Loss of nuclear DNA ligase III reverts PARP inhibitor resistance in BRCA1/53BP1 double-deficient cells by exposing ssDNA gaps.

Inhibitors of poly(ADP-ribose) (PAR) polymerase (PARPi) have entered the clinic for the treatment of homologous recombination (HR)-deficient cancers. Despite the success of this approach, preclinical and clinical research with PARPi has revealed multiple resistance mechanisms, highlighting the need for identification of novel functional biomarkers and combination treatment strategies. Functional genetic screens performed in cells and organoids that acquired resistance to PARPi by loss of 53BP1 identified loss of LIG3 as an enhancer of PARPi toxicity in BRCA1-deficient cells. Enhancement of PARPi toxicity by LIG3 depletion is dependent on BRCA1 deficiency but independent of the loss of 53BP1 pathway. Mechanistically, we show that LIG3 loss promotes formation of MRE11-mediated post-replicative ssDNA gaps in BRCA1-deficient and BRCA1/53BP1 double-deficient cells exposed to PARPi, leading to an accumulation of chromosomal abnormalities. LIG3 depletion also enhances efficacy of PARPi against BRCA1-deficient mammary tumors in mice, suggesting LIG3 as a potential therapeutic target.

Loss of p53 triggers WNT-dependent systemic inflammation to drive breast cancer metastasis.

Cancer-associated systemic inflammation is strongly linked to poor disease outcome in patients with cancer1,2. For most human epithelial tumour types, high systemic neutrophil-to-lymphocyte ratios are associated with poor overall survival3, and experimental studies have demonstrated a causal relationship between neutrophils and metastasis4,5. However, the cancer-cell-intrinsic mechanisms that dictate the substantial heterogeneity in systemic neutrophilic inflammation between tumour-bearing hosts are largely unresolved. Here, using a panel of 16 distinct genetically engineered mouse models for breast cancer, we uncover a role for cancer-cell-intrinsic p53 as a key regulator of pro-metastatic neutrophils. Mechanistically, loss of p53 in cancer cells induced the secretion of WNT ligands that stimulate tumour-associated macrophages to produce IL-1ß, thus driving systemic inflammation. Pharmacological and genetic blockade of WNT secretion in p53-null cancer cells reverses macrophage production of IL-1ß and subsequent neutrophilic inflammation, resulting in reduced metastasis formation. Collectively, we demonstrate a mechanistic link between the loss of p53 in cancer cells, secretion of WNT ligands and systemic neutrophilia that potentiates metastatic progression. These insights illustrate the importance of the genetic makeup of breast tumours in dictating pro-metastatic systemic inflammation, and set the stage for personalized immune intervention strategies for patients with cancer.

Intersections between disability, masculinities, and violence: experiences and insights from men with physical disabilities from three African countries.

BACKGROUND: Gender-transformative work in the Global South often focuses on transforming 'toxic masculinities' to prevent intimate partner violence (IPV), but there has been little research on whether and how constructions of masculinities by men with disabilities shape their experiences and perpetration of violence. METHODS: We used repeated in-depth interviews and content analysis to understand whether and how physical disability intersects with the construction of masculinities and experience/perpetration of violence among 15 adult men with physical disabilities participating in interventions to prevent IPV in Ghana, Rwanda, and South Africa. RESULTS: Societal expectations and participants' aspirations around masculinity impacted their vulnerability to violence mainly by men without disabilities. Participants reported experiences of disrespect and social exclusion in their communities and felt incapable of protecting themselves when being violated. Most participants felt they were not providing for their families and perceived themselves as having lost decision-making and positions of power in their homes. They expressed their disappointment with having reduced stamina, virility, and sexual prowess in intimate partnerships as a result of their disability. While participants reported that they could not attain key markers of idealized masculinity, placed upon and often internalized by themselves, they longed to achieve these markers to facilitate their inclusion and acceptance in their communities. CONCLUSIONS: Programmers addressing violence need to engage with men with physical disabilities and consider the intersectionality of masculinities and disability, how these reinforce patriarchal norms and how men with disabilities can be included and enabled to overcome their conflict between disability and masculinities.

