Micronuclear collapse from oxidative damage.

Chromosome-containing micronuclei are a hallmark of aggressive cancers. Micronuclei frequently undergo irreversible collapse, exposing their enclosed chromatin to the cytosol. Micronuclear rupture catalyzes chromosomal rearrangements, epigenetic abnormalities, and inflammation, yet mechanisms safeguarding micronuclear integrity are poorly understood. In this study, we found that mitochondria-derived reactive oxygen species (ROS) disrupt micronuclei by promoting a noncanonical function of charged multivesicular body protein 7 (CHMP7), a scaffolding protein for the membrane repair complex known as endosomal sorting complex required for transport III (ESCRT-III). ROS retained CHMP7 in micronuclei while disrupting its interaction with other ESCRT-III components. ROS-induced cysteine oxidation stimulated CHMP7 oligomerization and binding to the nuclear membrane protein LEMD2, disrupting micronuclear envelopes. Furthermore, this ROS-CHMP7 pathological axis engendered chromosome shattering known to result from micronuclear rupture. It also mediated micronuclear disintegrity under hypoxic conditions, linking tumor hypoxia with downstream processes driving cancer progression.

Harvest of epithelialized gingival grafts without application of hemostatic sutures: A randomized clinical trial using laser speckle contrast imaging.

BACKGROUND: This randomized controlled trial with two parallel arms and a 1:1 allocation ratio aimed to compare early microvascular healing (primary outcome), surgical times, and patient-reported outcomes (PROM) after harvesting palatal epithelialized gingival grafts (EGG), where hemostasis was achieved with sutures and hemostatic sponges (control) or with a sutureless approach (test). METHODS: From a total of 33 patients, 34 EGG were harvested. Thirty-two were randomized to the test/control group (n = 16) and two were excluded. Early palatal microvascular healing was assessed at 7, 14, and 30 days with laser speckle contrast imaging (LSCI). Postoperative bleeding, pain, discomfort, and analgesic consumption were assessed over 2 weeks with a dedicated questionnaire. RESULTS: A faster onset and resolution of postharvest hyperemia was observed in the test group where peak blood flow was reached at 7 days. No significant blood flow differences were observed between the groups at any of the evaluated timepoints. The mean surgical time was 13 min shorter in the test (p = 0.00). No significant differences were observed for postoperative bleeding and analgesic consumption at any timepoint. CONCLUSIONS: The tested approach represents a viable alternative to the standard one, providing no relevant differences in microvascular, clinical, and patient-related results, but with significantly shorter surgical times.

Profiling of the genetic features of patients with breast, ovarian, colorectal and extracolonic cancers: Association to CHEK2 and PALB2 germline mutations.

BACKGROUND AND AIMS: Cancer predisposition goes beyond BRCA and DNA Mismatch Repair (MMR) genes since multi-gene panel testing has become the routine diagnostic tool for hereditary cancer suspicion (HCS) cases. CHEK2 and PALB2 are some of the foremost-mutated non-BRCA/MMR actionable genes in families with a significant familial aggregation. Therefore, the purpose of this work is to unravel which tumours other than breast, ovary or colorectal display the patients. MATERIALS AND METHODS: We have analysed 528 probands that meet the inclusion criteria for Hereditary Breast and Ovarian Cancer and Lynch Syndrome established by our Hereditary Cancer Regional Program with a customized 35 genes-panel by using Ion Torrent™ Technology. RESULTS: We have identified pathogenic variants (PVs) in 61 families (1.55%), of which more than half (31 probands) harboured PVs in CHEK2 and PALB2 genes. Ours results reveal that not only were PVs CHEK2 and PALB2 carriers more likely to have family history of cancer not limited to breast, ovarian or colorectal cancers, but also they are prone to other extracolonic cancers, noteworthy endometrial and gastric cancers. CONCLUSIONS: Multigene panel testing improves the chance of finding PVs in actionable genes in families with HCS. In addition, the coexistence of variants should be recorded to implement a polygenic risk algorithm that might explain the missing heritability in the aforementioned families.

Non-cell-autonomous cancer progression from chromosomal instability.

