The germline mutational landscape of BRCA1 and BRCA2 in Brazil

The detection of germline mutations in BRCA1 and BRCA2 is essential to the formulation of clinical management strategies, and in Brazil, there is limited access to these services, mainly due to the costs/availability of genetic testing. Aiming at the identification of recurrent mutations that could be included in a low-cost mutation panel, used as a first screening approach, we compiled the testing reports of 649 probands with pathogenic/likely pathogenic variants referred to 28 public and private health care centers distributed across 11 Brazilian States. Overall, 126 and 103 distinct mutations were identified in BRCA1 and BRCA2, respectively. Twenty-six novel variants were reported from both genes, and BRCA2 showed higher mutational heterogeneity. Some recurrent mutations were reported exclusively in certain geographic regions, suggesting a founder effect. Our findings confirm that there is significant molecular heterogeneity in these genes among Brazilian carriers, while also suggesting that this heterogeneity precludes the use of screening protocols that include recurrent mutation testing only. This is the first study to show that profiles of recurrent mutations may be unique to different Brazilian regions. These data should be explored in larger regional cohorts to determine if screening with a panel of recurrent mutations would be effective.This work was supported in part by grants from Barretos Cancer Hospital (FINEP - CT-INFRA, 02/2010), Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP, 2013/24633-2 and 2103/23277-8), Fundação de Apoio à Pesquisa do Rio Grande do Norte (FAPERN), Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ), Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul (FAPERGS), Ministério da Saúde, the Breast Cancer Research Foundation (Avon grant #02-2013-044) and National Institute of Health/National Cancer Institute (grant #RC4 CA153828-01) for the Clinical Cancer Genomics Community Research Network. Support in part was provided by grants from Fundo de Incentivo a Pesquisa e Eventos (FIPE) from Hospital de Clínicas de Porto Alegre, by Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES, BioComputacional 3381/2013, Rede de Pesquisa em Genômica Populacional Humana), Secretaria da Saúde do Estado da Bahia (SESAB), Laboratório de Imunologia e Biologia Molecular (UFBA), INCT pra Controle do Câncer and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq). RMR and PAP are recipients of CNPq Productivity Grants, and Bárbara Alemar received a grant from the same agencyinfo:eu-repo/semantics/publishedVersio

LIME -- a gas TPC prototype for directional Dark Matter search for the CYGNO experiment

The CYGNO experiment aims at the development of a large gaseous TPC with GEM-based amplification and an optical readout by means of PMTs and scientific CMOS cameras for 3D tracking down to O(keV) energies, for the directional detection of rare events such as low mass Dark Matter and solar neutrino interactions. The largest prototype built so far towards the realisation of the CYGNO experiment demonstrator is the 50 L active volume LIME, with 4 PMTs and a single sCMOS imaging a 33$\times$33 cm\textsuperscript{2} area for 50 cm drift, that has been installed in underground Laboratori Nazionali del Gran Sasso in February 2022. We will illustrate LIME performances as evaluated overground in Laboratori Nazionali di Frascati by means of radioactive X-ray sources, and in particular the detector stability, energy response and energy resolution. We will discuss the MC simulation developed to reproduce the detector response and show the comparison with actual data. We will furthermore examine the background simulation worked out for LIME underground data taking and illustrate the foreseen expected measurement and results in terms of natural and materials intrinsic radioactivity characterisation and measurement of the LNGS underground natural neutron flux. The results that will be obtained by underground LIME installation will be paramount in the optimisation of the CYGNO demonstrator, since this is foreseen to be composed by multiple modules with the same LIME dimensions and characteristics

