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.

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.

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.

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.

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. METHODS: We assessed disability at baseline in three IPV prevention trials. We performed post-hoc analysis of intervention impacts at endline (22 or 24 months post-baseline) stratified by disability status at study baseline and tested an interaction term for disability at baseline by intervention arm for three sets of outcomes: (1) past year experiences of physical, sexual and severe IPV; (2) economic and livelihood outcomes; and (3) health, mental health and substance use outcomes. RESULTS: At baseline between 17.7% and 26.2% of women reported being disabled. For IPV prevention, in seven out of eight tests across three studies, women with and without disabilities had similar outcomes. For economic, health and substance use outcomes, there was more variation, with women with disabilities reporting both better and worse outcomes than women without disabilities; however there was no clear pattern in these differential results. CONCLUSION: IPV prevention programmes targeting general populations can prevent IPV among women with disabilities participants with benefits that mirror those for women without disabilities. Benefits for participants with and without disabilities on secondary programme outcomes related to economic empowerment and health may be more varied and should be explicitly monitored.

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. RESULTS: After adjusting for age, women with disabilities were more likely to experience past 12-month physical IPV (adjusted OR (aOR)=1.79; 95% CI 1.49 to 2.17), sexual IPV (aOR=1.98; 95% CI 1.36 to 2.89), emotional IPV (aOR=1.84; 95% CI 1.49 to 2.27) and economic IPV (aOR=1.66; 95% CI 1.45 to 1.89), with an overall association between disability and past 12-month physical/sexual IPV of aOR=1.93 (95% CI 1.52 to 2.46). Compared to women without disability, women with moderate and severe disability showed a trend of increasing risk of IPV in the past 12 months for each of physical, sexual, emotional and economic IPV. Overall, both women with moderate disability (aOR=1.86, 95% CI 1.57 to 2.21) and women with severe disability (aOR=2.63; 95% CI 1.95 to 3.55) were significantly more likely to experience any form of IPV when compared with women without disability. CONCLUSION: Women with disabilities are at increased risk of past-year IPV compared to women without disabilities across a range of settings in the Global South, and the risk of IPV increases with increasing severity of disability. IPV prevention and response efforts in these settings must find ways to include and address the needs of women with disabilities, including increased outreach and improved accessibility of programmes.

Functional Categorization of BRCA1 Variants of Uncertain Clinical Significance in Homologous Recombination Repair Complementation Assays.

PURPOSE: Because BRCA1 is a high-risk breast/ovarian cancer susceptibility gene, BRCA1 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 BRCA1 variants analyzed result in defective homologous recombination DNA repair (HRR). Thus, BRCA1 VUS may be categorized based on their functional impact on this pathway. EXPERIMENTAL DESIGN: Two hundred thirty-eight BRCA1 VUS-comprising most BRCA1 VUS known in the Netherlands and Belgium-were tested for their ability to complement Brca1-deficient mouse embryonic stem cells in HRR, using cisplatin and olaparib sensitivity assays and a direct repeat GFP (DR-GFP) HRR assay. Assays were validated using 25 known benign and 25 known pathogenic BRCA1 variants. For assessment of pathogenicity by a multifactorial likelihood analysis method, we collected clinical and genetic data for functionally deleterious VUS and VUS occurring in three or more families. RESULTS: All three assays showed 100% sensitivity and specificity (95% confidence interval, 83%-100%). Out of 238 VUS, 45 showed functional defects, 26 of which were deleterious in all three assays. For 13 of these 26 variants, we could calculate the probability of pathogenicity using clinical and genetic data, resulting in the identification of 7 (likely) pathogenic variants. CONCLUSIONS: We have functionally categorized 238 BRCA1 VUS using three different HRR-related assays. Classification based on clinical and genetic data alone for a subset of these variants confirmed the high sensitivity and specificity of our functional assays.

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 K14-cre;Cdh1Flox/Flox;Trp53Flox/Flox (KEP) mouse model of metastatic ILC. Inhibition of mTOR signaling blocked the growth of primary KEP tumors as well as the progression of metastatic disease. However, primary tumors and distant metastases eventually acquired resistance after long-term AZD8055 treatment, despite continued effective suppression of mTOR signaling in cancer cells. Interestingly, therapeutic responses were associated with increased expression of genes related to antigen presentation. Consistent with this observation, increased numbers of tumor-infiltrating major histocompatibility complex class II-positive (MHCII+) immune cells were observed in treatment-responsive KEP tumors. Acquisition of treatment resistance was associated with loss of MHCII+ cells and reduced expression of genes related to the adaptive immune system. The therapeutic efficacy of mTOR inhibition was reduced in Rag1-/- mice lacking mature T and B lymphocytes, compared to immunocompetent mice. Furthermore, therapy responsiveness could be partially rescued by transplanting AZD8055-resistant KEP tumors into treatment-naïve immunocompetent hosts. Collectively, these data indicate that the PI3K signaling pathway is an attractive therapeutic target in invasive lobular carcinoma, and that part of the therapeutic effect of mTOR inhibition is mediated by the adaptive immune system.