Chromosomal instability (CIN) is a driver of cancer metastasis1-4, yet the extent to which this effect depends on the immune system remains unknown. Using ContactTracing-a newly developed, validated and benchmarked tool to infer the nature and conditional dependence of cell-cell interactions from single-cell transcriptomic data-we show that CIN-induced chronic activation of the cGAS-STING pathway promotes downstream signal re-wiring in cancer cells, leading to a pro-metastatic tumour microenvironment. This re-wiring is manifested by type I interferon tachyphylaxis selectively downstream of STING and a corresponding increase in cancer cell-derived endoplasmic reticulum (ER) stress response. Reversal of CIN, depletion of cancer cell STING or inhibition of ER stress response signalling abrogates CIN-dependent effects on the tumour microenvironment and suppresses metastasis in immune competent, but not severely immune compromised, settings. Treatment with STING inhibitors reduces CIN-driven metastasis in melanoma, breast and colorectal cancers in a manner dependent on tumour cell-intrinsic STING. Finally, we show that CIN and pervasive cGAS activation in micronuclei are associated with ER stress signalling, immune suppression and metastasis in human triple-negative breast cancer, highlighting a viable strategy to identify and therapeutically intervene in tumours spurred by CIN-induced inflammation.

Epigenetic dysregulation from chromosomal transit in micronuclei.

Chromosomal instability (CIN) and epigenetic alterations are characteristics of advanced and metastatic cancers1-4, but whether they are mechanistically linked is unknown. Here we show that missegregation of mitotic chromosomes, their sequestration in micronuclei5,6 and subsequent rupture of the micronuclear envelope7 profoundly disrupt normal histone post-translational modifications (PTMs), a phenomenon conserved across humans and mice, as well as in cancer and non-transformed cells. Some of the changes in histone PTMs occur because of the rupture of the micronuclear envelope, whereas others are inherited from mitotic abnormalities before the micronucleus is formed. Using orthogonal approaches, we demonstrate that micronuclei exhibit extensive differences in chromatin accessibility, with a strong positional bias between promoters and distal or intergenic regions, in line with observed redistributions of histone PTMs. Inducing CIN causes widespread epigenetic dysregulation, and chromosomes that transit in micronuclei experience heritable abnormalities in their accessibility long after they have been reincorporated into the primary nucleus. Thus, as well as altering genomic copy number, CIN promotes epigenetic reprogramming and heterogeneity in cancer.

Sending of Unwanted Dick Pics as a Modality of Sexual Cyber-Violence: An Exploratory Study of Its Emotional Impact and Reactions in Women.

The sending of sexually explicit images by men to women without prior request, a practice commonly referred to as sending or receiving a "dick pic," is a fairly common manifestation of sexual cyber-violence that has grown in recent times. As research on this type of sexual cyber-violence is limited, the current study analyzed the prevalence of this phenomenon in a sample of 347 Spanish women between 18 and 30 years of age, studying the factors that influence the emotional impact reported by women if they received an unsolicited dick pic (using a hypothetical scenario) and exploring the various coping strategies that women would use in that situation. Results showed a significant prevalence of this type of cyber-violence in the sample, as 48.1% of the participants had received an unsolicited dick pic from an unknown man at some point. Women with lower levels of hostile sexism-but not of benevolent sexism-reported a higher depressed and angry/annoyed emotional impact of the sexual cyber-violence scenario. This was also the case for women with a less conservative political ideology, with less religious beliefs, as well as those women who perceived that their female friends receive this type of images frequently (descriptive norm) and who perceived that their female friends are less accepting of these situations (injunctive norm). In addition, from the strategies presented to the participants to cope with this situation of sexual cyber-violence, it was observed that a significant percentage of women would choose strategies, such as talking about the incident with other people and blocking the sender's access. Yet, fewer women would employ effective strategies, such as reporting the perpetrator's profile to the managers or administrators of the social network or reporting the incident to the police. This study is one of the first studies in Spain that addresses this new form of sexual cyber-violence against women by unknown men and suggests that, in online social networks, women experience the same situations of abuse, harassment, and sexual objectification that they have faced offline in everyday life. Therefore, more work needs to be done to raise awareness and try to prevent these situations, while also providing more support to these women so that they can adopt effective coping strategies.

Multiomics insights on the onset, progression, and metastatic evolution of breast cancer.

