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Ovarian cancer, in particularly high-grade serous ovarian cancer (HGSOC) and ovarian carcinosarcoma (OCS), are highly aggressive and deadly female cancers with limited treatment options. These tumors are generally unresponsive to immune check-point inhibitor (ICI) therapy and are referred to as immunologically "cold" tumors. Cell-based therapy, in particular, adoptive T-cell therapy, is an alternative immunotherapy option that has shown great potential, especially chimeric antigen receptor T cell (CAR-T) therapy in the treatment of hematologic malignancies. However, the efficacy of CAR-T therapy in solid tumors has been modest. This review explores the potential of another cell-based therapy, T-cell receptor therapy (TCR-T) as an alternate treatment option for immunological "cold" OC and OCS tumors., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Wu, Dand, Doig, Papenfuss, Scott, Ho and Ooi.)

Targeting cell division by chemotherapy is a highly effective strategy to treat a wide range of cancers. However, there are limitations of many standard-of-care chemotherapies: undesirable drug toxicity, side-effects, resistance and high cost. New small molecules which kill a wide range of cancer subtypes, with good therapeutic window in vivo, have the potential to complement the current arsenal of anti-cancer agents and deliver improved safety profiles for cancer patients. We describe results with a new anti-cancer small molecule, WEHI-7326, which causes cell cycle arrest in G2/M, cell death in vitro, and displays efficacious anti-tumor activity in vivo. WEHI-7326 induces cell death in a broad range of cancer cell lines, including taxane-resistant cells, and inhibits growth of human colon, brain, lung, prostate and breast tumors in mice xenografts. Importantly, the compound elicits tumor responses as a single agent in patient-derived xenografts of clinically aggressive, treatment-refractory neuroblastoma, breast, lung and ovarian cancer. In combination with standard-of-care, WEHI-7326 induces a remarkable complete response in a mouse model of high-risk neuroblastoma. WEHI-7326 is mechanistically distinct from known microtubule-targeting agents and blocks cells early in mitosis to inhibit cell division, ultimately leading to apoptotic cell death. The compound is simple to produce and possesses favorable pharmacokinetic and toxicity profiles in rodents. It represents a novel class of anti-cancer therapeutics with excellent potential for further development due to the ease of synthesis, simple formulation, moderate side effects and potent in vivo activity. WEHI-7326 has the potential to complement current frontline anti-cancer drugs and to overcome drug resistance in a wide range of cancers.

TP53 mutations are implicated in the progression of mucinous borderline tumors (MBOT) to mucinous ovarian carcinomas (MOC). Optimized immunohistochemistry (IHC) for TP53 has been established as a proxy for the TP53 mutation status in other ovarian tumor types. We aimed to confirm the ability of TP53 IHC to predict TP53 mutation status in ovarian mucinous tumors and to evaluate the association of TP53 mutation status with survival among patients with MBOT and MOC. Tumor tissue from an initial cohort of 113 women with MBOT/MOC was stained with optimized IHC for TP53 using tissue microarrays (75.2%) or full sections (24.8%) and interpreted using established criteria as normal or abnormal (overexpression, complete absence, or cytoplasmic). Cases were considered concordant if abnormal IHC staining predicted deleterious TP53 mutations. Discordant tissue microarray cases were re-evaluated on full sections and interpretational criteria were refined. The initial cohort was expanded to a total of 165 MBOT and 424 MOC for the examination of the association of survival with TP53 mutation status, assessed either by TP53 IHC and/or sequencing. Initially, 82/113 (72.6%) cases were concordant using the established criteria. Refined criteria for overexpression to account for intratumoral heterogeneity and terminal differentiation improved concordance to 93.8% (106/113). In the expanded cohort, 19.4% (32/165) of MBOT showed evidence for TP53 mutation and this was associated with a higher risk of recurrence, disease-specific death, and all-cause mortality (overall survival: HR = 4.6, 95% CI 1.5-14.3, p = 0.0087). Within MOC, 61.1% (259/424) harbored a TP53 mutation, but this was not associated with survival (overall survival, p = 0.77). TP53 IHC is an accurate proxy for TP53 mutation status with refined interpretation criteria accounting for intratumoral heterogeneity and terminal differentiation in ovarian mucinous tumors. TP53 mutation status is an important biomarker to identify MBOT with a higher risk of mortality.

