-up, although most were low grade. The risks of chronic irAEs should be integrated into treatment decision-making.

A multicenter characterization of hepatitis associated with immune checkpoint inhibitors.

Immune checkpoint inhibitors (ICI) predispose patients to immune-related adverse events (irAEs). Although hepatitis is a potentially lethal toxicity, the timing and outcomes have not been well described. In this retrospective study, patients from six international institutions were included if they were treated with ICIs and developed immune-related hepatitis. Patient and tumor characteristics, and hepatitis management and outcomes were evaluated. Of the 164 patients included, most were male (53.7%) with a median age of 63.0 years. Most patients had melanoma (83.5%) and stage IV disease (86.0%). Median follow-up was 585 days; median OS and PFS were not reached. The initial grade of hepatitis was most often grade 2 (30.5%) or 3 (45.7%) with a median time to onset of 61 days. Patients were most commonly asymptomatic (46.2%), but flu-like symptoms, including fatigue/anorexia (17.1%), nausea/emesis (14.0%), abdominal/back pain (11.6%), and arthralgias/myalgias (8.5%) occurred. Most patients received glucocorticoids (92.1%); the median time to improvement by one grade was 13.0 days, and the median time to complete resolution was 52.0 days. Second-line immunosuppression was required in 37 patients (22.6%), and steroid-dose re-escalation in 45 patients (27.4%). Five patients (3%) died of ICI-hepatitis or complications of hepatitis treatment. Ninety-one patients (58.6%) did not resume ICI; of 66 patients (40 grade 1/2, 26 grade 3/4) that were rechallenged, only 25.8% (n = 17) had recurrence. In this multi-institutional cohort, immune-related hepatitis was associated with excellent outcomes but frequently required therapy discontinuation, high-dose steroids, and second-line immunosuppression. Rechallenge was associated with a modest rate of hepatitis recurrence.

Identification and evaluation of antimicrobial resistance of enterococci isolated from raw ewes' and cows' milk collected in western Sicily: a preliminary investigation.

The present work was carried out to investigate the Antimicrobial Resistance (AMR) of enterococci isolated from raw ewes' and cows' milk. The samples were collected from eighteen semi-extensive dairy sheep and cow farms throughout western Sicily. Plate counts, carried out on Rapid Enterococcus Agar commonly used to detect food enterococci, revealed a maximal enterococcal concentration of approximately 4.58 Log Colony Forming Unit (CFU)/mL. Colonies were isolated and differentiated based on genetic analysis by Randomly Amplified Polymorphic DNA (RAPD)-PCR. Thirty-eight different strains were identified. Analysis by a species-specific multiplex PCR assay grouped the strains into three Enterococcus species such as Enterococcus durans, Enterococcus faecalis and Enterococcus faecium. The 38 strains were also investigated for their antimicrobial resistance by a phenotypic approach. All 38 Enterococcus displayed resistance to at least one or more of the antimicrobials tested confirmed that the dairy enterococci could be a vector for the dissemination of antimicrobial resistance. This work showed that enterococci with AMR traits are commonly present in semiextensive dairy sheep and cow farms of western Sicily pointed out the relevance of informing dairy makers and veterinary regarding the antimicrobial use in order to mitigate problems of public health and veterinary medicine.

Retrospective study on the hygienic quality of fresh ricotta cheeses produced in Sicily, Italy.