Breast cancer is the most common malignant neoplasm in women. Despite progress to date, 700,000 women worldwide died of this disease in 2020. Apparently, the prognostic markers currently used in the clinic are not sufficient to determine the most appropriate treatment. For this reason, great efforts have been made in recent years to identify new molecular biomarkers that will allow more precise and personalized therapeutic decisions in both primary and recurrent breast cancers. These molecular biomarkers include genetic and post-transcriptional alterations, changes in protein expression, as well as metabolic, immunological or microbial changes identified by multiple omics technologies (e.g., genomics, epigenomics, transcriptomics, proteomics, glycomics, metabolomics, lipidomics, immunomics and microbiomics). This review summarizes studies based on omics analysis that have identified new biomarkers for diagnosis, patient stratification, differentiation between stages of tumor development (initiation, progression, and metastasis/recurrence), and their relevance for treatment selection. Furthermore, this review highlights the importance of clinical trials based on multiomics studies and the need to advance in this direction in order to establish personalized therapies and prolong disease-free survival of these patients in the future.

A Large Case-Control Study Performed in Spanish Population Suggests That RECQL5 Is the Only RECQ Helicase Involved in Breast Cancer Susceptibility.

Around 50% of the familial breast cancer (BC) cases are estimated to be caused by germline variants in known low-, moderate-, and high-risk susceptibility genes, while the other half is of unknown genetic origin. In the present study, we wanted to evaluate the role of the RECQ helicases, some of which have been studied in the past as candidates, with unclear results about their role in the disease. Using next-generation sequencing (NGS) technology, we analyzed the whole coding sequence of BLM, RECQL1, RECQL4, RECQL5, and WRN in almost 2000 index cases from BC Spanish families that had previously tested negative for the known BC susceptibility genes (BRCAX) and compared the results with the controls extracted from gnomAD. Our results suggest that BLM, RECQL1, RECQL4, and WRN do not play a major role in BC susceptibility. However, in the combined analysis, joining the present results with those previously reported in a series of 1334 BC Spanish patients and controls, we found a statistically significant association between Loss of Function (LoF) variants in RECQL5 and BC risk, with an OR of 2.56 (p = 0.009; 95% CI, 1.18-4.98). Our findings support our previous work and places the RECQL5 gene as a new moderate-risk BC gene.

Increased Co-Occurrence of Pathogenic Variants in Hereditary Breast and Ovarian Cancer and Lynch Syndromes: A Consequence of Multigene Panel Genetic Testing?

The probability of carrying two pathogenic variants (PVs) in dominant cancer-predisposing genes for hereditary breast and ovarian cancer and lynch syndromes in the same patient is uncommon, except in populations where founder effects exist. Two breast cancer women that are double heterozygotes (DH) for both BRCA1/BRCA2, one ovarian cancer case DH for BRCA1/RAD51C, and another breast and colorectal cancer who is DH for BRCA2/PMS2 were identified in our cohort. Ages at diagnosis and severity of disease in BRCA1/BRCA2 DH resembled BRCA1 single-carrier features. Similarly, the co-existence of the BRCA2 and PMS2 mutations prompted the development of breast and colorectal cancer in the same patient. The first BRCA1/BRCA2 DH was identified by HA-based and Sanger sequencing (1 of 623 families with BRCA PVs). However, this ratio has increased up to 2.9% (1 DH carrier vs. 103 single PV carriers) since using a custom 35-cancer gene on-demand panel. The type of cancer developed in each DH patient was consistent with the independently inherited condition, and the clinical outcome was no worse than in patients with single BRCA1 mutations. Therefore, the clinical impact, especially in patients with two hereditary syndromes, lies in genetic counseling tailor-made for each family based on the clinical guidelines for each syndrome. The number of DH is expected to be increased in the future as a result of next generation sequencing routines.

Minigene-based splicing analysis and ACMG/AMP-based tentative classification of 56 ATM variants.