Technical Design Report - TDR CYGNO-04/INITIUM

The aim of this Technical Design Report is to illustrate the technological choices foreseen to be implemented in the construction of the CYGNO-04 demonstrator, motivate them against the experiment physics goals of CYGNO-30 and demonstrate the financial sustainability of the project. CYGNO-04 represents PHASE 1 of the long term CYGNO roadmap, towards the development of large high precision tracking gaseous Time Projection Chamber (TPC) for directional Dark Matter searches and solar neutrino spectroscopy. The CYGNO project1 peculiarities reside in the optical readout of the light produced during the amplification of the primary ionization electrons in a stack of triple Gas Electron Multipliers (GEMs), thanks to the nice scintillation properties of the chosen He:CF4 gas mixture. To this aim, CYGNO is exploiting the fast progress in commercial scientific Active Pixel Sensors (APS) development for highly performing sCMOS cameras, whose high granularity and sensitivity allow to significantly boost tracking, improve particle identification and lower the energy threshold. The X-Y track project obtained from the reconstruction of the sCMOS images is combined with a PMT measurement to obtain a full 3D track reconstruction. In addition, several synergic R&Ds based on the CYGNO experimental approach are under development in the CYGNO collaboration (see Sec 2) to further enhance the light yield by means of electro luminescence after the amplification stage, to improve the tracking performances by exploiting negative ion drift operation within the INITIUM ERC Consolidator Grant, and to boost the sensitivity to O(GeV) Dark Matter masses by employing hydrogen rich target towards the development of PHASE 2 (see Sec. 1.2). While still under optimization and subject to possible significant improvements, the CYGNO experimental approach performances and capabilities demonstrated so far with prototypes allow to foresee the development of an O(30) m3 experiment by 2026 for a cost of O(10) MEUROs. A CYGNO-30 experiment would be able to give a significant contribution to the search and study of Dark Matter with masses below 10 GeV/c2 for both SI and SD coupling. In case of a Dark Matter observation claim by other experiments, the information provided by a directional detector such as CYGNO would be fundamental to positively confirm the galactic origin of the allegedly detected Dark Matter signal. CYGNO-30 could furthermore provide the first directional measurement of solar neutrinos from the pp chain, possibly extending to lower energies the Borexino measurement2. In order to reach this goal, the CYGNO project is proceeding through a staged approach. The PHASE 0 50 L detector (LIME, recently installed underground LNGS) will validate the full performances of the optical readout via APS commercial cameras and PMTs and the Montecarlo simulation of the expected backgrounds. The full CYGNO-04 demonstrator will be realized with all the technological and material choices foreseen for CYGNO-30, to demonstrate the scalability of the experimental approach and the potentialities of the large PHASE 2 detector to reach the expected physics goals. The first PHASE 1 design anticipated a 1 m3 active volume detector with two back-to-back TPCs with a central cathode and 500 mm drift length. Each 1 m2 readout area would have been composed by 9 + 9 readout modules having the LIME PHASE 0 dimensions and layout. Time (end of INITIUM project by March 2025) and current space availability at underground LNGS (only Hall F) forced the rescaling of the PHASE 1 active volume and design to a 0.4 m3, hence CYGNO-04. CYGNO-04 will keep the back-to-back double TPC layout with 500 mm drift length each, but with an 800 x 500 mm2 readout area covered by a 2 + 2 modules based on LIME design. The reduction of the detector volume has no impact on the technological objectives of PHASE 1, since the modular design with central cathode, detector materials and shieldings and auxiliary systems are independent of the total volume. The physics reach (which is a byproduct of PHASE 1 and NOT an explicit goal) will be only very partially reduced (less than a factor 2 overall) since a smaller detector volume implies also a reduced background from internal materials radioactivity. In addition, the cost reduction of CYGNO-04 of about 1⁄3 with respect to CYGNO-1 illustrated in the CDR effectively makes the overall project more financially sustainable (see CBS in the last section). In summary this document will explain: the physical motivation of the CYGNO project and the technical motivations of the downscale of the PHASE 1 to CYGNO-04, 400 liters of active volume, with respect to the demonstrator presented in the CDR; the results of R&D and the Montecarlo expectations for PHASE 0; the technical choices, procedures and the executive drawings of CYGNO-04 in the Hall F of the LNGS; safety evaluations and the interference/request to the LNGS services; Project management, WBS/WBC, WP, GANTT, ec

The CYGNO Experiment

The search for a novel technology able to detect and reconstruct nuclear and electron recoil events with the energy of a few keV has become more and more important now that large regions of high-mass dark matter (DM) candidates have been excluded. Moreover, a detector sensitive to incoming particle direction will be crucial in the case of DM discovery to open the possibility of studying its properties. Gaseous time projection chambers (TPC) with optical readout are very promising detectors combining the detailed event information provided by the TPC technique with the high sensitivity and granularity of latest-generation scientific light sensors. The CYGNO experiment (a CYGNus module with Optical readout) aims to exploit the optical readout approach of multiple-GEM structures in large volume TPCs for the study of rare events as interactions of low-mass DM or solar neutrinos. The combined use of high-granularity sCMOS cameras and fast light sensors allows the reconstruction of the 3D direction of the tracks, offering good energy resolution and very high sensitivity in the few keV energy range, together with a very good particle identification useful for distinguishing nuclear recoils from electronic recoils. This experiment is part of the CYGNUS proto-collaboration, which aims at constructing a network of underground observatories for directional DM search. A one cubic meter demonstrator is expected to be built in 2022/23 aiming at a larger scale apparatus (30 m$^3$--100 m$^3$) at a later stage

Determination of argon and xenon absolute electroluminescence yields in Gas Proportional Scintillation Counters