In pursuit of intimacy: disability stigma, womanhood and intimate partnerships in South Africa.

Notions of womanhood inculcate naturalised ideologies of femininity, sexuality, motherhood and caregiving. The paper asks how disability stigma intersects with womanhood to characterise intimate partnerships in South Africa. In-depth interviews with 30 women with a range of disabilities were conducted in informal settlements in Cape Town. Findings suggest that disability stigma may hamper attainment of normative womanhood and sexual relationships for women with disabilities in South Africa. Limited opportunities to meet potential partners, hegemonic gender expectations and restricted sexual and physical contact shape their intimate partnerships. However, women with disabilities also challenge ableist constructs of normalcy and discredit negative images of disabled womanhood. Because of this, theoretical models of intimate partner violence should consider the influence of disability on constructions of sexuality and norms in intimate partnerships. Building on women with disabilities' stigma-avoidance strategies will help facilitate better relationship outcomes. Social norms interventions with broader society, communities, women with disabilities and their partners, family and carers can help destabilise assumptions that women with disabilities are unable to have long-lasting and fulfilling sexual and intimate partnerships. Moreover, accessible and relevant sexuality education and information on relationships, intimate partner violence, maternal and sexual and reproductive health care can ensure healthy and safe intimate partnerships for women with disabilities.

Psychosocial group interventions to improve psychological well-being in adults living with HIV.

BACKGROUND: Being diagnosed with human immunodeficiency virus (HIV), and labelled with a chronic, life-threatening, and often stigmatizing disease, can impact on a person's well-being. Psychosocial group interventions aim to improve life-functioning and coping as individuals adjust to the diagnosis. OBJECTIVES: To examine the effectiveness of psychosocial group interventions for improving the psychological well-being of adults living with HIV/AIDS. SEARCH METHODS: We searched the following electronic databases up to 14 March 2016: the Cochrane Central Register of Controlled Trials (CENTRAL) published in the Cochrane Library (Issue 2, 2016), PubMed (MEDLINE) (1996 to 14 March 2016), Embase (1996 to 14 March 2016), and Clinical Trials.gov. SELECTION CRITERIA: Randomized controlled trials (RCTs) or quasi-RCTs that compared psychosocial group interventions with versus control (standard care or brief educational interventions), with at least three months follow-up post-intervention. We included trials that reported measures of depression, anxiety, stress, or coping using standardized scales. DATA COLLECTION AND ANALYSIS: Two review authors independently screened abstracts, applied the inclusion criteria, and extracted data. We compared continuous outcomes using mean differences (MD) with 95% confidence intervals (95% CIs), and pooled data using a random-effects model. When the included trials used different measurement scales, we pooled data using standardized mean difference (SMD) values. We reported trials that we could not include in the meta analysis narratively in the text. We assessed the certainty of the evidence using the GRADE approach. MAIN RESULTS: We included 16 trials (19 articles) that enrolled 2520 adults living with HIV. All the interventions were multifaceted and included a mix of psychotherapy, relaxation, group support, and education. The included trials were conducted in the USA (12 trials), Canada (one trial), Switzerland (one trial), Uganda (one trial), and South Africa (one trial), and published between 1996 and 2016. Ten trials recruited men and women, four trials recruited homosexual men, and two trials recruited women only. Interventions were conducted with groups of four to 15 people, for 90 to 135 minutes, every week for up to 12 weeks. All interventions were conducted face-to-face except two, which were delivered by telephone. All were delivered by graduate or postgraduate trained health, psychology, or social care professionals except one that used a lay community health worker and two that used trained mindfulness practitioners.Group-based psychosocial interventions based on cognitive behavioural therapy (CBT) may have a small effect on measures of depression, and this effect may last for up to 15 months after participation in the group sessions (SMD -0.26, 95% CI -0.42 to -0.10; 1139 participants, 10 trials, low certainty evidence). Most trials used the Beck Depression Inventory (BDI), which has a maximum score of 63, and the mean score in the intervention groups was around 1.4 points lower at the end of follow-up. This small benefit was consistent across five trials where participants had a mean depression score in the normal range at baseline, but trials where the mean score was in the depression range at baseline effects were less consistent. Fewer trials reported measures of anxiety, where there may be little or no effect (four trials, 471 participants, low certainty evidence), stress, where there may be little or no effect (five trials, 507 participants, low certainty evidence), and coping (five trials, 697 participants, low certainty evidence).Group-based interventions based on mindfulness have not demonstrated effects on measures of depression (SMD -0.23, 95% CI -0.49 to 0.03; 233 participants, 2 trials, very low certainty evidence), anxiety (SMD -0.16, 95% CI -0.47 to 0.15; 62 participants, 2 trials, very low certainty evidence), or stress (MD -2.02, 95% CI -4.23 to 0.19; 137 participants, 2 trials, very low certainty evidence). No mindfulness based interventions included in the studies had any valid measurements of coping. AUTHORS' CONCLUSIONS: Group-based psychosocial interventions may have a small effect on measures of depression, but the clinical importance of this is unclear. More high quality evidence is needed to assess whether group psychosocial intervention improve psychological well-being in HIV positive adults.

