Rare genetic variant burden in DPYD predicts severe fluoropyrimidine-related toxicity risk

Preemptive targeted pharmacogenetic testing of candidate variations in DPYD is currently being used to limit toxicity associated with fluoropyrimidines. The use of innovative next generation sequencing (NGS) approaches could unveil additional rare (minor allele frequency <1%) genetic risk variants. However, their predictive value and management in clinical practice are still controversial, at least partly due to the challenges associated with functional analyses of rare variants. The aim of this study was to define the predictive power of rare DPYD variants burden on the risk of severe fluoropyrimidine-related toxicity. The DPYD coding sequence and untranslated regions were analyzed by NGS in 120 patients developing grade 3–5 (NCI-CTC vs3.0) fluoropyrimidine-related toxicity and 104 matched controls (no-toxicity). The functional impact of rare variants was assessed using two different in silico predictive tools (i.e., Predict2SNP and ADME Prediction Framework) and structural modeling. Plasma concentrations of uracil (U) and dihydrouracil (UH2) were quantified in carriers of the novel variants. Here, we demonstrate that the burden of rare variants was significantly higher in patients with toxicity compared to controls (p = 0.007, Mann-Whitney test). Carriers of at least one rare missense DPYD variant had a 16-fold increased risk in the first cycle and an 11-fold increased risk during the entire course of chemotherapy of developing a severe adverse event compared to controls (p = 0.013 and p = 0.0250, respectively by multinomial regression model). Quantification of plasmatic U/UH2 metabolites and in silico visualization of the encoded protein were consistent with the predicted functional effect for the novel variations. Analysis and consideration of rare variants by DPYD-sequencing could improve prevention of severe toxicity of fluoropyrimidines and improve patients’ quality of life

Applications of Genetic Programming to Finance and Economics: Past, Present, Future

While the origins of Genetic Programming (GP) stretch back over fifty years, the field of GP was invigorated by John Koza’s popularisation of the methodology in the 1990s. A particular feature of the GP literature since then has been a strong interest in the application of GP to real-world problem domains. One application domain which has attracted significant attention is that of finance and economics, with several hundred papers from this subfield being listed in the Genetic Programming Bibliography. In this article we outline why finance and economics has been a popular application area for GP and briefly indicate the wide span of this work. However, despite this research effort there is relatively scant evidence of the usage of GP by the mainstream finance community in academia or industry. We speculate why this may be the case, describe what is needed to make this research more relevant from a finance perspective, and suggest some future directions for the application of GP in finance and economics

Long-term health effects of the occupational exposure to DDT: a preliminary report

We conducted a proportional mortality study of 1043 deaths among men who took part in an antimalarial campaign in Sardinia, Italy from 1946 to 1950. DDT comprised 94% of the insecticide used during the campaign, and was sprayed over the soil of the entire region at an average concentration of 10 mg/m2, as well as in all dwellings and animal shelters. Expected deaths were derived from the proportional mortality rates of the general Italian male population, specific by cause, 5-year age groups, and 5-year calendar periods in the period from 1956 to 1992. The proportional mortality ratio (PMR) for cardiovascular diseases was significantly decreased, while nonmalignant respiratory diseases showed a 22% increase in risk of borderline statistical significance. Significant increases in risk among workers exposed to DDT in application or inspection jobs were observed for liver and biliary tract cancer (PMR = 228; 95% C.I. = 143-345) and multiple myeloma (PMR = 341; 95% C.I. = 110-795). The PMR for myeloid leukemia was also increased (PMR = 189; 95% C.I. = 38-552), although it was not statistically significant. PMRs for liver and biliary tract cancer and myeloid leukemia were also elevated among workers who did not have direct occupational contact with DDT (liver and biliary cancer: PMR = 210; 95% C.I. = 117-346; myeloid leukemia: PMR = 170; 95% C.I. = 19-614). No trends occurred according to length of employment in exposed jobs. These preliminary results are somewhat in agreement with experimental studies in rodents and previous epidemiologic findings. Expansion of the cohort to include all applications, and collection of information to improve exposure assessment is needed to clarify these finding

Clonal Evolution of TP53 c.375+1G>A Mutation in Pre- and Post- Neo-Adjuvant Chemotherapy (NACT) Tumor Samples in High-Grade Serous Ovarian Cancer (HGSOC)

Carboplatin/paclitaxel is the reference regimen in the treatment of advanced high-grade serous ovarian cancer (HGSOC) in neo-adjuvant chemotherapy (NACT) before interval debulking surgery (IDS). To identify new genetic markers of platinum-resistance, next-generation sequencing (NGS) analysis of 26 cancer-genes was performed on paired matched pre- and post-NACT tumor and blood samples in a patient with stage IV HGSOC treated with NACT-IDS, showing platinum-refractory/resistance and poor prognosis. Only the TP53 c.375+1G>A somatic mutation was identified in both tumor samples. This variant, associated with aberrant splicing, was in trans configuration with the 72Arg allele of the known germline polymorphism TP53 c.215C>G (p. Pro72Arg). In the post-NACT tumor sample we observed the complete expansion of the TP53 c.375+1G>A driver mutant clone with somatic loss of the treatment-sensitive 72Arg allele. NGS results were confirmed with Sanger method and immunostaining for p53, BRCA1, p16, WT1, and Ki-67 markers were evaluated. This study showed that (i) the splice mutation in TP53 was present as an early driver mutation at diagnosis; (ii) the mutational profile was shared in pre- and post-NACT tumor samples; (iii) the complete expansion of a single dominant mutant clone through loss of heterozygosity (LOH) had occurred, suggesting a possible mechanism of platinum-resistance in HGSOC under the pressure of NACT