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. The data were analysed thematically and compared across the settings. Participants described experiencing disability-related stigma, discrimination, exclusion, and for women, increased vulnerability to IPV. Barriers to full participation in programs included limited accessibility, and lack of disability-specific materials, recruitment or outreach. Enablers of inclusion included recruitment and monitoring strategies aimed at people with disabilities, partnering with a local disabled people's organization, training staff in disability inclusion, and raising awareness of disability rights. The data encouragingly suggests that inclusion of women and men with disabilities in IPV prevention programs designed for the general population has beneficial outcomes. Inclusion can prevent violence, promote their wellbeing, support economic empowerment, and challenge disability-related stigma and discrimination.

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.

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.

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. The most common forms of violence women with disabilities experience are psychological violence, financial abuse, neglect, and deprivation, with disability stigma playing a central role and contributing to how women with disabilities are exploited and dehumanized. Constructions of women as asexual shape their sexual relationships and experiences of sexual violence. This article identifies that women with disabilities are more at risk and experience additional layers of violence than women without disabilities. These additional risks and layers of violence need to be recognized and inform interventions to prevent and respond to violence against women with disabilities in the country. Prevention of violence against women with physical disabilities in South Africa needs to address the role of disability stigma that shapes the types of violence they experience, change gender norms, and create accessible and safe environments and economic empowerment opportunities.

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. Reflecting on lessons from a qualitative study on violence against women living with disabilities in South Africa, the paper considers what could be of value for GBV researchers and ethics review committees in low-middle income countries (LMICs). It aims to stimulate debate around the integration of reasonable accommodation, accessibility, and equal participation of women with disabilities in planning and conducting ethical GBV research. The paper recommends that considerations are practically applied and tested in other LMICs, and thereafter critiqued in consultation with a range of stakeholders and women with disabilities, to enhance best practice and form a basis for developing guidelines for undertaking ethical and inclusive GBV research in LMICs.

"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. We followed an iterative, multi-phased process of curriculum development that involved research, theoretical frameworks and piloting. A systematic review highlighted the absence of psychosocial interventions targeting heterosexual HIV positive populations living in high HIV prevalence and resource-poor settings. Formative studies demonstrated risk and social factors associated with adjustment and coping with HIV, emphasising the need for interventions that acknowledge gendered experiences. Our pilot of Sondela demonstrated high levels of relevance and feasibility. Men appreciated the workshop "space" to openly talk about their HIV positive status and what is means for their role as partners and fathers and friends. Women valued the skills and approaches because they were relevant to "real life" situations and not just about HIV. Sondela promises to be valuable in supporting health system initiatives and psychosocial support to strengthen linkages to and retention in HIV care, and this suggests a need for rigorous evaluation of Sondela to establish evidence for its effectiveness in a general population.

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.

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. It is unclear whether all pathogenic BRCA1 mutations have similar effects on the response to therapy. Here, we have investigated mammary tumorigenesis and therapy sensitivity in mice carrying the Brca1185stop and Brca15382stop alleles, which respectively mimic the 2 most common BRCA1 founder mutations, BRCA1185delAG and BRCA15382insC. Both the Brca1185stop and Brca15382stop mutations predisposed animals to mammary tumors, but Brca1185stop tumors responded markedly worse to HRD-targeted therapy than did Brca15382stop tumors. Mice expressing Brca1185stop mutations also developed therapy resistance more rapidly than did mice expressing Brca15382stop. We determined that both murine Brca1185stop tumors and human BRCA1185delAG breast cancer cells expressed a really interesting new gene domain-less (RING-less) BRCA1 protein that mediated resistance to HRD-targeted therapies. Together, these results suggest that expression of RING-less BRCA1 may serve as a marker to predict poor response to DSB-inducing therapy in human cancer patients.

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. The introduction of frameshift mutations to exon 11 resulted in nonsense-mediated mRNA decay of full-length, but not the BRCA1-Δ11q isoform. CRISPR/Cas9 gene editing as well as overexpression experiments revealed that the BRCA1-Δ11q protein was capable of promoting partial PARPi and cisplatin resistance relative to full-length BRCA1, both in vitro and in vivo Furthermore, spliceosome inhibitors reduced BRCA1-Δ11q levels and sensitized cells carrying exon 11 mutations to PARPi treatment. Taken together, our results provided evidence that cancer cells employ a strategy to remove deleterious germline BRCA1 mutations through alternative mRNA splicing, giving rise to isoforms that retain residual activity and contribute to therapeutic resistance. Cancer Res; 76(9); 2778-90. ©2016 AACR.