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.

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.

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.

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.

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.

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

: Children with disabilities are more likely to experience violence or injury at school and at home, but there is little evidence from Central Asia. : 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. : 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'.

How do programmes to prevent intimate partner violence among the general population impact women with disabilities? Post-hoc analysis of three randomised controlled trials.

Introduction: Women with disabilities experience higher rates of intimate partner violence (IPV) than women without disabilities. There remains limited evidence about whether IPV prevention interventions for the general population have benefits for women with disabilities that compare to those for women without disabilities. Using data from IPV prevention randomised controlled trials in diverse locations (Rwanda, South Africa and Afghanistan), we assess whether outcomes differed by disability status.

Intimate partner violence among women with and without disabilities: a pooled analysis of baseline data from seven violence-prevention programmes.

Introduction: Intimate partner violence (IPV) is a serious public health and human rights violation which impacts approximately one in three women worldwide. Some existing evidence suggests that women with disabilities are at higher risk of IPV, but is largely limited in geographical scope to the Global North, and comparison across settings has been hampered by inconsistent measurement of both IPV and disability.

Methods: Pooled analysis of baseline data from 8549 adult women participating in seven IPV prevention studies in five countries across Africa and Asia that used collaborative, comparative measurement strategies to assess both disability and IPV.

Functional Categorization of Variants of Uncertain Clinical Significance in Homologous Recombination Repair Complementation Assays.

Purpose: Because is a high-risk breast/ovarian cancer susceptibility gene, sequence variants of uncertain clinical significance (VUS) complicate genetic counseling. As most VUS are rare, reliable classification based on clinical and genetic data is often impossible. However, all pathogenic variants analyzed result in defective homologous recombination DNA repair (HRR).

Response of metastatic mouse invasive lobular carcinoma to mTOR inhibition is partly mediated by the adaptive immune system.

Effective treatment of invasive lobular carcinoma (ILC) of the breast is hampered by late detection, invasive growth, distant metastasis, and poor response to chemotherapy. Phosphoinositide 3-kinase (PI3K) signaling, one of the major druggable oncogenic signaling networks, is frequently activated in ILC. We investigated treatment response and resistance to AZD8055, an inhibitor of mammalian target of rapamycin (mTOR), in the (KEP) mouse model of metastatic ILC.

How people with disabilities experience programs to prevent intimate partner violence across four countries.

Women with disabilities are more vulnerable to violence, including intimate partner violence (IPV), yet the majority of emerging IPV prevention programs fail to explicitly consider the needs of participants with disabilities. Women and men living with disabilities engaged with IPV prevention programs in four countries were interviewed to explore how disability shaped their experiences of gender, violence, IPV, and whether the programs met their disability related needs. In-depth interviews were conducted with 16 women and 15 men living with disabilities in Ghana, Rwanda, Tajikistan and South Africa.

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 cancer. For most human epithelial tumour types, high systemic neutrophil-to-lymphocyte ratios are associated with poor overall survival, and experimental studies have demonstrated a causal relationship between neutrophils and metastasis. However, the cancer-cell-intrinsic mechanisms that dictate the substantial heterogeneity in systemic neutrophilic inflammation between tumour-bearing hosts are largely unresolved.

Ethical considerations for disability-inclusive gender-based violence research: Reflections from a South African qualitative case study.

Globally, women with disabilities experience heightened and unique forms of violence compared to men with disabilities and women without disabilities. Yet formalised guidelines for their inclusion in gender-based violence (GBV) research is lacking. This paper draws on ethical guidelines for researching violence against women, and studies on the ethicality of including people with disabilities in research, to advocate for women with disabilities' inclusion and safety in GBV research.

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.

"I was in the darkness but the group brought me light": Development, relevance and feasibility of the Sondela HIV adjustment and coping intervention.

Developing interventions that address psychosocial wellbeing of people living with HIV is critical to ensure strong linkages to and retention in HIV care. This paper describes the development of Sondela, an HIV adjustment and coping intervention for heterosexual men and women living with HIV, and its relevance and feasibility in the South African context. Sondela is a six three-hour, small group-based, participatory workshop series.

