A transcriptome-based signature of pathological angiogenesis predicts breast cancer patient survival.

The specific genes and molecules that drive physiological angiogenesis differ from those involved in pathological angiogenesis, suggesting distinct mechanisms for these seemingly related processes. Unveiling genes and pathways preferentially associated with pathologic angiogenesis is key to understanding its mechanisms, thereby facilitating development of novel approaches to managing angiogenesis-dependent diseases. To better understand these different processes, we elucidated the transcriptome of the mouse retina in the well-accepted oxygen-induced retinopathy (OIR) model of pathological angiogenesis. We identified 153 genes changed between normal and OIR retinas, which represent a molecular signature relevant to other angiogenesis-dependent processes such as cancer. These genes robustly predict the survival of breast cancer patients, which was validated in an independent 1,000-patient test cohort (40% difference in 15-year survival; p = 2.56 x 10-21). These results suggest that the OIR model reveals key genes involved in pathological angiogenesis, and these may find important applications in stratifying tumors for treatment intensification or for angiogenesis-targeted therapies.

Frequency of carriers for rare recessive Mendelian diseases in a Brazilian cohort of 320 patients.

Several Mendelian disorders follow an autosomal recessive inheritance pattern. Epidemiological information on many inherited disorders may be useful to guide health policies for rare diseases, but it is often inadequate, particularly in developing countries. We aimed to calculate the carrier frequencies of rare autosomal recessive Mendelian diseases in a cohort of Brazilian patients using whole exome sequencing (WES). We reviewed the molecular findings of WES from 320 symptomatic patients who had carrier status for recessive diseases. Using the Hardy-Weinberg equation, we estimated recessive disease frequencies (q2 ) considering the respective carrier frequencies (2pq) observed in our study. We calculated the sensitivity of carrier screening tests based on lists of genes from five different clinical laboratories that offer them in Brazil. A total of 425 occurrences of 351 rare variants were reported in 278 different genes from 230 patients (71.9%). Almost half (48.8%) were carriers of at least one heterozygous pathogenic/likely pathogenic variant for rare metabolic disorders, while 25.9% of epilepsy, 18.1% of intellectual disabilities, 15.6% of skeletal disorders, 10.9% immune disorders, and 9.1% of hearing loss. We estimated that an average of 67% of the variants would not have been detected by carrier screening panels. The combined frequencies of autosomal recessive diseases were estimated to be 26.39/10,000 (or ~0.26%). This study shows the potential research utility of WES to determine carrier status, which may be a possible strategy to evaluate the clinical and social burden of recessive diseases at the population level and guide the optimization of carrier screening panels.

Baryon Acoustic Oscillations from Integrated Neutral Gas Observations: an instrument to observe the 21cm hydrogen line in the redshift range 0.13 < z < 0.45 - status update.

BINGO (BAO from Integrated Neutral Gas Observations) is a unique radio telescope designed to map the intensity of neutral hydrogen distribution at cosmological distances, making the first detection of Baryon Acoustic Oscillations (BAO) in the frequency band 980 MHz - 1260 MHz, corresponding to a redshift range 0.127 < z < 0.449. BAO is one of the most powerful probes of cosmological parameters and BINGO was designed to detect the BAO signal to a level that makes it possible to put new constraints on the equation of state of dark energy. The telescope will be built in Paraíba, Brazil and consists of two \thicksim 40m mirrors, a feedhorn array of 50 horns, and no moving parts, working as a drift-scan instrument. It will cover a 15 ^{\circ} ∘ declination strip centered at \sim \delta ∼ δ =-15 ^{\circ} ∘ , mapping \sim ∼ 5400 square degrees in the sky. The BINGO consortium is led by University of São Paulo with co-leadership at National Institute for Space Research and Campina Grande Federal University (Brazil). Telescope subsystems have already been fabricated and tested, and the dish and structure fabrication are expected to start in late 2020, as well as the road and terrain preparation.

Exome sequencing and targeted gene panels: a simulated comparison of diagnostic yield using data from 158 patients with rare diseases.