The ataxia telangiectasia-mutated (ATM) protein is a major coordinator of the DNA damage response pathway. ATM loss-of-function variants are associated with 2-fold increased breast cancer risk. We aimed at identifying and classifying spliceogenic ATM variants detected in subjects of the large-scale sequencing project BRIDGES. A total of 381 variants at the intron-exon boundaries were identified, 128 of which were predicted to be spliceogenic. After further filtering, we ended up selecting 56 variants for splicing analysis. Four functional minigenes (mgATM) spanning exons 4-9, 11-17, 25-29, and 49-52 were constructed in the splicing plasmid pSAD. Selected variants were genetically engineered into the four constructs and assayed in MCF-7/HeLa cells. Forty-eight variants (85.7%) impaired splicing, 32 of which did not show any trace of the full-length (FL) transcript. A total of 43 transcripts were identified where the most prevalent event was exon/multi-exon skipping. Twenty-seven transcripts were predicted to truncate the ATM protein. A tentative ACMG/AMP (American College of Medical Genetics and Genomics/Association for Molecular Pathology)-based classification scheme that integrates mgATM data allowed us to classify 29 ATM variants as pathogenic/likely pathogenic and seven variants as likely benign. Interestingly, the likely pathogenic variant c.1898+2T>G generated 13% of the minigene FL-transcript due to the use of a noncanonical GG-5'-splice-site (0.014% of human donor sites). Circumstantial evidence in three ATM variants (leakiness uncovered by our mgATM analysis together with clinical data) provides some support for a dosage-sensitive expression model in which variants producing ≥30% of FL-transcripts would be predicted benign, while variants producing ≤13% of FL-transcripts might be pathogenic. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Anxiety and intimate relationships in times of lockdown due to COVID-19.

OBJECTIVE: The virulence of COVID-19 has been particularly problematic in countries such as Spain. This led the government to decide that the population should be locked down at home to reduce the spread of the disease and avoid the collapse of the health system. Considering this, this study analyzed the changes in intimate relationships that occurred during lockdown in terms of dyadic adjustment, conflict, and quality of the relationship, as well as their relationship with anxiety symptoms. METHOD: Cross-sectional questionnaire-based study with adults (N = 342) aged 20-67 years who lived in Spain. Each participant completed self-report measures of anxiety (State-Trait Anxiety Inventory state and trait subscales), dyadic adjustment (Dyadic Adjustment Scale), relationship conflict and quality, and sociodemographic variables. RESULTS: The results showed significant levels of state anxiety, which was associated with poorer dyadic adjustment and a decrease in the perceived quality of relationships since the start of lockdown. Increased partner conflict seems to be an important predictor of dyadic adjustment and relationship quality during social isolation. CONCLUSIONS: This study suggests that the COVID-19 pandemic has negatively affected the mental health of the population, especially women. This finding is closely associated with difficulties with one's cohabiting partner (e.g., worse dyadic adjustment), but the most determining factor seems to be the previous state of the relationship. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Effect of the Lockdown Due to COVID-19 on Sexuality: The Mediating Role of Sexual Practices and Arousal in the Relationship Between Gender and Sexual Self-Esteem.

The scientific evidence suggests that COVID-19 is affecting much more than the physical health of individuals, particularly in places where a lockdown has been established to slow down the spread of the virus. An area that may be particularly affected is human sexuality. This study explored the impact of the situation generated by COVID-19 on the sexuality of 201 adults living in Spain. We collected data cross-sectionally through an online survey during the month of April 2020. Results showed a reduction of sexual self-esteem and a decrease in the number of interpersonal sexual relations, although the frequency of masturbation and the consumption of pornography did not vary compared to previous levels. A regression analysis showed that masturbation, the ability to maintain sexual arousal and interpersonal sex were mediating variables in the relationship between gender - specifically being male - and having higher sexual self-esteem during the lockdown. This study provides new insight on the relevance of certain sexual behaviors in a pandemic situation with considerable social restrictions and on the effect of this situation on sexual self-esteem and arousal. It brings some clarity on the relationship between sexual self-esteem and gender, about which there is currently no consensus in the scientific literature.

Loss of polycomb repressive complex 1 activity and chromosomal instability drive uveal melanoma progression.