'Something for something': the importance of talking about transactional sex with youth in South Africa using a resilience-based approach.

Transactional sex is a common feature of sexual relationships in South Africa but has severe health implications for those who engage in it. This paper presents perspectives on transactional sex based on interviews and focus group discussions with young people in Gauteng and Limpopo, South Africa. The discussions were part of an evaluation of a peer education programme promoting HIV prevention called Vhutshilo, aimed at 14-16 year olds. The session on transactional sex entitled 'Something for Something' evoked strong responses from youth. Youth recognised transactional sex as a common phenomenon in their communities and associated it with many risks. However, when comparing young people's qualitative responses to the impact of the session as measured by the quantitative impact survey, no significant differences were discernible between youth in the programme and those in a control group who were not exposed to the session. Further analysis showed that the content of the session was limited to the negative consequences and health risks of transactional sex and focused mostly on the adverse contexts in South Africa that force youth into such relationships. The session did little to situate transactional relationships within the everyday realities of sexual decision making and youth values of peer status and consumerism. We argue that the session's findings reveal a narrow understanding of the dynamic contexts under which transactional sex occurs and fails to take into account the resilience of youth to make choices of whether or not to engage in such relationships, and how they can engage in these types of relationships safely. We conclude that HIV prevention curriculums need to leverage youth resilience and protective skills within the confines of difficult economic and social circumstances to allow them to successfully navigate safer sexual relationships.

FIRRM/C1orf112 mediates resolution of homologous recombination intermediates in response to DNA interstrand crosslinks.

DNA interstrand crosslinks (ICLs) pose a major obstacle for DNA replication and transcription if left unrepaired. The cellular response to ICLs requires the coordination of various DNA repair mechanisms. Homologous recombination (HR) intermediates generated in response to ICLs, require efficient and timely conversion by structure-selective endonucleases. Our knowledge on the precise coordination of this process remains incomplete. Here, we designed complementary genetic screens to map the machinery involved in the response to ICLs and identified FIRRM/C1orf112 as an indispensable factor in maintaining genome stability. FIRRM deficiency leads to hypersensitivity to ICL-inducing compounds, accumulation of DNA damage during S-G2 phase of the cell cycle, and chromosomal aberrations, and elicits a unique mutational signature previously observed in HR-deficient tumors. In addition, FIRRM is recruited to ICLs, controls MUS81 chromatin loading, and thereby affects resolution of HR intermediates. FIRRM deficiency in mice causes early embryonic lethality and accelerates tumor formation. Thus, FIRRM plays a critical role in the response to ICLs encountered during DNA replication.

Multi-omics analysis reveals distinct non-reversion mechanisms of PARPi resistance in BRCA1- versus BRCA2-deficient mammary tumors.

