Multi-omic biomarker discovery and network analyses to elucidate the molecular mechanisms of lung cancer premalignancy

Lung cancer (LC) is the leading cause of cancer death in the US, claiming over 160,000 lives annually. Although CT screening has been shown to be efficacious in reducing mortality, the limited access to screening programs among high-risk individuals and the high number of false positives contribute to low survival rates and increased healthcare costs. As a result, there is an urgent need for preventative therapeutics and novel interception biomarkers that would enhance current methods for detection of early-stage LC. This thesis addresses this challenge by examining the hypothesis that transcriptomic changes preceding the onset of LC can be identified by studying bronchial premalignant lesions (PMLs) and the normal-appearing airway epithelial cells altered in their presence (i.e., the PML-associated airway field of injury). PMLs are the presumed precursors of lung squamous cell carcinoma (SCC) whose presence indicates an increased risk of developing SCC and other subtypes of LC. Here, I leverage high-throughput mRNA and miRNA sequencing data from bronchial brushings and lesion biopsies to develop biomarkers of PML presence and progression, and to understand regulatory mechanisms driving early carcinogenesis. First, I utilized mRNA sequencing data from normal-appearing airway brushings to build a biomarker predictive of PML presence. After verifying the power of the 200-gene biomarker to detect the presence of PMLs, I evaluated its capacity to predict PML progression and detect presence of LC (Aim 1). Next, I identified likely regulatory mechanisms associated with PML severity and progression, by evaluating miRNA expression and gene coexpression modules containing their targets in bronchial lesion biopsies (Aim2). Lastly, I investigated the preservation of the PML-associated miRNAs and gene modules in the airway field of injury, highlighting an emergent link between the airway field and the PMLs (Aim 3). Overall, this thesis suggests a multi-faceted utility of PML-associated genomic signatures as markers for stratification of high-risk smokers in chemoprevention trials, markers for early detection of lung cancer, and novel chemopreventive targets, and yields valuable insights into early lung carcinogenesis by characterizing mRNA and miRNA expression alterations that contribute to premalignant disease progression towards LC.2020-01-2

Global epidemiology of Zika and Chikungunya virus human infections

Zika virus was discovered in 1947. The first reported case of Zika fever was in a sentinel rhesus monkey in Uganda in 1947, while the first human cases were reported in Nigeria in 1954. Since the first evidence of human infection, Zika was active in several countries in Africa and Asia, as sporadic cases and serological evidence of Zika human infections have been demonstrated in several reports. The outbreak of Zika in Yap Island in 2007 is considered the first emergency of this infection. Since then Zika has spread worldwide with a large ongoing epidemic in South and Central America. A huge concern nowadays is about the relationship between Zika infection and microcephaly and about the sexual transmission of the virus. The first identified outbreak of Chikungunya human infection, with an incidence estimated at 23%, was reported from July 1952 to March 1953 in the Southern Province of the current Tanzania. Since then Chikungunya circulated mainly in continental Africa with limited outbreaks. The virus started to spread east bound involving most of the areas surroundings the Indian Ocean. In 2004/2005 a large outbreak developed in La Reunion a French territory in the Indian Ocean: from this point Chikungunya spread to India and from there, due a viraemic traveller returning from Kerala, to Italy where in the summer of 2007 the first outbreak with local viral transmission in a temperate climate zone occurred. In the following years Chikungunya moved to the Caribbean and South America. Recently also the USA experienced the spread of this virus and a limited outbreak based again on local spreading occurred in the French Department of Var, in August 2017