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.

BRCA1185delAG tumors may acquire therapy resistance through expression of RING-less BRCA1.

Heterozygous germline mutations in breast cancer 1 (BRCA1) strongly predispose women to breast cancer. BRCA1 plays an important role in DNA double-strand break (DSB) repair via homologous recombination (HR), which is important for tumor suppression. Although BRCA1-deficient cells are highly sensitive to treatment with DSB-inducing agents through their HR deficiency (HRD), BRCA1-associated tumors display heterogeneous responses to platinum drugs and poly(ADP-ribose) polymerase (PARP) inhibitors in clinical trials.

The BRCA1-Δ11q Alternative Splice Isoform Bypasses Germline Mutations and Promotes Therapeutic Resistance to PARP Inhibition and Cisplatin.

Breast and ovarian cancer patients harboring BRCA1/2 germline mutations have clinically benefitted from therapy with PARP inhibitor (PARPi) or platinum compounds, but acquired resistance limits clinical impact. In this study, we investigated the impact of mutations on BRCA1 isoform expression and therapeutic response. Cancer cell lines and tumors harboring mutations in exon 11 of BRCA1 express a BRCA1-Δ11q splice variant lacking the majority of exon 11.

Additional Layers of Violence: The Intersections of Gender and Disability in the Violence Experiences of Women With Physical Disabilities in South Africa.

South Africa has unprecedented levels of violence and many South African women are exposed to violence during their lifetime. This article explores how gender and disability intersect in women's experiences of violence during their lifetime. Repeat in-depth qualitative interviews with 30 physically disabled women in Cape Town reveal that women with physical disabilities are exposed to various forms of violence, and shows how their impairments shape their violence experiences.

'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.

A high-throughput functional complementation assay for classification of BRCA1 missense variants.

Unlabelled: Mutations in BRCA1 and BRCA2 account for the majority of hereditary breast and ovarian cancers, and therefore sequence analysis of both genes is routinely conducted in patients with early-onset breast cancer. Besides mutations that clearly abolish protein function or are known to increase cancer risk, a large number of sequence variants of uncertain significance (VUS) have been identified. Although several functional assays for BRCA1 VUSs have been described, thus far it has not been possible to conduct a high-throughput analysis in the context of the full-length protein.

Measuring change in vulnerable adolescents: findings from a peer education evaluation in South Africa.

Introduction: In the context of poverty and HIV and AIDS, peer education is thought to be capable of providing vulnerable youth with psychosocial support as well as information and decision-making skills otherwise limited by scarce social and material resources. As a preventative education intervention method, peer education is a strategy aimed at norms and peer group influences that affect health behaviours and attitudes. However, too few evaluations of peer-led programmes are available, and they frequently fail to reflect real differences between those who have been recipients of peer education and those who have not.

BRCA1 RING function is essential for tumor suppression but dispensable for therapy resistance.

Hereditary breast cancers are frequently caused by germline BRCA1 mutations. The BRCA1(C61G) mutation in the BRCA1 RING domain is a common pathogenic missense variant, which reduces BRCA1/BARD1 heterodimerization and abrogates its ubiquitin ligase activity. To investigate the role of BRCA1 RING function in tumor suppression and therapy response, we introduced the Brca1(C61G) mutation in a conditional mouse model for BRCA1-associated breast cancer.

Bereavement, silence and culture within a peer-led HIV/AIDS-prevention strategy for vulnerable children in South Africa.

In addressing the psychosocial effects of the HIV and AIDS pandemic among vulnerable children, the issue of bereavement appears inadequately addressed. Amid the global discourse on children orphaned and made vulnerable by HIV and AIDS, this paper explores how cultural contexts and social environments in South Africa shape children's experience of grief. The argument draws on a number of qualitative studies and uses empirical evidence from an evaluation of a peer-led HIV/AIDS-prevention strategy aimed at providing psychosocial support for 10- to 13-year-old South African children living in resource-poor communities.