Abstract
Evaluation of the functional impact of germline BRCA1 variants that are likely to be associated to breast and ovarian cancer could help to investigate the mechanism of BRCA1 tumorigenesis. ...Expression of pathogenic BRCA1 missense variants increased homologous recombination (HR) and gene reversion (GR) in yeast. We thought to exploit yeast genetics to shed light on BRCA1-induced genome instability and tumorigenesis. We determined the effect on GR of several neutral and pathogenic BRCA1 variants in the yeast strain RSY6wt and its isogenic DSB repair mutants, such as mre11∆, rad50∆ and rad51∆. In the RSY6wt, four out of five pathogenic and two out of six neutral variants significantly increased GR; rad51∆ strain, the pathogenic variants C61G and A1708E induced a weak but significant increase in GR. On the other hand, in rad50∆ mutant expressing the pathogenic variants localised at the BRCT domain, a further GR increase was seen. The neutral variant N132K and the VUS A1789T induced a weak GR increase in mre11∆ mutant. Thus, BRCA1 missense variants require specific genetic functions and presumably induced GR by different mechanisms. As DNA repair is regulated by cell cycle, we determined the effect on GR of BRCA1 variants in cell cycle-arrested RSYwt cells. GR is highly BRCA1-inducible in S-phase-arrested cells as compared to G1 or G2. Sequence analysis of genomic DNA from ILV1 revertant clones showed that BRCA1-induced ilv1-92 reversion by base substitution when GR is at least 6-fold over the control. Our study demonstrated that BRCA1 may interfere with yeast DNA repair functions that are active in S-phase causing high level of GR. In addition, we confirmed here that yeast could be a reliable model to investigate the mechanism and genetic requirements of BRCA1-induced genome instability. Finally, developing yeast-based assays to characterise BRCA1 missense variants could be useful to design more precise therapies.
Abstract
The breast and ovarian cancer susceptibility genes, BRCA1 and BRCA2, are key players in the homologous recombination (HR) repair pathway and act as tumor suppressors by maintaining genome ...stability. The yeast Saccharomyces cerevisiae has no BRCA1/2 homolog; however, a number of HR genes are evolutionary conserved between human and yeast. Among them, RAD52 is involved in DNA double strand break (DSB) repair by HR, and promotes genome stability. We previously reported that the heterologous expression of cancer-associated BRCA1/2 missense variants in growing yeast cultures affects both spontaneous HR and gene reversion (GR) suggesting that yeast could be a reliable system to assess the functional impact of variants. Because inhibition of Rad52p is lethal in BRCA1/2 mutated tumors, and Rad52p is conserved between humans and yeast, we asked if the effect of BRCA1/2 variants on HR and GR could be affected by loss of RAD52. We found that the rad52∆ mutation predominantly suppressed the stimulation of HR in yeast by pathogenic BRCA1 variants but also facilitated increased GR by pathogenic variants. Conversely, the rad52∆ mutation stimulated HR by a pathogenic BRCA2 variant in yeast but had no effect on GR. These results demonstrate a functional interplay between the pathogenic BRCA1/2 variants and Rad52p in budding yeast, supporting the use of budding yeast as a suitable system for evaluating potential chemotherapeutic strategies.
Yeast is a good model to investigate the complex genetic interaction in cancer.
Abstract BRCA1 interacts with several proteins implicated in homologous and non homologous recombination and in mismatch repair. The aim of this study is to determine if MSH2 , a well known partner ...of BRCA1 involved in DNA repair, may contribute to breast and ovarian cancer development and progression. To better understand the functional interaction between BRCA1 and MSH2, we studied the effect of the deletion of MSH2 gene on BRCA1-induced genome instability in yeast. Preliminary results in yeast indicated that MSH2 and BRCA1 may interact to modulate homologous recombination (HR). We also carried out a genetic and epigenetic profiling of MSH2 gene by mutational analysis and promoter methylation evaluation in 9 breast and 2 ovarian tumors from carriers of BRCA1 unknown significance variants (VUS). 2/2 ovarian and 2/9 breast tumors carried MSH2 somatic mutations possible pathogenics (4/11, 36%): a missense mutation in exon 3 (p.G162R), a duplication of exon 1 and a deletion of exon 2. In addition, two germline synonymous variants in exon 11 were identified. None of the tumors showed promoter methylation. In conclusion, a surprisingly high frequency of MSH2 gene mutations has been found in tumor tissues from BRCA1 VUS carrier patients. This result supports the indication deriving from the yeast model that BRCA1 driven tumorigenesis may be modulated by MSH2.