Pré-sal: geologia e exploração

Pre-salt is the world’s greatest oil-related finding of the past 50 years. Pre-salt oillies in reserves located below large and thick salt layers found offshore Brazil,along the coast from the states of Espírito Santo to Santa Catarina, in deepand ultra-deep waters, and situated below 3-to-4-km-thick rock layers, underthe seabed. The investigations carried out so far in some pre-salt areas haveshown that giant and super-giant fields are likely to exist. Such fields couldplace Brazil among the leading oil producers as they are thought to hold upto 16 billion barrels of recoverable oil equivalent – boe (sum of oil and naturalgas), and are likely to yield from 70 to 100 billion barrels of oil equivalent. Thisarticle deals with the geological conditions and the past scenario in whichpre-salt reserves were formed, the characteristics of the oil system, estimatedreserves, exploration and production.O pré-sal é a maior descoberta petrolífera mundial dos últimos cinquentaanos. O petróleo do pré-sal está alojado em reservatórios situados abaixode extensa e espessa camada de sal que ocorre na região costa-afora doEspírito Santo até Santa Catarina, em águas profundas e ultraprofundas,localizados sob 3 a 4 km de rochas abaixo do fundo marinho. As investigaçõesjá realizadas em algumas áreas do pré-sal revelaram prováveis camposgigantes e supergigantes com volumes recuperáveis de até 16 bilhões debarris de óleo equivalente – boe (somatório de petróleo e gás natural), epotencial de ocorrência de 70 a 100 bilhões de barris de óleo equivalente,o que colocaria o Brasil entre os principais países produtores. Este artigoaborda as condições geológicas e o cenário do passado no qual foramformadas as reservas do pré-sal, as características do sistema petrolífero,reservas projetadas, exploração e produção

Centrotemporal spikes during NREM sleep: The promoting action of thalamus revealed by simultaneous EEG and fMRI coregistration

Benign childhood epilepsy with centrotemporal spikes (BECTS) has been investigated through EEG\u2013fMRI with the aim of localizing the generators of the epileptic activity, revealing, in most cases, the activation of the sensory\u2013motor cortex ipsilateral to the centrotemporal spikes (CTS). In this case report, we investigated the brain circuits hemodynamically involved by CTS recorded during wakefulness and sleep in one boy with CTS and a language disorder but without epilepsy. For this purpose, the patient underwent EEG\u2013fMRI coregistration. During the \u201cawake session\u201d, fMRI analysis of right-sided CTS showed increments of BOLD signal in the bilateral sensory\u2013motor cortex. During the \u201csleep session\u201d, BOLD increments related to right-sided CTS were observed in a widespread bilateral cortical\u2013subcortical network involving the thalamus, basal ganglia, sensory\u2013motor cortex, perisylvian cortex, and cerebellum. In this patient, who fulfilled neither the diagnostic criteria for BECTS nor that for electrical status epilepticus in sleep (ESES), the transition from wakefulness to sleep was related to the involvement of a widespread cortical\u2013subcortical network related to CTS. In particular, the involvement of a thalamic\u2013perisylvian neural network similar to the one previously observed in patients with ESES suggests a common sleep-related network dysfunction even in cases with milder phenotypes without seizures. This finding, if confirmed in a larger cohort of patients, could have relevant therapeutic implication

From Monoamine Oxidase Inhibition to Antiproliferative Activity: New Biological Perspectives for Polyamine Analogs

: Monoamine oxidases (MAOs) are well-known pharmacological targets in neurological and neurodegenerative diseases. However, recent studies have revealed a new role for MAOs in certain types of cancer such as glioblastoma and prostate cancer, in which they have been found overexpressed. This finding is opening new frontiers for MAO inhibitors as potential antiproliferative agents. In light of our previous studies demonstrating how a polyamine scaffold can act as MAO inhibitor, our aim was to search for novel analogs with greater inhibitory potency for human MAOs and possibly with antiproliferative activity. A small in-house library of polyamine analogs (2-7) was selected to investigate the effect of constrained linkers between the inner amine functions of a polyamine backbone on the inhibitory potency. Compounds 4 and 5, characterized by a dianiline (4) or dianilide (5) moiety, emerged as the most potent, reversible, and mainly competitive MAO inhibitors (Ki < 1 μM). Additionally, they exhibited a high antiproliferative activity in the LN-229 human glioblastoma cell line (GI50 < 1 μM). The scaffold of compound 5 could represent a potential starting point for future development of anticancer agents endowed with MAO inhibitory activity