Chromosomal instability (CIN) and epigenetic alterations have been implicated in tumor progression and metastasis; yet how these two hallmarks of cancer are related remains poorly understood. By integrating genetic, epigenetic, and functional analyses at the single cell level, we show that progression of uveal melanoma (UM), the most common intraocular primary cancer in adults, is driven by loss of Polycomb Repressive Complex 1 (PRC1) in a subpopulation of tumor cells. This leads to transcriptional de-repression of PRC1-target genes and mitotic chromosome segregation errors. Ensuing CIN leads to the formation of rupture-prone micronuclei, exposing genomic double-stranded DNA (dsDNA) to the cytosol. This provokes tumor cell-intrinsic inflammatory signaling, mediated by aberrant activation of the cGAS-STING pathway. PRC1 inhibition promotes nuclear enlargement, induces a transcriptional response that is associated with significantly worse patient survival and clinical outcomes, and enhances migration that is rescued upon pharmacologic inhibition of CIN or STING. Thus, deregulation of PRC1 can promote tumor progression by inducing CIN and represents an opportunity for early therapeutic intervention.

Association of CNR1 and INSIG2 polymorphisms with antipsychotics-induced weight gain: a prospective nested case-control study.

Weight gain is a frequent and severe adverse reaction in patients taking antipsychotics. The objective was to further investigate in a natural setting influential risk factors associated with clinically significant weight gain. An observational follow-up study was conducted. Patients when initiating treatment with whatever antipsychotic were included; a structured questionnaire was applied at baseline, 3 and 6 months later; a blood sample was obtained. In a nested case-control approach, patients with an increase ≥ 7% of their initial weight were considered as cases, the remaining, as controls. The results showed that, out of 185 patients, 137 completed the 6-month follow-up (cases, 38; controls, 99). Weight gain gradually and significantly increased in cases (baseline, 65.0 kg; 6 months, 74.0 kg) but not in controls (65.6 kg and 65.8 kg, respectively). Age (adjusted OR = 0.97, 95% CI = 0.96-0.99, p = 0.004), olanzapine (adjusted OR = 2.98, 95% CI = 1.13-7.80, p = 0.027) and quetiapine (adjusted OR = 0.25, 95% = 0.07-0.92, p = 0.037) significantly associated with weight gain. An association was also found for the CNR1 (rs1049353) and INSIG2 (rs7566605) polymorphisms. In conclusion, an increased risk of antipsychotics-induced weight gain was observed for younger age and olanzapine, and a relative lower risk for quetiapine. A potential role of CNR1 rs1049353 and INSIG2 rs7566605 polymorphisms is suggested.

ARID1A genomic alterations driving microsatellite instability through somatic MLH1 methylation with response to immunotherapy in metastatic lung adenocarcinoma: a case report.

BACKGROUND: Tumor molecular screening allows categorization of molecular alterations to select the best therapeutic strategy. AT-rich interactive domain-containing 1A (ARID1A) gene mutations are present in gastric, endometrial, and clear cell ovarian tumors. Inactivation of this gene impairs mismatch repair (MMR) machinery leading to an increased mutation burden that correlates with microsatellite instability (MSI), associated with tumor-infiltrating lymphocytes and programmed death ligand 1 (PD-L1) expression. This is the first case report in lung adenocarcinoma of ARID1A gene alterations leading to sporadic MSI, through somatic mutL homolog 1 (MLH1) promoter methylation, with an MLH1 gene mutation as the second somatic hit. CASE PRESENTATION: A 50-year-old never-smoker Bulgarian woman, with no comorbidities and no family history of cancer, was diagnosed with metastatic lung adenocarcinoma. PD-L1 immunohistochemistry (IHC) of tissue biopsies on right groin adenopathies resulted in 30% positivity. Liquid biopsy test reported actionable alterations in ARID1A gene, rearranged during transfection (RET) gene fusions, epidermal growth factor receptor (EGFR) gene R776H mutation, breast cancer (BRCA) genes 1/2, and cyclin-dependent kinase inhibitor 2A (CDKN2A) gene mutations. The patient was treated with immunotherapy, and showed a treatment response lasting for 19 months until a new metastasis appeared at the right deltoid muscle. Genomic analysis of a sample of this metastasis confirmed PD-L1 positivity of greater than 50% with CD8+ T cells expression and showed MSI with a deleterious c.298C>T (p.R100*) MLH1 gene mutation. Multiplex ligation-dependent probe amplification (MLPA) of this sample unveiled MLH1 gene promoter methylation. The MLH1 gene mutation and the MLH1 gene methylation were not present at the germline setting. CONCLUSIONS: In this particular case, we show that ARID1A gene mutations with sporadic MSI due to somatic MLH1 gene promoter methylation and MLH1 gene mutation could change the prognosis and define the response to immunotherapy in a patient with lung adenocarcinoma. Comprehensive solid and liquid biopsy tests are useful to find out resistance mechanisms to immune checkpoint inhibitors. Our data encourages the development of new therapies against ARID1A mutations and epigenomic methylation when involved in MSI neoplasms.