The present work was carried out to investigate the microbiological profile of Sicilian ewes' ricotta cheeses during fifteen years of investigations (2002-2016). The samples were collected between those conferred to the Istituto Zooprofilattico Sperimentale della Sicilia (IZSSi) Adelmo Mirri, Palermo (Italy), by the competent authority during official control, by food business operator in HACCP systems and in research projects. Enterobacteriaceae, Escherichia coli and coagulase-positive staphylococci (CPS) were found only in some samples. Bacillus cereus was detected in c.a. 16% of samples but the level of contaminations did not reach the threshold that leads to significant toxin production. Pathogenic bacteria such as Listeria monocytogenes, Salmonella spp. and Brucella spp. were never detected. Furthermore, a total of 47 of lactic acid bacteria (LAB) strains were identified at species level by sequencing the 16S rRNA gene, resulting in the identification of 10 species belonging to four genera Enterococcus, Lactobacillus, Lactococcus and Leuconostoc, commonly employed as starter and non starter cultures in different traditional cheese. Results of this study highlighted an improvement of the hygienic conditions of the Sicilian ewes' ricotta cheeses during the last ten years of investigation. This observation was confirmed from reduction of undesired microorganisms such as Enterobacteriaceae, E.coli and CPS, used to define the process hygiene criteria. However, in order to improve the final quality of this product are needed further strategy such as the dairy makers training, with the aim to apply a good hygienic practices during the production.

Formation and Characterization of Early Bacterial Biofilms on Different Wood Typologies Applied in Dairy Production.

The main hypothesis of this work was that Sicilian forestry resources are suitable for the production of equipment to be used in cheese making and indigenous milk lactic acid bacteria (LAB) are able to develop stable biofilms providing starter and nonstarter cultures necessary for curd fermentation and cheese ripening, respectively. Hence, the present work was carried out with deproteinized whey to evaluate LAB biofilm formation on different woods derived from tree species grown in Sicily. Microbiological and scanning electron microscopy analyses showed minimal differences in microbial levels and compositions for the neoformed biofilms. The specific investigation of Salmonella spp., Listeria monocytogenes, Escherichia coli, coagulase-positive staphylococci (CPS), and sulfite-reducing anaerobes did not generate any colony for all vats before and after bacterial adhesion. LAB populations dominated all vat surfaces. The highest levels (7.63 log CFU/cm2) were registered for thermophilic cocci. Different colonies were characterized physiologically, biochemically, and genetically (at strain and species levels). Six species within the genera Enterococcus, Lactobacillus, Lactococcus, and Streptococcus were identified. The species most frequently present were Lactobacillus fermentum and Lactococcus lactis LAB found on the surfaces of the wooden vats in this study showed interesting characteristics important for dairy manufacture. To thoroughly investigate the safety of the wooden vat, a test of artificial contamination on new Calabrian chestnut (control wood) vats was carried out. The results showed that LAB represent efficient barriers to the adhesion of the main dairy pathogens, probably due to their acidity and bacteriocin generation.IMPORTANCE This study highlights the importance of using wooden vats for traditional cheese production and provides evidence for the valorization of the Sicilian forest wood resources via the production of dairy equipment.

Myocardial infarction marker levels are influenced by prothrombin and tumor necrosis factor-α gene polymorphisms in young patients.

Polymorphisms of genes encoding key factors for the control and activation of inflammatory response and coagulation cascade regulation may play a role in genetic susceptibility to acute myocardial infarction (AMI). This study sought to analyze the effect of TNF -308G/A and pro-thrombin (FII) 20210G/A polymorphisms on the laboratory parameters of young patients affected by AMI. Results indicated that TNF -308A positive genotype frequencies were increased in these patients and that a genetically determined higher production of TNF-α is associated in young subjects to a more severe cardiac damage as depicted by higher levels of troponin, Creatine kinase-MB Isoenzyme (mCK-MB) and a significant increased plasma fibrinogen levels. Similar and probably additive effects on might have a genetically determined increased production of pro-thrombin even if no significant differences in genotype frequencies of pro-thrombin (FII) 20210G/A polymorphisms were observed in this study. All together these results, indicating the relationship among genetically determined TNFα and FII production and increased levels of tissue damage markers of AMI, suggest that a complex genetic background, might be involved in susceptibility to AMI in young men influencing the extension and severity of the disease.

Genetics of longevity. data from the studies on Sicilian centenarians.