Next-generation sequencing (NGS) has altered clinical genetic testing by widening the access to molecular diagnosis of genetically determined rare diseases. However, physicians may face difficulties selecting the best diagnostic approach. Our goal is to estimate the rate of possible molecular diagnoses missed by different targeted gene panels using data from a cohort of patients with rare genetic diseases diagnosed with exome sequencing (ES). For this purpose, we simulated a comparison between different targeted gene panels and ES: the list of genes harboring clinically relevant variants from 158 patients was used to estimate the theoretical rate of diagnoses missed by NGS panels from 53 different NGS panels from eight different laboratories. Panels presented a mean rate of missed diagnoses of 64% (range 14%-100%) compared to ES, representing an average predicted sensitivity of 36%. Metabolic abnormalities represented the group with highest mean of missed diagnoses (86%), while seizure represented the group with lowest mean (46%). Focused gene panels are restricted in covering select sets of genes implicated in specific diseases and they may miss molecular diagnoses of rare diseases compared to ES. However, their role in genetic diagnosis remains important especially for well-known genetic diseases with established genetic locus heterogeneity.

Diagnostic power and clinical impact of exome sequencing in a cohort of 500 patients with rare diseases.

Rare diseases comprise a diverse group of conditions, most of which involve genetic causes. We describe the variable spectrum of findings and clinical impacts of exome sequencing (ES) in a cohort of 500 patients with rare diseases. In total, 164 primary findings were reported in 158 patients, representing an overall diagnostic yield of 31.6%. Most of the findings (61.6%) corresponded to autosomal dominant conditions, followed by autosomal recessive (25.6%) and X-linked (12.8%) conditions. These patients harbored 195 variants, among which 43.6% are novel in the literature. The rate of molecular diagnosis was considerably higher for prenatal samples (67%; 4/6), younger children (44%; 24/55), consanguinity (50%; 3/6), gastrointestinal/liver disease (44%; 16/36) and syndromic/malformative conditions (41%; 72/175). For 15.6% of the cohort patients, we observed a direct potential for the redirection of care with targeted therapy, tumor screening, medication adjustment and monitoring for disease-specific complications. Secondary findings were reported in 37 patients (7.4%). Based on cost-effectiveness studies in the literature, we speculate that the reports of secondary findings may influence an increase of 123.2 years in the life expectancy for our cohort, or 0.246 years/cohort patient. ES is a powerful method to identify the molecular bases of monogenic disorders and redirect clinical care.

Cognitive performance of individuals with animal hoarding.

BACKGROUND: The purpose of this study was to characterize the cognitive performance of individuals with animal hoarding. METHODS: This is a cross-sectional study, in which 33 individuals between the ages of 29 to 84 (M = 61.39; SD = 12.69) with animal hoarding have been assessed. The participants completed a neurocognitive battery including measures of general cognitive functioning, visual memory and organization, verbal fluency, and verbal reasoning. RESULTS: Data suggest that individuals with animal hoarding have high rates of cognitive deficits related to visual memory and verbal reasoning. CONCLUSIONS: Based on the performance tests used, we can suggest the existence of cognitive difficulties related especially to the executive functions of individuals with animal hoarding in this sample.

A comparison between SOLiD 5500XLand Ion Torrent PGM-derived miRNA expression profiles in two breast cell lines.