Metastasis and Immune Evasion from Extracellular cGAMP Hydrolysis.

Cytosolic DNA is characteristic of chromosomally unstable metastatic cancer cells, resulting in constitutive activation of the cGAS-STING innate immune pathway. How tumors co-opt inflammatory signaling while evading immune surveillance remains unknown. Here, we show that the ectonucleotidase ENPP1 promotes metastasis by selectively degrading extracellular cGAMP, an immune-stimulatory metabolite whose breakdown products include the immune suppressor adenosine. ENPP1 loss suppresses metastasis, restores tumor immune infiltration, and potentiates response to immune checkpoint blockade in a manner dependent on tumor cGAS and host STING. Conversely, overexpression of wild-type ENPP1, but not an enzymatically weakened mutant, promotes migration and metastasis, in part through the generation of extracellular adenosine, and renders otherwise sensitive tumors completely resistant to immunotherapy. In human cancers, ENPP1 expression correlates with reduced immune cell infiltration, increased metastasis, and resistance to anti-PD-1/PD-L1 treatment. Thus, cGAMP hydrolysis by ENPP1 enables chromosomally unstable tumors to transmute cGAS activation into an immune-suppressive pathway. SIGNIFICANCE: Chromosomal instability promotes metastasis by generating chronic tumor inflammation. ENPP1 facilitates metastasis and enables tumor cells to tolerate inflammation by hydrolyzing the immunotransmitter cGAMP, preventing its transfer from cancer cells to immune cells.This article is highlighted in the In This Issue feature, p. 995.

Hereditary Leiomyomatosis and Renal Cell Cancer Syndrome in Spain: Clinical and Genetic Characterization.

Hereditary leiomyomatosis and renal cell cancer syndrome (HLRCC) is a very rare hereditary disorder characterized by cutaneous leiomyomas (CLMs), uterine leiomyomas (ULMs), renal cysts (RCys) and renal cell cancers (RCCs). We aimed to describe the genetics, clinical features and potential genotype-phenotype associations in the largest cohort of fumarate hydratase enzyme mutation carriers known from Spain using a multicentre, retrospective study of individuals with a genetic or clinical diagnosis of HLRCC. We collected clinical information from medical records, analysed genetic variants and looked for genotype-phenotype associations. Analyses were performed using R 3.6.0. software. We included 197 individuals: 74 index cases and 123 relatives. CLMs were diagnosed in 65% of patients, ULMs in 90% of women, RCys in 37% and RCC in 10.9%. Twenty-seven different pathogenic variants were detected, 12 (44%) of them not reported previously. Patients with missense pathogenic variants showed higher frequencies of CLMs, ULMs and RCys, than those with loss-of-function variants (p = 0.0380, p = 0.0015 and p = 0.024, respectively). This is the first report of patients with HLRCC from Spain. The frequency of RCCs was lower than those reported in the previously published series. Individuals with missense pathogenic variants had higher frequencies of CLMs, ULMs and RCys.

Ciberviolencia en las relaciones de pareja: una revisión sobre su metodología de investigación / Cyber dating violence: A Review of Its Research Methodology