The demographic and social changes of the past decades have determined improvements in public health and longevity. So, the number of centenarians is increasing as a worldwide phenomenon. Scientists have focused their attention on centenarians as optimal model to address the biological mechanisms of "successful and unsuccessful ageing". They are equipped to reach the extreme limits of human life span and, most importantly, to show relatively good health, being able to perform their routine daily life and to escape fatal age-related diseases, such as cardiovascular diseases and cancer. Thus, particular attention has been centered on their genetic background and immune system. In this review, we report our data gathered for over 10 years in Sicilian centenarians. Based on results obtained, we suggest longevity as the result of an optimal performance of immune system and an over-expression of anti-inflammatory sequence variants of immune/inflammatory genes. However, as well known, genetic, epigenetic, stochastic and environmental factors seem to have a crucial role in ageing and longevity. Epigenetics is associated with ageing, as demonstrated in many studies. In particular, ageing is associated with a global loss of methylation state. Thus, the aim of future studies will be to analyze the weight of epigenetic changes in ageing and longevity.

Single nucleotide polymorphisms (SNPs) of pro-inflammatory/anti-inflammatory and thrombotic/fibrinolytic genes in patients with acute ischemic stroke in relation to TOAST subtype.

BACKGROUND: The genetic basis of complex diseases like ischemic stroke probably consists of several predisposing risk factors, such as genes involved in inflammation and thrombotic pathways. On this basis the aim of our study was to evaluate the role of SNPs (single nucleotide polymorphisms) of some pro-inflammatory/anti-inflammatory and coagulation/fibrinolytic genes in patients with acute ischemic stroke. METHODS: The study population consisted of 144 consecutive Caucasian adult patients who were hospitalized in the Internal Medicine Department at the University of Palermo between November 2006 and January 2008, and who met inclusion criteria. The cases were patients admitted with a diagnosis of acute ischemic stroke, and age-matched (± 3 years) control subjects: patients admitted to our Internal Medicine Department for any cause other than acute cardiovascular and cerebrovascular events and for routine checkup examinations. Molecular analysis of alleles at the -308 nucleotide (-308G/A) of TNF-α gene, -1082/-819 haplotypes of IL-10 gene, IL-1RN exon 2 VNR polymorphism, alleles at the -174 nucleotide (-174G/C) of IL-6 gene, PAI-1675 5G/4G polymorphism, alleles at the -7351 nucleotide (-7351C/T) of tPA gene was undertaken in both patient groups. RESULTS: We analyzed 96 subjects with acute ischemic stroke and 48 control subjects. We observed a significantly higher frequency of IL-10 1082 AA genotype in stroke patients with a significant risk trend. We also reported a higher frequency in stroke subjects with a significant risk trend of the TPA 7351-CT genotype and of IL-1RN-VNTR 86 bp 2/2 genotype. Moreover, we observed a significant relationship with TOAST subtype only with regard to CC TPA genotype and 1/1 IL-1 VNTR 86 bp and lacunar strokes. CONCLUSIONS: Ischemic stroke is a common multifactor disease, which is affected by a number of genetic mutations and environmental factors. Our findings showing a relationship between pro-inflammatory/anti-inflammatory and thrombotic/fibrinolytic genes SNPs and ischemic stroke may contribute to delineate a possible stroke risk profile in subjects with cerebrovascular risk factors.

Cytokine serum profile in a group of Sicilian nonagenarians.

The aim of our study was to evaluate the possibility of using multiplex analysis of the cytokine profile as a marker for successful aging by comparing cytokine plasmatic levels of a group of Sicilian nonagenarians with those of young controls. We analyzed a panel of 17 cytokines, comprehensive of haematopoietic factors T helper 1 (Th1), Th2, inflammation regulatory cytokines, and chemokines. The assay was carried out using the Luminex system. Interleukin (IL)-6 levels (p = 0.01) were increased in nonagenarians, whereas no modifications of other proinflammatory cytokines and chemokines were observed. Interferon-gamma (IFN-γ) and IL-2 levels are unmodified, suggesting a substantial maintenance of relevant T cell functions. In addition, a significant increase of IL-12 serum levels in nonagenarians versus young controls that might be related to the increase of natural killer (NK) cell functions characterizing aging processes was observed. The analysis of Th2 cytokines show an increase of IL-13 and a reduction of IL-4 levels mirroring the maintenance of some effector's mechanisms of the immunoresponse in advanced ages. Our results suggest that the multiplex analysis of cytokine levels might be useful in defining a successful aging profile.