Next-generation sequencing (NGS) platforms allow the analysis of hundreds of millions of molecules in a single sequencing run, revolutionizing many research areas. NGS-based microRNA studies enable expression quantification in unprecedented scale without the limitations of closed-platforms. Yet, whereas a massive amount of data produced by these platforms is available, comparisons of quantification/discovery capabilities between platforms are still lacking. Here we compare two NGS-platforms: SOLiD and PGM, by evaluating their microRNA identification/quantification capabilities using two breast-derived cell-lines. A high expression correlation (R2 > 0.9) was achieved, encompassing 97% of the miRNAs, and the few discrepancies in miRNA counts were attributable to molecules that have very low expression. Quantification divergences indicative of artefactual representation were seen for 14 miRNAs (higher in SOLiD-reads) and another 10 miRNAs more abundant in PGM-data. An inspection of these revealed an increased and statistically significant count of uracyls and uracyl-stretches for PGM-enriched miRNAs, compared to SOLiD and to the miRBase. In parallel, adenines and adenine-stretches were enriched for SOLiDderived miRNA reads. We conclude that, whereas both platforms are overall consistent and can be used interchangeably for microRNA expression studies, particular sequence features appear to be indicative of specific platform bias, and their presence in microRNAs should be considered for database-analyses.

Psychopathological Comorbid Symptoms in Animal Hoarding Disorder.

The main goal of this research is to describe the psychopathological symptoms comorbid to animal hoarding disorder. This is a cross-sectional study with a sample of a 33 individuals sample diagnosed with animal hoarding disorder. For data collection, a Sociodemographic Data questionnaire and a Semi-Structured Clinical Interview were used, based on the DSM-5 Level 1 Cross-Cutting Symptom Measure. The sample consisted of 24 women (72.7%) and 9 men (27.30%), with a prevalence of 64% of the elderly. The mean number of self-reported animals per residence was 41.12 (DP = 24.41), totaling 1357 animals: 915 (68%) dogs, 382 (28%) cats, and 50 (4%) ducks. The results indicated animal hoarding disorder the comorbid psychopathological symptoms of depression (36%), anxiety (36%), memory deficits (27%), mania (21%) and obsessive-compulsive disorder (18%). The analyses revealed a higher occurrence of these symptoms among participants who had hoarded animals for over 20 years.

Systemic oxidative stress as a possible mechanism underlying the pathogenesis of mild endometriosis-related infertility.

RESEARCH QUESTION: Does systemic oxidative stress occur during the early follicular phase of the menstrual cycle in infertile women with minimal (stage I) or mild (stage II) endometriosis? Are serum oxidative stress markers during the early follicular phase of the menstrual cycle good predictors of successful gestation in these women who undergo ovarian stimulation for intracytoplasmic sperm injection (ICSI)? MATERIALS AND METHODS: A pilot study (prospective case-control study) was conducted in a University Hospital. Serum samples were obtained during the early follicular phase of the natural cycle preceding ovarian stimulation for ICSI of infertile women (with and without stage I and II endometriosis, the latter having male factor infertility). Total hydroperoxides (FOX1), malondialdehyde, advanced oxidation protein products, reduced glutathione, superoxide dismutase, total antioxidant capacity (TAC), 8-hydroxy-2'-deoxyguanosine (8OHdG) and vitamin E were analysed in serum from 35 women with stage I or II endometriosis and 60 control women. The accuracy of oxidative stress markers for predicting clinical pregnancy and live births was determined by receiver operator characteristic curves. RESULTS: Women with stage I and II endometriosis showed lower serum 8OHdG concentrations (16.02 ng/ml) compared with the control group (22.08 ng/ml). The best predictor for clinical pregnancy and live births was TAC, whereas FOX1 was the best predictor of clinical pregnancy in the control group. CONCLUSIONS: Infertile women with stage I and II endometriosis present systemic oxidative stress during the early follicular phase of the menstrual cycle. Some oxidative stress markers were good predictors of clinical pregnancy and live births after ICSI. Serum TAC was predictive of clinical pregnancy and live births after ICSI in women with stage I or II endometriosis.

BRCA1 deficiency is a recurrent event in early-onset triple-negative breast cancer: a comprehensive analysis of germline mutations and somatic promoter methylation.