Tese de doutoramento em Física, na especialidade de Física Tecnológica, apresentada à Faculdade de Ciências e Tecnologia da Universidade de CoimbraElectroluminescence (EL), as the signal amplification method of primary ionisation signal, developed in the 70’s in Gas Proportional Scintillation Counters (GPSC) with noble gas filling, has played an important role in applications to many fields such as X-ray astronomy, plasma physics, medical instrumentation and high-energy physics, up to rising of solid state detectors in the mid 90’s. However, in the last decade EL amplification recovered importance in experiments for rare event detection, such as direct dark matter search and double beta decay. Low count rates and high background imply the need for high signal amplification with statistical fluctuations as low as possible. EL studies are needed for correct detector simulation. While for xenon the literature reported several studies on absolute measurements of EL yield, both experimental and from simulation, yet with disperse results, for argon only one experimental result was reported and its results were ten times lower than the Monte Carlo values from studies performed in our group. The lack of coherent results raised the necessity to study the absolute EL yield in the noble gases xenon and argon thoroughly. In the present work, absolute measurements have been performed for the EL yields of xenon and argon in a uniform electric field GPSC. The obtained results agree with those from Monte Carlo simulation, at room temperature, and with the most recent experimental results measured at cryogenic temperatures reported in the literature, for xenon. We have demonstrated, for the first time that the EL yield, at room temperature, is as high as predicted by the Monte Carlo simulation. Furthermore, studies were performed on the absolute EL yield produced in the strong, variable electric fields of the electron avalanches produced in GEMs and THGEMs. The obtained results have shown that the EL yield values can be more than two orders of magnitude higher than those reached in the commonly used uniform field gaps. This fact can be important if photosensors others than PMTs, with less sensitivity and with area occupancy lower than 100%, are used because of less mass burden and lower radioactivity rates, such as APDs and G-APDs. For the above mentioned studies a simple, straightforward method was used for absolute EL yield measurements, using LAAPDs simultaneously irradiated with EL pulses and X-rays. These X-rays are used as a reference for the absolute determination of the charge carriers produced in the LAAPD by the EL pulses. This technique has been successfully applied, during the last decade, for absolute measurements of primary scintillation yield from organic and inorganic crystals, being suitable for the measurements on EL carried out under the scope of this thesis.A electroluminescência (EL) em Contadores Gasosos de Cintilação Proporcional (CGCP) com enchimento a gases nobres foi desenvolvida na década de 70 como método de amplificação da ionização primária e desempenhou um papel relevante em aplicações a áreas tão diversas como a astronomia, a física dos plasmas, a instrumentação médica e a física das altas energias. Este protagonismo perdurou até meados da década de 90, época em que surgiram os detectores de estado sólido com qualidade e áreas de detecção melhoradas. A EL reconquistou interesse durante a última década em experiências dedicadas à detecção de eventos raros, como é o caso da procura da matéria negra e do decaimento beta duplo. As baixas taxas de contagem aliadas ao elevado nível de radiação de fundo, característicos destas experiências, definem a necessidade de uma grande amplificação do sinal, associada a baixas flutuações estatísticas, características intrínsecas à amplificação por EL. A correcta simulação de detectores obriga a estudos de EL mais profundos. Na literatura são referidos diversos estudos, tanto experimentais como de simulação, de medições absolutas para o rendimento de EL em xénon, sendo que os resultados apresentavam valores díspares. Para o árgon foi encontrado na literatura um único estudo experimental, cujos valores eram cerca de dez vezes inferiores aos de simulações de Monte Carlo efectuados no nosso grupo. A falta de resultados coerentes suscitou a necessidade de estudar o rendimento absoluto de EL nos gases nobres xénon e árgon. No presente trabalho foram efectuadas medições absolutas para o rendimento de EL em xénon e árgon num CGCP de campo eléctrico uniforme. Os resultados obtidos estão em concordância, tanto com os de simulação de Monte Carlo para a temperatura ambiente como, para o xénon, com os resultados experimentais efectuados a temperaturas criogénicas mencionados na literatura. Mostrou-se, pela primeira vez, que o rendimento de EL à temperatura ambiente é tão elevado como o previsto por simulação de Monte Carlo. Foram igualmente efectuados estudos para o rendimento da EL produzida nos campos eléctricos elevados e variáveis das avalanches de electrões produzidas em GEMs e THGEMs. Os resultados obtidos mostram que estes valores podem ser mais do que duas ordens de grandeza superiores aos obtidos na configuração de campo uniforme. Este facto pode ser importante quando forem utilizados fotosensores que não os PMTs, tais como os APDs ou G-APDs, com menor sensibilidade e/ou uma cobertura em termos de área inferior a 100%, mas que têm níveis de radioactividade menores. Os estudos acima mencionados foram efectuados utilizando um método simples e directo para a medição do rendimento absoluto de EL, com recurso a LAAPDs irradiados em simultâneo com impulsos de EL e raios X. Estes últimos são utilizados como referência para a determinação absoluta dos portadores de carga produzidos no LAAPD pelos impulsos de EL