Italian Children Exposure to Bisphenol A: Biomonitoring Data from the LIFE PERSUADED Project

A human biomonitoring (HBM) study on bisphenol A (BPA) in Italian children and adolescents was performed within the LIFE PERSUADED project, considering the residing areas, sex and age. The median urinary BPA level was 7.02 mu g/L, with children living in the South of Italy or in urban areas having higher levels than those residing in the North or in rural areas. Children aged 4-6 years had higher BPA levels than those aged 7-10 and 11-14 years, but no differences were detected between sexes. The exposure in Italian children was higher compared to children from other countries, but lower than the HBM guidance value (135 mu g/L). The estimated daily intake was 0.17 mu g/kg body weight (bw) per day, about 24-fold below the temporary Tolerable Daily Intake of 4 mu g/kg bw per day established by the European Food Safety Authority. However, this threshold was exceeded in 1.44% of the enrolled children, raising concern about the overall exposure of Italian young population

PRELIMINARY U-Pb LA-ICPMS ZIRCON ANALYSES FROM THE GOIAS COMPLEXES: SHRIMP COMPARISON AND INTRUSION AGE

Cana Brava, Niquelàndia and Barro Alto are three mafic-ultramafic layered intrusions (from N to S) which form a - 350 km, NNE-trend belt within the Brasilia Belt (Goiés state, Brazil). Presently, their intrusion ages and geologica! evolution are stili debated. The Niquelàndia and Barro Alto complexes are forrned by two main sequences: the upper sequence and the lower one. Some authors suggest that the two sequences represent two separate intrusions: the upper sequence would be a Mesoproterozoic intrusion at - 1.3 Ga, whereas the lower sequence a Neoproterozic one at - 790 Ma. According to this interpretation, the two sequences were re-crystallized by Neoproterozoic metamorphism and exhumed and juxtaposed during the Brazilian event of formation of the Gondwana continent. Another model suggests that the two sequences are part of the same intrusion, which occurred during the Neoproterozoic and was exhumed during the Brazilian event. New U-Pb SHRIMP-II zircon analyses were perforrned at the Universidade de Sào Paulo from samples from Cana Brava and Barro Alto, the two least-known complexes in order to clarify the sequence of events that led to their forrnation. Analyses were then replicated at the CIGS of the Università di Modena e Reggio Emilia using a X Series" quadrupole ICP-MS coupled with a New Wave UP-213 Nd:YAG laser ablation system. Zircons were sampled through a 40 micron spot (static mode), using a He flux of 0.6 l/min, with an energy density of - 6 J/cm2. Daily instrument calibration was perforrned with the NIST 610 standard, monitoring also the oxide production rate {232Th160/232Th << 0.01 %). Laser-induced elemental fractionation was corrected by repeated analyses of the standard zircon TEMORA2 (Black et al., 2004). A secondary reference materia! (zircon CZ3) was used to check the precision and accuracy of the corrections. Our LA-ICP-MS data are preliminary, but very promising being the accuracy of the measured ratio within the SHRIMP variability. We are currently working to improve the precision of our methodology, which however is now comparable with literature LA-ICP-MS data (propagated 2SE - 2-6%; Horstwood et al., 2008). Overall, the isotopic data of Cana Brava and Barro Alto complexes previde for a coeval Neoproterozoic intrusion age at - 790 Ma. These ages are consistent with those reported in literature for Niquelàndia. Mesoproterozoic ages, consistent with the forrnation age of the metavolcanic-metasedimentary sequence in magmatic contaci with the complexes, were found in inherited zircon cores. Our data clearly show that the Goiàs complexes are formed by single bodies intruded during the Neoproterozoic at -790 Ma and that the hypothesis of two separate intrusions juxtaposed by tectonic must be discarded