PURPOSE: BRCA1 germline mutation is closely associated with triple-negative breast cancer. BRCA deficiency leads to impaired DNA repair and tumor development, and understanding this deficiency, in both hereditary and sporadic scenarios, is of great clinical and biological interest. Here, we investigated germline or somatic events that might lead to BRCA1 impairment in triple-negative breast cancer. We also analyzed the clinical implications associated with BRCA deficiency. METHODS: Next-generation sequencing for the BRCA1/2 genes and multiplex ligation-dependent probe amplification (MLPA) for the BRCA1 gene were performed for mutation screening. A customized bisulfite next-generation sequencing approach was used for assessing BRCA1 promoter methylation status in tumor tissue. RESULTS: A total of 131 triple-negative cases were assessed, and germline pathogenic variants were detected in 13.0% of all cases and in 26% of cases diagnosed in young women. Most germline pathogenic variants (88.2%) occurred in the BRCA1 gene. BRCA1 promoter hypermethylation was detected in 20.6% of tumors; none of these tumors were in BRCA1/2 pathogenic variant carriers. BRCA1 impairment by either germline or somatic events was significantly more frequent in young women (55% in those ≤ 40 years; 33% in those 41-50 years; 22% in those > 50 years of age) and associated with better overall and disease-free survival rates in this group of patients. CONCLUSIONS: BRCA1 deficiency was recurrent in early-onset triple-negative breast cancer in Brazilian patients and associated with improved survival. With the new treatment modalities being investigated, including poly (ADP-ribose)-polymerase (PARP) inhibitor therapy, our results suggest that a significant proportion of young women with this subtype of tumor might benefit from PARP inhibitor treatment, which warrants further investigation.

A genomic case study of desmoplastic small round cell tumor: comprehensive analysis reveals insights into potential therapeutic targets and development of a monitoring tool for a rare and aggressive disease.

BACKGROUND: Genome-wide profiling of rare tumors is crucial for improvement of diagnosis, treatment, and, consequently, achieving better outcomes. Desmoplastic small round cell tumor (DSRCT) is a rare type of sarcoma arising from mesenchymal cells of abdominal peritoneum that usually develops in male adolescents and young adults. A specific translocation, t(11;22)(p13;q12), resulting in EWS and WT1 gene fusion is the only recurrent molecular hallmark and no other genetic factor has been associated to this aggressive tumor. Here, we present a comprehensive genomic profiling of one DSRCT affecting a 26-year-old male, who achieved an excellent outcome. METHODS: We investigated somatic and germline variants through whole-exome sequencing using a family based approach and, by array CGH, we explored the occurrence of genomic imbalances. Additionally, we performed mate-paired whole-genome sequencing for defining the specific breakpoint of the EWS-WT1 translocation, allowing us to develop a personalized tumor marker for monitoring the patient by liquid biopsy. RESULTS: We identified genetic variants leading to protein alterations including 12 somatic and 14 germline events (11 germline compound heterozygous mutations and 3 rare homozygous polymorphisms) affecting genes predominantly involved in mesenchymal cell differentiation pathways. Regarding copy number alterations (CNA) few events were detected, mainly restricted to gains in chromosomes 5 and 18 and losses at 11p, 13q, and 22q. The deletions at 11p and 22q indicated the presence of the classic translocation, t(11;22)(p13;q12). In addition, the mapping of the specific genomic breakpoint of the EWS-WT1 gene fusion allowed the design of a personalized biomarker for assessing circulating tumor DNA (ctDNA) in plasma during patient follow-up. This biomarker has been used in four post-treatment blood samples, 3 years after surgery, and no trace of EWS-WT1 gene fusion was detected, in accordance with imaging tests showing no evidence of disease and with the good general health status of the patient. CONCLUSIONS: Overall, our findings revealed genes with potential to be associated with risk assessment and tumorigenesis of this rare type of sarcoma. Additionally, we established a liquid biopsy approach for monitoring patient follow-up based on genomic information that can be similarly adopted for patients diagnosed with a rare tumor.

Upregulated genes at 2q24 gains as candidate oncogenes in hepatoblastomas.