FOCOLAI DI BLUE TONGUE: OSSERVAZIONI SULLE TIPOLOGIE DI SUOLI, NUMEROSIT\uc0 DEGLI INSETTI VETTORI E DANNI CORRELATI

In Sudafrica esistono zone di quarantena per i cavalli al fine di poterli movimentare verso paesi esteri senza esportare la African Horse Sickness (Peste Equina), patologia che prevede lo stesso vettore della febbre catarrale degli ovini. Tali zone sono caratterizzate da abbondanza di terreni prevalentemente salmastri. Questo dato, nonch\ue8 le osservazioni raccolte in Sardegna durante le diverse ondate epidemiche susseguitesi nel periodo 2000- 2007, che hanno fatto rilevare come alcuni allevamenti di specifici territori (penisola del Sinis, Giara di Gesturi, ecc.) mostravano una morbilit\ue0 - mortalit\ue0 estremamente ridotta rispetto agli allevamenti circostanti - se non addirittura rappresentano una sorta di enclave circoscritta -, hanno suggerito di effettuare specifici sopralluoghi finalizzati alla valutazione geologica dei suoli. \uc8 stata anche valutata la compatibilit\ue0 di questi territori con l\u92habitat ideale per l\u92insetto vettore e contemporaneamente con gli altri fattori di rischio noti, correlati allo sviluppo di Culicoides imicola e, di conseguenza, all\u92ingresso del virus e al possibile sviluppo di focolai di Blue Tongue. Dalla verifica dei suoli e dalla sovrapposizione delle mappe della mortalit\ue0 osservata nel corso della prima epidemia di Blue Tongue (2000-2001), si \ue8 rilevato che il danno osservato nei focolai non era distribuito omogeneamente nel territorio. Al fine di validare il presupposto scientifico citato in premessa (terreni salmastri), si \ue8 verificato puntualmente quanto accaduto durante la prima epidemia in alcuni comuni della Sardegna, per i quali si era in possesso della georeferenziazione degli allevamenti sede di focolaio, verificando il tipo di suolo nel quale tali allevamenti insistevano. Dall\u92analisi dei dati \ue8 emerso che esistono forti correlazioni tra la tipologia di pH del suolo, unito alla granulometria e al drenaggio dello stesso. I tipi di suolo sono individuabili in Acidi o sub acidi (AC) e Neutri, Subalcalini o Alcalini (AK). Si sono individuate in funzione del tipo di suolo due categorie di allevamenti sede di focolaio ed \ue8 stata verificata la differenza esistente tra le somme dei danni totali osservate negli allevamenti appartenenti ai due gruppi (AC vs AK), che si \ue8 mostrata statisticamente significativa. Questo dato di estremo interesse pare confermare l\u92assunto teorico basato sulla ipotesi che certi terreni sono meno favorenti lo sviluppo di C. imicola, con una forte correlazione con il pH del terreno stesso. L\u92applicazione pratica di tale osservazione \ue8 quella che si sta cercando di attuare in Sardegna ovvero quella di \u93alcalinizzare\u94 i siti considerati di massimo rischio per la riproduzione dell\u92insetto vettore situati in prossimit\ue0 di allevamenti ovicaprini, attraverso l\u92utilizzo di alcune sostanze (es. latte di calce), in quantit\ue0 e modalit\ue0 valutate in funzione della tipologia di suolo e della relativa permeabilit\ue0 dello stesso. Viene descritta l\u92esperienza in un sito pilota e i risultati preliminari ottenuti

Clinical presentations and surgical management of liver hydatidosis: our 20 year experience

Background. Hydatidosis/echinococcosis of the liver is a very old problem in Greece and still exists, although it is declining. We have reviewed our 20 years’ experience, and here we report the various clinical presentations of the disease and evaluate the clinical outcome of the surgical procedures performed. Patients and methods. We conducted a retrospective analysis of the past 20 years’ medical records; 35 patients (males 34%, females 66%, mean age 58 years) were treated surgically. Results. The presenting symptoms or findings leading to the diagnosis of liver echinococcosis were jaundice (six cases, 17%), abdominal pain (five cases, 14%), gastrointestinal discomfort of the upper abdomen (e.g. nausea, vomiting, distention, anorexia) (two cases, 6%), acute pancreatitis (one case, 3%) and portal hypertension (one case, 3%). The rest of the cases were diagnosed incidentally (20 cases, 57%). External drainage and cystectomy with omentoplasty was performed in 21 cases (60%) and pericystectomy in 14 cases (40%). The mean hospital stay was 16.8 days. Morbidity and mortality were 18% and 3%, respectively, with no statistically significant differences between the two surgical approaches. The recurrence rate averaged 3%. Discussion. A high index of suspicion is recommended when variable clinical manifestations of the upper abdomen are present. Meeting all criteria for surgical treatment of hydatid disease, external drainage and cystectomy should be the standard surgical procedure. Pericystectomy could be used for peripherally located liver cysts that are only partially surrounded by parenchyma. Resection procedures are considered too radical for a benign disease. Appropriate randomized controlled studies are needed to establish the definite surgical management of liver hydatidosis, including modern techniques such as laparoscopy and transcutaneous puncture under US guidance (PAIR technique)