BRCA1 and BRCA2 both function in DNA double-strand break repair by homologous recombination (HR). Due to their HR defect, BRCA1/2-deficient cancers are sensitive to poly(ADP-ribose) polymerase inhibitors (PARPis), but they eventually acquire resistance. Preclinical studies yielded several PARPi resistance mechanisms that do not involve BRCA1/2 reactivation, but their relevance in the clinic remains elusive. To investigate which BRCA1/2-independent mechanisms drive spontaneous resistance in vivo, we combine molecular profiling with functional analysis of HR of matched PARPi-naive and PARPi-resistant mouse mammary tumors harboring large intragenic deletions that prevent reactivation of BRCA1/2. We observe restoration of HR in 62% of PARPi-resistant BRCA1-deficient tumors but none in the PARPi-resistant BRCA2-deficient tumors. Moreover, we find that 53BP1 loss is the prevalent resistance mechanism in HR-proficient BRCA1-deficient tumors, whereas resistance in BRCA2-deficient tumors is mainly induced by PARG loss. Furthermore, combined multi-omics analysis identifies additional genes and pathways potentially involved in modulating PARPi response.

Comprehensive characterization of pre- and post-treatment samples of breast cancer reveal potential mechanisms of chemotherapy resistance.

When locally advanced breast cancer is treated with neoadjuvant chemotherapy, the recurrence risk is significantly higher if no complete pathologic response is achieved. Identification of the underlying resistance mechanisms is essential to select treatments with maximal efficacy and minimal toxicity. Here we employed gene expression profiles derived from 317 HER2-negative treatment-naïve breast cancer biopsies of patients who underwent neoadjuvant chemotherapy, deep whole exome, and RNA-sequencing profiles of 22 matched pre- and post-treatment tumors, and treatment outcome data to identify biomarkers of response and resistance mechanisms. Molecular profiling of treatment-naïve breast cancer samples revealed that expression levels of proliferation, immune response, and extracellular matrix (ECM) organization combined predict response to chemotherapy. Triple negative patients with high proliferation, high immune response and low ECM expression had a significantly better treatment response and survival benefit (HR 0.29, 95% CI 0.10-0.85; p = 0.02), while in ER+ patients the opposite was seen (HR 4.73, 95% CI 1.51-14.8; p = 0.008). The characterization of paired pre-and post-treatment samples revealed that aberrations of known cancer genes were either only present in the pre-treatment sample (CDKN1B) or in the post-treatment sample (TP53, APC, CTNNB1). Proliferation-associated genes were frequently down-regulated in post-treatment ER+ tumors, but not in triple negative tumors. Genes involved in ECM were upregulated in the majority of post-chemotherapy samples. Genomic and transcriptomic differences between pre- and post-chemotherapy samples are common and may reveal potential mechanisms of therapy resistance. Our results show a wide range of distinct, but related mechanisms, with a prominent role for proliferation- and ECM-related genes.

Peer victimization and experiences of violence at school and at home among school age children with disabilities in Pakistan and Afghanistan.

Background: Children with disabilities are more likely to experience violence or injury at school and at home, but there is little evidence from Central Asia. Objective: To describe the prevalence of disability and associations with peer violence perpetration and victimization, depression, corporal punishment, school performance and school attendance, among middle school children in Pakistan and Afghanistan. Method: This is a secondary analysis of data gathered in the course of evaluations of interventions to prevent peer violence conducted in Pakistan and Afghanistan as part of the 'What Works to Prevent Violence against Women and Girls Global Programme'. In Pakistan, the research was conducted in 40 schools, and disability was assessed at midline in 1516 interviews with Grade 7s. In Afghanistan, the data were from the baseline study conducted in 11 schools with 770 children. Generalized Linear Mixed Modeling was used to assess associations with disability. Results: In Afghanistan, the prevalence of disability was much higher for girls (22.1%) than boys (12.9%), while in Pakistan 6.0% of boys and girls reported a disability. Peer violence victimization was strongly associated with disability in Afghanistan and marginally associated in Pakistan. In Pakistan, perpetration of peer violence was associated with disability. In both countries, disability was significantly associated with higher depression scores. Food insecurity was strongly associated with disability in Afghanistan. Conclusion: Disability is highly prevalent in Afghanistan and Pakistan schools and this is associated with a greater risk of experiencing and perpetrating peer violence. It is important to ensure that all children can benefit from school-based prevention interventions.