Four different Marine Rapid Environmental Assessment (MREA) procedures are compared with a focus on underwater acoustic performance. Co-located oceanographic-acoustic data were collected during the ...summer of 2015 in the Northwestern Mediterranean in the framework of a sea trial led by the NATO Centre for Maritime Research and Experimentation. The data were used to link MREA procedures and ocean-acoustic validation in a seamless framework. The MREA procedures consider Conductivity Temperature Depth (CTD) data, operational products from the Copernicus Marine Service, and two dynamical downscaling systems (with and without data assimilation). A portion of the oceanographic data are used for the assimilation procedure, and the remaining portion is withheld from the assimilation system for use as an independent verifying dataset. The accuracy of modelled acoustic properties is evaluated using the sound speed estimates from the different MREA methodologies as inputs to an acoustic model, and then comparing the modelled and observed acoustic arrival intensities and temporal structure. In 95% of the studied cases, the assimilative dynamical downscaling approach provides acoustic results equaling or exceeding in skill those modelled with the sound speed extracted from CTD casts. Acoustic assessment results indicate that our implementation of dynamical downscaling has skill at oceanographic scales of 4 km, about ten times larger than the ocean model horizontal resolution.
Manufacturing processes involving chemical agents are evolving at great speed. In this context, managing chemical risk is especially important towards preventing both occupational accidents and major ...accidents. Directive 89/391/EEC and Directive 2012/18/EU, respectively, are enforced in the European Union (EU) to this end. These directives may be further complemented by the recent ISO 45001:2018 standard regarding occupational health and safety management systems. These three management systems are closely related. However, scientific literature tackles the researching of these accidents independently. Thus, the main objective of this work is to identify and analyse the links and transitional spaces between the risk management of both types of accident. Among the results obtained, three transitional spaces can be pointed out which result from the intersection of the three systems mentioned. Similarly, the intersection of these spaces gives shape to a specific transitional space defined by the individual directives linked to Directive 89/391/EEC. These results are limited from a regulatory and technical perspective. Thus, the results are a starting point towards developing models that integrate the management systems studied.
Background: Psoriatic disease, a chronic immune-mediated systemic inflammatory condition, significantly impairs patients’ quality of life. The advent of highly targeted biological therapies has ...transformed treatment strategies, emphasizing the importance of selecting the most effective and cost-efficient option. Secukinumab, an IL-17A inhibitor, has demonstrated efficacy and safety in treating moderate-to-severe plaque psoriasis (PsO). However, long-term real-world data on its effectiveness and persistence rate are limited. Methods: This retrospective study, conducted across eight Italian dermatology centers, aimed to evaluate the 6-year persistence rate and effectiveness of secukinumab in patients with PsO. Additionally, the study investigated the onset of psoriatic arthritis during treatment. Results: Overall, 166 adult patients were analyzed. Their median age was 53.9 years. The mean BMI was 26.5. Of the 166 patients, 64 were bio-experienced while 102 were bio-naïve. A progressive reduction in PsO severity measured by PASI scores over 6 years of treatment was revealed: the PASI score decreased from a baseline value of 18.1 (±9.1) to 0.7 (±1.6) after 6 years of follow-up. Adverse events, including mucocutaneous fungal infections and cardiovascular disturbances, were reported in 19.9% of patients. The persistence rate was 86.8% at 24 months, decreasing to 66.4% at 72 months. Psoriatic arthritis onset during treatment was observed in 15 (9.0%) of patients. Conclusions: This study highlights the sustained effectiveness and favorable safety profile of secukinumab over 6 years, providing valuable real-world evidence. Understanding the long-term persistence rate and predictors of discontinuation could help clinicians optimize treatment decisions and improve patient outcomes in PsO management. We found that the absence of scalp PsO, no involvement of the genital area and normal weight were the best factors of persistence in secukinumab treatment in the long term.