En los últimos años ha aumentado el interés por el estudio de la ciberviolencia en la pareja, sin embargo es necesario examinar la metodología de investigación que sustenta las evidencias obtenidas hasta el momento. Este artículo presenta una revisión sistemática de la literatura científica que analiza 30 instrumentos de medida de ciberviolencia en la pareja de adolescentes y jóvenes adultos utilizados a lo largo de estos años. Los principales resultados muestran una elevada pluralidad metodológica, conceptual y terminológica, observándose un reducido número de instrumentos con suficientes garantías psicométricas. Predominan los trabajos de procedencia estadounidense y, entre los instrumentos aplicados en muestras españolas, destaca una infrarrepresentación de indicadores de ciberviolencia de tipo sexual, lo que limita la comprensión de esta problemática. Esta investigación aporta información sobre el estado actual en el estudio de la ciberviolencia en la pareja y pone de relieve deficiencias metodológicas en la construcción del conocimiento en este campo de estudio. Este trabajo permite una mejor comprensión de la disparidad de resultados señalada por investigaciones previas, especialmente referidas a prevalencia, frecuencia y diferencias de género en este tipo de comportamientos violentos, además de sentar las bases para abordar el fenómeno desde el rigor científico

The interest for the study of the cyber dating abuse has increased in the last years; however, it is necessary to examine the research methodology that supports the evidence obtained so far. This paper presents a systematic review of the scientific literature that analyzes 30 measuring instruments of cyber dating abuse in adolescent and young adults used along these years. The main results show a methodological, conceptual and terminological plurality, observing a small number of instruments with sufficient psychometric guarantees. The instruments come mostly from the United States, and of the instruments applied to Spanish samples, few include indicators of sexual cyber dating abuse, which limits the understanding of this problem. This research provides information on the current status of the study of cyber dating abuse and highlights methodological shortcomings in the construction of knowledge in this field of study. This study allows a better understanding of the disparity of results indicated by previous research, especially referring to prevalence, frequency and gender differences in this type of violent behavior, as well as laying the foundations for addressing the phenomenon from scientific rigor

Germline Genetic Findings Which May Impact Therapeutic Decisions in Families with a Presumed Predisposition for Hereditary Breast and Ovarian Cancer.

In this study, we aim to gain insight in the germline mutation spectrum of ATM, BARD1, BRIP1, ERCC4, PALB2, RAD51C and RAD51D in breast and ovarian cancer families from Spain. We have selected 180 index cases in whom a germline mutation in BRCA1 and BRCA2 was previously ruled out. The importance of disease-causing variants in these genes lies in the fact that they may have possible therapeutic implications according to clinical guidelines. All variants were assessed by combined annotation dependent depletion (CADD) for scoring their deleteriousness. In addition, we used the cancer genome interpreter to explore the implications of some variants in drug response. Finally, we compiled and evaluated the family history to assess whether carrying a pathogenic mutation was associated with age at diagnosis, tumour diversity of the pedigree and total number of cancer cases in the family. Eight unequivocal pathogenic mutations were found and another fourteen were prioritized as possible causal variants. Some of these molecular results could contribute to cancer diagnosis, treatment selection and prevention. We found a statistically significant association between tumour diversity in the family and carrying a variant with a high score predicting pathogenicity (p = 0.0003).

A comprehensive custom panel evaluation for routine hereditary cancer testing: improving the yield of germline mutation detection.

BACKGROUND: In the context of our Regional Program of Hereditary Cancer, individuals fulfilling the criteria are tested for germline mutations to subsequently establish the clinical management. Our standard diagnostic approach focuses on sequencing a few classic high-risk genes, a method that frequently renders uninformative genetic results. This study aims to examine the improved yield offered by an On-Demand panel. METHODS: We designed an On-Demand panel for the analysis of 35-genes associated with inherited cancer susceptibility in a total of 128 cases of Hereditary Breast and Ovarian Cancer (HBOC) and Hereditary Nonpolyposis Colorectal Cancer (HNPCC). RESULTS: Eighteen deleterious mutations were detected, in both routinely (BRCA2, MLH1, MSH2, PMS2) and non-routinely (ATM, BLM, BRIP1, CHEK2, MUTYH) tested genes. The screening extended to 35 genes rendered by patients carrying several- up to 6-Variants of Unknown Significance (VUS). Moreover, we confirmed the splicing disruption at RNA level for a not previously reported BRIP1 splicing mutation. Using an On-Demand panel, we identified 18 pathogenic mutation carriers, seven of which would have gone unnoticed with traditional analysis. CONCLUSIONS: Our results reinforce the utility of NGS gene panels in the diagnostic routine to increase the performance of genetic testing, especially in individuals from families with overlapping cancer phenotypes.