AIM: Cytogenetic data of hepatoblastomas, a rare embryonal tumor of the liver, mostly consist of descriptions of whole-chromosome aneuploidies and large chromosome alterations. High-resolution cytogenetics may provide clues to hepatoblastoma tumorigenesis and indicate markers with clinical significance. PATIENTS & METHODS: We used array-CGH (180K) to screen for genomic imbalances in nine hepatoblastomas. Additionally, we investigated the expression pattern of selected genes exhibiting copy number changes. RESULTS: Analysis showed mainly whole-chromosome or chromosome-arm aneuploidies, but some focal aberrations were also mapped. Expression analysis of 48 genes mapped at one 10 Mb amplification at 2q24 revealed upregulation of DAPL1, ERMN, GALNT5, SCN1A and SCN3A in the set of tumors compared with differentiated livers. CONCLUSION: These genes appear as candidates for hepatoblastoma tumorigenesis.

Tetrandrine for Targeting Therapy Resistance in Cancer.

During the last five decades, there has been tremendous development in our understanding of cancer biology and the development of new and novel therapeutics to target cancer. However, despite these advances, cancer remains the second leading cause of death across the globe. Most cancer deaths are attributed to the development of resistance to current therapies. There is an urgent and unmet need to address cancer therapy resistance. Tetrandrine, a bis-benzyl iso-quinoline, has shown a promising role as an anti-cancer agent. Recent work from our laboratory and others suggests that tetrandrine and its derivatives could be an excellent adjuvant to the current arsenal of anti-cancer drugs. Herein, we provide an overview of resistance mechanisms to current therapeutics and review the existing literature on the anti-cancer effects of tetrandrine and its potential use for overcoming therapy resistance in cancer.

Combining and concentrating nanocelluloses for cryogels with remarkable strength and wet resilience.

Cellulose cryogels are promising eco-friendly materials that exhibit low density, high porosity, and renewability. However, the applications of these materials are limited by their lower mechanical and water resistance compared to petrochemical-based lightweight materials. In this work, nanocelluloses were functionalized with cationic and anionic groups, and these nanomaterials were combined to obtain strong and water-resilient cryogels. To prepare the cryogels, anionic and cationic micro- and nanofibrils (CNFs) were produced at three different sizes and combined in various weight ratios, forming electrostatic complexes. The complex phase was concentrated by centrifugation and freeze-dried. Porous and open cellular structures were assembled in all compositions tested (porosity >90 %). Compressive testing revealed that the most resistant cryogels (1.7 MPa) were obtained with equivalent amounts of negatively and positively charged CNFs with lengths between 100 and 1200 nm. The strength at this condition was achieved as CNF electrostatic complexes assembled in thick cells, as observed by synchrotron X-ray tomography. In addition to mechanical strength, electrostatic complexation provided remarkable structural stability in water for the CNF cryogels, without compromising their biodegradability. This route by electrostatic complexation is a practical strategy to combine and concentrate nanocelluloses to tailor biodegradable lightweight materials with high strength and wet stability.

Size-structure-property relationship of wood particles in aqueous and dry insulative foams.

Three size-fractionated samples of pine beetle-killed wood particles were used to prepare lightweight insulative foams. The foams were produced by foam-forming an aqueous slurry containing wood particles (125-1000 µm), a polymer binder, and surfactant, followed by oven drying. The effect of wood particle size on the aqueous foam stability, structure, and performance of insulative foams was investigated. While all aqueous foams were highly stable, aqueous foam stability increased with decreasing particle size. For dry foams, the cell size distribution was similar for all particle sizes as it was primarily controlled by the surfactant; differences occurred within the cell wall structure. A size-structure-property relationship was identified using x-ray micro-computed tomography where smaller particles produced lighter cell wall frameworks, leading to lower densities and decreased thermal conductivity and compressive strength. Larger particles produced denser cell wall frameworks that were more resistant to deformation, although all dry foams had sufficient mechanical properties for use as insulation panels. Thermal conductivity for all wood particle size-fractionated samples was <0.047 W m-1 K-1 making the foams similar to expanded polystyrene/polyurethane and supporting their use as thermal insulation in buildings.