BACKGROUND:
Over the past few decades, several surgical approaches have been proposed to treat hemorrhoids.
OBJECTIVE:
This multicenter study aimed to compare transanal hemorrhoidal artery ligation ...and conventional excisional hemorrhoidectomy for grade III hemorrhoidal disease.
DESIGN:
Multicenter retrospective study.
SETTINGS:
Any center belonging to the Italian Society of Colorectal Surgery in which at least 30 surgical procedures per year for hemorrhoidal disease were performed was able to join the study.
PATIENTS:
Clinical data from patients with Goligher’s grade III hemorrhoidal disease who underwent excisional hemorrhoidectomy or hemorrhoidal artery ligation were retrospectively analyzed after a 24-month follow-up period.
MAIN OUTCOME MEASURES:
The primary aims were to evaluate the adoption of 2 different surgical techniques and to compare them in terms of symptoms, postoperative adverse events, and recurrences at a 24-month follow-up.
RESULTS:
Data from 1681 patients were analyzed. The results of both groups were comparable in terms of postoperative clinical score by multiple regression analysis and matched case–control analysis. Patients who underwent excisional hemorrhoidectomy had a significantly higher risk of postoperative complication (adjusted OR = 1.58;
p
= 0.006). A secondary analysis highlighted that excisional hemorrhoidectomy performed with new devices and hemorrhoidal artery ligation reported a significantly lower risk for complications than excisional hemorrhoidectomy performed with traditional monopolar diathermy. At the 24-month follow-up assessment, recurrence was significantly higher in the hemorrhoidal artery ligation group (adjusted OR = 0.50;
p
= 0.001). A secondary analysis did not show a higher risk of recurrences based on the type of device.
LIMITATIONS:
The retrospective design and the self-reported nature of data from different centers.
CONCLUSIONS:
Hemorrhoidal artery ligation is an effective option for grade III hemorrhoidal disease; however, it is burdened by a high risk of recurrences. Excisional hemorrhoidectomy performed with newer devices is competitive in terms of postoperative complications.
HEMORROIDECTOMÍA POR ESCISIÓN VERSUS DESARTERIALIZACIÓN CON MUCOPEXIA PARA EL TRATAMIENTO DE LA ENFERMEDAD HEMORROIDAL DE GRADO 3: EL ESTUDIO MULTICÉNTRICO EMODART3
ANTECEDENTES:
En las últimas décadas se han propuesto varios abordajes quirúrgicos para el tratamiento de las hemorroides.
OBJETIVO:
Este estudio multicéntrico tiene como objetivo comparar la ligadura de la arteria hemorroidal transanal y la hemorroidectomía por escisión convencional para la enfermedad hemorroidal de grado III.
DISEÑO:
Estudio retrospectivo multicéntrico.
ÁMBITO:
Cualquier centro perteneciente a la Sociedad Italiana de Cirugía Colorrectal en el que se realizaron al menos 30 procedimientos quirúrgicos por año para la enfermedad hemorroidal pudo participar en el estudio.
PACIENTES:
Los datos clínicos de pacientes con enfermedad hemorroidal de grado III de Goligher que se sometieron a hemorroidectomía por escisión o ligadura de arterias hemorroidales se analizaron retrospectivamente después de un período de seguimiento de 24 meses.
PRINCIPALES MEDIDAS DE RESULTADO:
Los objetivos primarios fueron evaluar la adopción de dos técnicas quirúrgicas diferentes y compararlas en términos de síntomas, eventos adversos posoperatorios y recurrencias a los 24 meses de seguimiento.