Analysis of polymorphisms Leiden Factor V G1691A and prothrombin G20210A as risk factors for acute myocardial infarction.

Thrombotic risk increases in elderly, therefore, the understanding of the genetic predisposition of hypercoagulability could make the difference in the prevention of venous and/or arterial thrombotic events. Laboratory evaluation of hyperfibrinogenemia, increased Factor VII levels, antiphospholipid antibodies presence and hyperhomocysteinemia are considered to have a consistent high predictivity for arterial thrombophilic diseases. Anyway, a large debate exists on the validity of testing Leiden Factor V (FV) G1691A and/or prothrombin (FII) G20210A polymorphisms in patients affected by arterial thrombotic diseases, despite of the several observations described. Here we report data strongly suggesting that at least the FII G20210A polymorphism might be considered an important risk factor for acute myocardial infarction in aged patients (55-80 years old). On the other hand, in spite of a not different genotypic and allelic distribution for the Leiden FV G1691A mutation, the presence of one or both the two polymorphisms is significantly higher among cases than in controls. In conclusion, our data suggest that FII G20210A and/or Leiden FV might be involved as risk factor for arterial disorders in about 5% of old subjects, justifying the opportunity of a genetic screening and an eventual preventive treatment, in particular in old subjects in which other and major risk factors, as hypertension and atherosclerosis, are detected.

Polymorphisms of ß-defensin genes in Valle del Belice dairy sheep.

The aim of this work was to study ß-defensin 1 (SBD1) and ß-defensin 2 (SBD2) genes in Valle del Belice dairy sheep in order to identify polymorphisms that can be utilized as markers of the analyzed genes, and search for the functional effects and roles of the identified polymorphisms (variation of the amino acid sequence of the protein and stability of mRNA molecule). The study was conducted on 300 randomly selected animals belonging to four flocks. A total of seven SNPs were identified, two in SBD1 and five in SBD2. The two SNPs identified in SBD2 coding region, at position 1659 and position 1667, were non-synonymous, leading to amino acid changes in the protein product. Nevertheless, the functional effects predicted by the two SNPs demonstrated that amino acid substitutions may not have effect on ß-defensin 2 protein function. Moreover, we demonstrated that SBD2 mutant sequence shows changes in mRNA secondary structure. These results suggest that identified SNPs could play a role in the modulation of the immune response.

Role of prothrombotic polymorphisms in successful or unsuccessful aging.

The study of the genetic profile of centenarians aims to identify the genes and allelic variants which may influence a greater life expectancy and that can be considered as predisposing factors associated to the aging diseases, such as Alzheimer. Centenarians, that represent a cohort of selected survivors, show an hypercoagulability state characterised by striking signs of high coagulation enzyme activity, as directly assessed by the tested higher plasma level of some important factors involved in the haemostasis balance. Anyway, these individuals seem to have a reduced susceptibility to dementia, as well as to cardiovascular events. In this study we analyze the frequencies of Leiden Factor V polymorphism (G1691A), and G20210A of prothrombin (FII) in three cohorts of subjects: patients with Alzheimer's disease (unsuccessful aging), nonagenarians (successful aging) and young healthy controls, to assess whether allelic variants associated to the modification of haemostatic system function, may play a role in the protection or susceptibility to Alzheimer disease, as well as to reach a successful aging. No significant differences were observed in the frequencies of the three groups studied. These results indicate that the presence or absence of the gene variants examined did not influence the achievement of advanced age and are not risk factors for Alzheimer's disease. The state of hypercoagulability and the possession of these risk alleles appear to be compatible with the achievement of longevity and are not implied as risk factors in Alzheimer disease development.