Modeling the Thermal Inactivation of Monascus ruber Ascospores Isolated from Green Olive (Arauco Cultivar) Storage Brine: An Alternative Strategy to Reduce Antifungal Chemical Agents.

Monascus ruber is an important fungus that causes spoilage in table olives, resulting in the darkening of the brine, the softening of the fruit, increased pH, and apparent mycelial growth. This study aimed to evaluate this resistance, providing a model to determine the optimal processing conditions for mitigating fungal contamination and prolonging shelf life without antifungal agents while optimizing pasteurization to reduce energy consumption. The resistance in brine (3.5% NaCl; pH 3.5) from Arauco cultivar green olives imported from Argentina was assessed. Four predictive models (log linear, log linear + shoulder, log linear + tail, log linear + shoulder + tail) estimated kinetic parameters for each survival curve. Log linear + shoulder + tail provided the best fit for 70 °C and 75 °C, with low RMSE (0.171 and 0.112) and high R2 values (0.98 and 0.99), respectively, while the log linear model was used for 80 °C. Decimal reduction times at 70, 75, and 80 °C were 24.8, 5.4, and 1.6 min, respectively, with a z-value of 8.2 °C. The current regulatory processes are insufficient to eliminate M. ruber at requisite levels, considering reduced antifungal agents.

Circulating tumor DNA in diffuse large B-cell lymphoma: analysis of response assessment, correlation with PET/CT and clone evolution.

INTRODUCTION: Circulating tumor DNA (ctDNA) can be obtained from cell-free DNA (cfDNA) andis a new technique for genotyping, response assessment and prognosis in lymphoma. METHODS: Eighteen patients with samples at diagnosis (ctDNA1), after treatment (ctDNA2) and extracted from diagnostic tissue (FFPE) were evaluated. RESULTS: In all patients, at least one mutation in cfDNA was detected at diagnosis. CREBBP was the most frequent mutated gene (67 %). In 12 of the 15 patients with complete remission, the mutation attributed to the disease found at diagnosis cleared with treatment. A reduction in the ctDNA was observed after treatment in 14 patients, 12 of whom achieved complete remission. Correlations were found between the ctDNA at diagnosis and total metabolic tumor volume (r = 0.51; p-value = 0.014) and total lesion glycolysis 2.5 (r = 0.47; p-value = 0.024) by PET at diagnosis and between ctDNA at diagnosis and radiomic features of the lesions with the largest standardized uptake value. There was a strong inverse correlation between ΔctDNA1 and ΔSUVmax by PET/CT (r = -0.8788; p-value = 0.002). CONCLUSION: Analysis of ctDNA and PET/CT in large B-cell lymphoma are complementary data for evaluating tumor burden and tumor clearance after treatment. Analysis of radiomic data might help to identify tumor characteristics and their changes after treatment.

Pheochromocytoma/Paraganglioma (PPGL): A Misdiagnosed Cause of Hypertension during Pregnancy.

Hypertension (HT) during pregnancy is not an infrequent obstetric problem, reaching a prevalence of 5-10%. This condition is highly associated with both maternal and fetal complications if not precisely diagnosed and managed. Even though primary HT, obesity, and preeclampsia are the main causes of HT in this period, other less familiar conditions must be considered during the investigation. Pheochromocytoma and paraganglioma (PPGL) are chromaffin cell tumors that produce, store, and secrete catecholamines, leading to HT and other adrenergic manifestations. Recognition of PPGL is crucial since misdiagnosis and improper management can lead to high morbidity and mortality, particularly during pregnancy. We report on two cases of PPGL diagnosed during pregnancy with different managements. Case 1 is a 25-year-old female at 31 weeks of first pregnancy, whose severe HT and life-threatening symptoms prompted an emergency delivery without previous confirmation or medical treatment of a suspected PPGL. After confirmation, a right adrenal PPGL was surgically resected 4 months later, following 15 days of medical therapy. Case 2 is a 22-year-old female at 18 weeks of pregnancy whose symptomatic PPGL was resected in the second trimester. A next-generation sequencing panel, including 23 PPGL-related genes, found no germline pathogenic variants (GPVs) in case 1 and an exon 1-4 germinative heterozygous deletion of the MAX gene in case 2. Despite the different medical approaches, both cases had satisfactory outcomes. Although uncommon, PPGL should be considered in the differential diagnosis of HT in pregnancy since missing the diagnosis and failing to introduce appropriate and timely treatment may lead to dramatic consequences for the mother and fetus. PPGL diagnosed during reproductive age is likely to result from GPV, prompting genetic investigation and counseling.