RESULTADOS:
Se analizaron datos de 1681 pacientes. Los 2 grupos resultaron ser comparables en términos de puntuación clínica posoperatoria mediante análisis de regresión múltiple y análisis de casos y controles emparejados. Los pacientes sometidos a hemorroidectomía excisional tuvieron un riesgo significativamente mayor de complicaciones posoperatorias (odds ratio ajustado = 1,58; p = 0,006). Un análisis secundario destacó que la hemorroidectomía por escisión realizada con nuevos dispositivos y la ligadura de la arteria hemorroidal informaron un riesgo significativamente menor de complicaciones que la hemorroidectomía por escisión realizada con diatermia monopolar tradicional. En la evaluación de seguimiento de 24 meses, la recurrencia fue significativamente mayor en el grupo de ligadura de la arteria hemorroidal (razón de probabilidad ajustada = 0,50; p = 0,001). Un análisis secundario no mostró un mayor riesgo de recurrencias según el tipo de dispositivo.
LIMITACIONES:
El diseño retrospectivo y el carácter autoinformado de los datos de diferentes centros.
CONCLUSIÓN:
HAL es una opción efectiva para la enfermedad hemorroidal grado III; sin embargo, se ve afectado por un alto riesgo de recurrencias. La hemorroidectomía por escisión realizada con dispositivos más nuevos es competitiva en términos de complicaciones posoperatorias.
(Traducción—Dr Yolanda Colorado
)
This paper shows the interlayer fatigue performance evaluated by the Sapienza shear testing machine. The tests can be performed by placing double layer specimens in several inclinations, in order to ...reproduce a variety of expected ratios between the normal and the shear stress. The machine manages loads with any kind of waveform and is particularly able to simulate the stress trends expected in field in points located just outside the wheel path. In this experimentation, the machine applies a triangular waveform load computed by a linear elastic multilayer program at the depth of the first pavement interface. A fatigue law is estimated considering the number of repetitions that causes the interface failure. A linear regression in the log-log graph suitably fits the experimental results for the analyzed conditions of temperature and interface type.
To measure the effectiveness of pneumococcal conjugated vaccine (PCV13) against Community Acquired Pneumonia (CAP) and invasive pneumococcal disease, 2 years after the vaccine (2+1) was included into ...the National Immunization Program of Argentina, and to describe variables associated with bacterial pneumonia and hospitalization.
This was a prospective, population-based surveillance study of CAP incidence (ambulatory and hospitalized) among children less than 5 years of age in the Department of Concordia (Entre Rios, Argentina) from April 2014 - March 2016. The diagnosis of probable bacterial pneumonia (PBP) was determined following the standardized WHO protocol. Incidence during the post-vaccine introduction period was compared with the results from a previous study that used similar methodology for the pre-PCV13 introduction period from 2002 - 2005.
During the study period, 330 patients had a clinical diagnosis of CAP, of which 92 were PBP (6 with pleural effusion). S. pneumoniae was not isolated from any sample. No factors associated with PBP were found in multivariable analysis. The decrease in PBP and pleural effusion was significant in relation to the previous study: 63% (P < 0.0001) and 80.9% (P < 0.003), respectively. PCV13 uptake was 97.3% for the 1st dose and 84.8% for the booster dose.
PCV13 was effective to reduce incidence of consolidated pneumonia and pleural effusion, among children less than 5 years of age in Concordia, Argentina. Vaccination is a very effective public health strategy for reducing vaccine preventable diseases, with impact on burden of disease and hospitalization.
The present contribution aims at providing an innovative method for the assessment of human barriers, specifically addressing the framework of the energy industry, including offshore operations. ...Introducing a revised framework to analyse human errors, the methodology developed aims at extending the current Human Reliability Analysis (HRA) methods including psychosocial factors and barriers. The new methodology was developed extending and tailoring to the specific context the well-known framework set by two widely used HRA methodologies (SPAR-H and HEART). An innovative holistic framework, dedicated to the wide range of operations of the energy industry, was developed to assess human error probability (HEP). Human factors were considered safety barriers against human error: more specifically, workers were considered having an active role in shaping their own performance. The method developed introduced a revision of the Generic Task Types (GTT). Each GTT was then associated with a Nominal Error Probability (NEP). The NEP is then modified by the assessment of correction factors obtained from the assessment of conditions affecting task performance, in analogy with the Performance Shaping Factors (PSF) approach introduced by SPAR-H. The method proved to be easy to apply and the results obtained clearly show that human factors play a significant role in preventing workers from making errors while performing tasks by reducing human error probability.
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