When breaks get hot:inflammatory signaling in BRCA1/2-mutant cancers

Genomic instability and inflammation are intricately connected hallmark features of cancer. DNA repair defects due to BRCA1/2 mutation instigate immune signaling through the cGAS/STING pathway. The subsequent inflammatory signaling provides both tumor-suppressive as well as tumor-promoting traits. To prevent clearance by the immune system, genomically instable cancer cells need to adapt to escape immune surveillance. Currently, it is unclear how genomically unstable cancers, including BRCA1/2-mutant tumors, are rewired to escape immune clearance. Here, we summarize the mechanisms by which genomic instability triggers inflammatory signaling and describe adaptive mechanisms by which cancer cells can 'fly under the radar' of the immune system. Additionally, we discuss how therapeutic activation of the immune system may improve treatment of genomically instable cancers

Genomic instability, inflammatory signaling and response to cancer immunotherapy

Genomic and chromosomal instability are hallmarks of cancer and shape the genomic composition of cancer cells, thereby determining their behavior and response to treatment. Various genetic and epigenetic alterations in cancer have been linked to genomic instability, including DNA repair defects, oncogene-induced replication stress, and spindle assembly checkpoint malfunction. A consequence of genomic and chromosomal instability is the leakage of DNA from the nucleus into the cytoplasm, either directly or through the formation and subsequent rupture of micronuclei. Cytoplasmic DNA subsequently activates cytoplasmic DNA sensors, triggering downstream pathways, including a type I interferon response. This inflammatory signaling has pleiotropic effects, including enhanced anti-tumor immunity and potentially results in sensitization of cancer cells to immune checkpoint inhibitors. However, cancers frequently evolve mechanisms to avoid immune clearance, including suppression of inflammatory signaling. In this review, we summarize inflammatory signaling pathways induced by various sources of genomic instability, adaptation mechanisms that suppress inflammatory signaling, and implications for cancer immunotherapy

The effects of physical activity interventions on psychosocial outcomes in adolescents: A meta-analytic review

Physical activity interventions are often implemented in the adolescent mental health care practice to prevent or treat psychosocial problems. To date, no systematic review of the effect of these physical activity interventions in adolescents has been conducted. In the current study, four multilevel meta-analyses were performed to assess the overall effect of physical activity interventions on externalizing problems, internalizing problems, self-concept, and academic achievement in adolescents. In addition, possible moderating factors were examined. In total, 57 studies reporting on 216 effect sizes were included, and the results showed significant small-to-moderate effects of physical activity interventions on externalizing problems (d = 0.320), internalizing problems (d = 0.316), self-concept (d = 0.297), and academic achievement (d = 0.367). Further, moderator analyses showed that outcome, study, sample, and intervention characteristics influenced the effects of physical activity interventions on psychosocial outcomes. Implications for theory and practice concerning the use of physical activity interventions in adolescent mental health care practice are discussed

Modeling effects of rumination on free recall using ACT-R

Ruminative thinking, characterized by a recurrent focus on negative and self-related thought, is a key cognitive vulnerability marker of depression and, therefore, a key individual difference variable. This study aimed to develop a computational cognitive model of rumination focusing on the organization and retrieval of information in memory, and how these mechanisms differ in individuals prone to rumination and individuals less prone to rumination. Adaptive Control of Thought-Rational (ACT-R) was used to develop a rumination model by adding memory chunks with negative valence to the declarative memory. In addition, their strength of association was increased to simulate recurrent negative focus, thereby making it harder to disengage from. The ACT-R models were validated by comparing them against two empirical datasets containing data from control and depressed participants. Our general and ruminative models were able to recreate the benchmarks of free recall while matching the behavior exhibited by the control and the depressed participants, respectively. Our study shows that it is possible to build a computational theory of rumination that can accurately simulate the differences in free recall dynamics between control and depressed individuals. Such a model could enable a more fine-tuned investigation of underlying cognitive mechanisms of depression and potentially help to improve interventions by allowing them to more specifically target key mechanisms that instigate and maintain depression

Shaping the BRCAness mutational landscape by alternative double-strand break repair, replication stress and mitotic aberrancies

Tumours with mutations in the BRCA1/BRCA2 genes have impaired double-stranded DNA break repair, compromised replication fork protection and increased sensitivity to replication blocking agents, a phenotype collectively known as 'BRCAness'. Tumours with a BRCAness phenotype become dependent on alternative repair pathways that are error-prone and introduce specific patterns of somatic mutations across the genome. The increasing availability of next-generation sequencing data of tumour samples has enabled identification of distinct mutational signatures associated with BRCAness. These signatures reveal that alternative repair pathways, including Polymerase θ-mediated alternative end-joining and RAD52-mediated single strand annealing are active in BRCA1/2-deficient tumours, pointing towards potential therapeutic targets in these tumours. Additionally, insight into the mutations and consequences of unrepaired DNA lesions may also aid in the identification of BRCA-like tumours lacking BRCA1/BRCA2 gene inactivation. This is clinically relevant, as these tumours respond favourably to treatment with DNA-damaging agents, including PARP inhibitors or cisplatin, which have been successfully used to treat patients with BRCA1/2-defective tumours. In this review, we aim to provide insight in the origins of the mutational landscape associated with BRCAness by exploring the molecular biology of alternative DNA repair pathways, which may represent actionable therapeutic targets in in these cells

Moreel kompas: een onderzoek naar de determinanten van integer handelen van politiemedewerkers

Criminal Justice: Legitimacy, accountability, and effectivit

Impact of nutritional status and body composition on postoperative outcomes after pelvic exenteration for locally advanced and locally recurrent rectal cancer

BACKGROUND: Pelvic exenteration for locally advanced rectal cancer (LARC) and locally recurrent (LRRC) rectal cancer provides radical resection and local control, but is associated with considerable morbidity. The aim of this study was to determine risk factors, including nutritional status and body composition, for postoperative morbidity and survival after pelvic exenteration in patients with LARC or LRRC. METHODS: Patients with LARC or LRRC who underwent total or posterior pelvic exenteration in a tertiary referral centre from 2003 to 2018 were analysed retrospectively. Nutritional status was assessed using the Malnutrition Universal Screening Tool (MUST). Body composition was estimated using standard-of-care preoperative CT of the abdomen. Logistic regression analyses were performed to identify risk factors for complications with a Clavien-Dindo grade of III or higher. Risk factors for impaired overall survival were calculated using Cox proportional hazards analysis. RESULTS: In total, 227 patients who underwent total (111) or posterior (116) pelvic exenteration were analysed. Major complications (Clavien-Dindo grade at least III) occurred in 82 patients (36.1 per cent). High risk of malnutrition (MUST score 2 or higher) was the only risk factor for major complications (odds ratio 3.99, 95 per cent c.i. 1.76 to 9.02) in multivariable analysis. Mean follow-up was 44.6 months. LRRC (hazard ratio (HR) 1.61, 95 per cent c.i. 1.04 to 2.48) and lymphovascular invasion (HR 2.20, 1.38 to 3.51) were independent risk factors for impaired overall survival. CONCLUSION: A high risk of malnutrition according to the MUST is a strong risk factor for major complications in patients with LARC or LRRC undergoing exenteration surgery