External beam radiation therapy for recurrent or residual thyroid cancer: What is the best treatment time and the best candidate for long-term local disease control?

INTRODUCTION: Cervical disease control might be challenging in advanced thyroid cancer (DTC). Indications for cervical external beam radiation therapy (EBRT) are controversial. PURPOSE: To identify clinical and molecular factors associated with control of cervical disease with EBRT. METHODS: Retrospective evaluation and molecular analysis of the primary tumor DTC patients who underwent cervical EBRT between 1995 and 2022 was performed. RESULTS: Eighty adults, median age of 61 years, were included. T4 disease was present in 43.7%, lymph node involvement in 42.5%, and distant metastasis in 47.5%. Those with cervical progression were older (62.5 vs. 57.3, p = 0.04) with more nodes affected (12.1 vs. 2.8, p = 0.04) and had EBRT performed later following surgery (76.6 vs. 64 months, p = 0.05). EBRT associated with multikinase inhibitors showed longer overall survival than EBRT alone (64.3 vs. 37.9, p = 0.018) and better local disease control. Performing EBRT before radioiodine (RAI) was associated with longer cervical progression-free survival (CPFS) than was RAI before (67.5 vs. 34.5, p < 0.01). EBRT ≥2 years after surgery was associated with worse CPFS (4.9 vs. 34, p = 0.04). The most common molecular alterations were ERBB2, BRAF, FAT1, RET and ROS1 and TERT mutation was predictive of worse disease control after EBRT (p = 0.04). CONCLUSION: Younger patients, with fewer affected nodes and treated earlier after surgery had better cervical disease control. Combination of EBRT with MKI improved OS. TERT mutation might indicate worse responders to EBRT; however, further studies are necessary to clarify the role of molecular testing in selecting candidates for cervical EBRT.

Impact of genetic background as a risk factor for atherosclerotic cardiovascular disease: A protocol for a nationwide genetic case-control (CV-GENES) study in Brazil.

Atherosclerotic Cardiovascular Disease (ASCVD) represents the leading cause of death worldwide, and individual screening should be based on behavioral, metabolic, and genetic profile derived from data collected in large population-based studies. Due to the polygenic nature of ASCVD, we aimed to assess the association of genomics with ASCVD risk and its impact on the occurrence of acute myocardial infarction, stroke, or peripheral artery thrombotic-ischemic events at population level. CardioVascular Genes (CV-GENES) is a nationwide, multicenter, 1:1 case-control study of 3,734 patients in Brazil. Inclusion criterion for cases is the first occurrence of one of the ASCVD events. Individuals without known ASCVD will be eligible as controls. A core lab will perform the genetic analyses through low-pass whole genome sequencing and whole exome sequencing. In order to estimate the independent association between genetic polymorphisms and ASCVD, a polygenic risk score (PRS) will be built through a hybrid approach including effect size of each Single Nucleotide Polymorphism (SNP), number of effect alleles observed, sample ploidy, total number of SNPs included in the PRS, and number of non-missing SNPs in the sample. In addition, the presence of pathogenic or likely pathogenic variants will be screened in 8 genes (ABCG5, ABCG8, APOB, APOE, LDLR, LDLRAP1, LIPA, PCSK9) associated with atherosclerosis. Multiple logistic regression will be applied to estimate adjusted odds ratios (OR) and 95% confidence intervals (CI), and population attributable risks will be calculated. Clinical trial registration: This study is registered in clinicaltrials.gov (NCT05515653).