Contadores gasosos de cintilação proporcional com enchimento a árgon para espectrometria de raios X

Tese de mestrado em Instrumentação e Microelectrónic

Risk-benefit assessment of Bacillus Calmette-Guérin vaccination, anti-phenolic glycolipid I serology, and Mitsuda test response: 10-year follow-up of household contacts of leprosy patients

Abstract: INTRODUCTION: Despite multidrug therapy, leprosy remains a public health issue. The intradermal Bacillus Calmette-Guérin (BCG) vaccine, Mitsuda test (lepromin skin test), and anti-phenolic glycolipid I (PGL-I) serology are widely used in leprosy studies and have shown great epidemiological value. METHODS: This longitudinal study evaluated the relative risks and benefits of these three tools by comparing results observed in household contacts (HHCs) of leprosy patients who developed leprosy with those of HHCs who did not in a population of 2,992 individuals monitored during a 10-year period. RESULTS : Seventy-five (2.5%) new leprosy cases were diagnosed, including 28 (0.9%) co-prevalent cases. Therefore, for the risk-benefit assessment, 47 (1.6%) HHCs were considered as truly diagnosed during follow-up. The comparison between healthy and affected contacts demonstrated that not only did BCG vaccination increase protection, but boosters also increased to 95% relative risk (RR) reduction when results for having two or more scars were compared with having no scars [RR, 0.0459; 95% confidence interval (CI), 0.006-0.338]. Similarly, Mitsuda reactions >7mm in induration presented 7-fold greater protection against disease development compared to reactions of 0-3mm (RR, 0.1446; 95% CI, 0.0566-0.3696). In contrast, anti-PGL-I ELISA seropositivity indicated a 5-fold RR increase for disease outcome (RR, 5.688; 95% CI, 3.2412-9.9824). The combined effect of no BCG scars, Mitsuda reaction of <7mm, and seropositivity to anti-PGL-I increased the risk for leprosy onset 8-fold (RR, 8.109; 95% CI, 5.1167-12.8511). CONCLUSIONS: The adoption of these combined assays may impose measures for leprosy control strategies

Oxidative stress assessment by glutathione peroxidase activity and glutathione levels in response to selenium supplementation in patients with Mucopolysaccharidosis I, II and VI

Abstract We assessed levels of plasma selenium (Se), selenoproteins and their change after Se supplementation in patients with mucopolysaccharidosis (MPS) types I, II and VI. This was done in a retrospective study of the medical records of 30 patients with MPS I (n=13), MPS II (n=9) and MPS VI (n=8) who were being treated with enzyme replacement therapy. As part of routine nutritional monitoring, Se levels were measured, revealing that 28 patients (93.3%) had values below the normal range. Therefore, they received supplementation for 12 months, and Se was measured after 6 and 12 months. Glutathione peroxidase (GPx) activity, total glutathione (GSHt), oxidized glutathione (GSSG) and reduced glutathione (GSH) were measured at baseline and 6 months after Se supplementation. The mean GSHt at baseline was 7.90 ± 2.36 μmol/g Hb, and after Se supplementation it was 5.76 ± 1.13 μmol/g Hb; GSH/GSSG was 2.3 ± 1.16 at baseline and 0.58 ± 0.38 after supplementation. GPx activity was 16.46 ± 3.31 U/g Hb at baseline and 4.53 ± 4.92 U/g Hb after Se supplementation. The difference was shown to be statistically significant by paired t-test. In conclusion, our study demonstrated that oxidative stress parameters were altered by Se supplementation in patients with MPS I, II and VI who were previously deficient in Se

Epidemiologia da doença meningocócica na cidade do Rio de Janeiro: modificações após vacinação contra os sorogrupos B e C

A Doença Meningocócica tem sido um sério problema de saúde pública no município do Rio de Janeiro nos últimos 10 anos, com altas taxas de incidência em crianças de baixa idade, elevada letalidade e predomínio do sorogrupo B. Em dezembro de 1994 foi realizada a segunda campanha de vacinação anti-meningocócica contra os sorogrupos B e C, visando à imunização de crianças de 6 meses a 13 anos de idade. Foram vacinadas com duas doses cerca de 950 mil crianças. A vacina utilizada foi a produzida pelo Instituto Finlay de Cuba. Em 1995 foi observada uma modificação no comportamento da doença, quando passou a predominar o sorogrupo C e aumentou a incidência global da doença, particularmente entre os menores de 1 ano, adolescentes e adultos jovens. Nos grupos etários vacinados, a incidência foi menor que no ano de 1994, em função da diminuição do sorogrupo B. Não foram observadas modificações importantes no comportamento da letalidade