Background: Homologous recombination repair deficiency (HRD) is a frequent feature of high-grade serous ovarian, fallopian tube and peritoneal carcinoma (HGSC) and is associated with sensitivity to PARP inhibitor (PARPi) therapy. HRD testing provides an opportunity to optimise PARPi use in HGSC but methodologies are diverse and clinical application remains controversial., Materials and Methods: To define best practice for HRD testing in HGSC the ESMO Translational Research and Precision Medicine Working Group launched a collaborative project that incorporated a systematic review approach. The main aims were to (i) define the term 'HRD test'; (ii) provide an overview of the biological rationale and the level of evidence supporting currently available HRD tests; (iii) provide recommendations on the clinical utility of HRD tests in clinical management of HGSC., Results: A broad range of repair genes, genomic scars, mutational signatures and functional assays are associated with a history of HRD. Currently, the clinical validity of HRD tests in ovarian cancer is best assessed, not in terms of biological HRD status per se, but in terms of PARPi benefit. Clinical trials evidence supports the use of BRCA mutation testing and two commercially available assays that also incorporate genomic instability for identifying subgroups of HGSCs that derive different magnitudes of benefit from PARPi therapy, albeit with some variation by clinical scenario. These tests can be used to inform treatment selection and scheduling but their use is limited by a failure to consistently identify a subgroup of patients who derive no benefit from PARPis in most studies. Existing tests lack negative predictive value and inadequately address the complex and dynamic nature of the HRD phenotype., Conclusions: Currently available HRD tests are useful for predicting likely magnitude of benefit from PARPis but better biomarkers are urgently needed to better identify current homologous recombination proficiency status and stratify HGSC management., Competing Interests: Disclosures REM receives consultancy fees from Merck, TESARO-GSK and Clovis Oncology, speaker bureau from Roche and TESARO and travel grants from AstraZeneca and TESARO. LRY receives research funding from the Wellcome Trust (Clinical Career Development Fellowship 214584/Z/18/Z). AL receives consultancy fees from Ability, Astra Zeneca, Clovis, GamaMabs, GSK, MSD, Merck Serono, and TESARO, research funding from Merus, GamaMabs, Inivata, and Sanofi Investigator and fees for trials with Ability, Agenus, AstraZeneca, BMS, Boehringer. IRC is the principal investigator of PAOLA1 trial; receives honoraria from AstraZeneca, Clovis, TESARO and Pharma Mar; consulting/advisory board fees from AstraZeneca, Roche, Clovis, TESARO, Genmab, Pharma Mar, MSD and Pfizer; research funding from MSD; travel expenses from AstraZeneca, GSK and Roche. JAL received fees for Advisory Boards and Lectures for AstraZeneca; Clovis Oncology; GSK. Advisory Boards from MSD/Merck; Eisai; Artios; Amgen; Regeneron. Grants AstraZeneca; MSD/Merck. SPS is a founder and shareholder of Canexia Health Inc. VS developed EP3502700A1: methods based on the detection of rad51 foci in tumour cells and developed EP3502700A1: methods based on the detection of rad51 foci in tumour cells and receives research funding from AstraZeneca and Tesaro; received consultancy, SAB membership or honoraria payments from Abbvie. CJL receives research funding from AstraZeneca, Merck KGaA, and Artios; received consultancy, SAB membership or honoraria payments from Syncona, Sun Pharma, Gerson Lehrman Group, Merck KGaA, Vertex, AstraZeneca, Tango, 3rd Rock, Ono Pharma, and Artios. CJL has stock in Tango and OVIBIO and is also a named inventor on patents describing the use of DNA repair inhibitors and stands to gain from the development as part of the ICR ‘Rewards to Inventors’ scheme. JJ is an advisory board member of Artios Pharma. DKC received research funding from Cancer Research UK (C51058/A25407), Celgene and Astra Zeneca, and speaker bureau from Celgene. DB receives research grant funding from Astra Zeneca, Genentech/Roche, Beigene, and paid consultancy from Exo Therapeutics. SNZ holds multiple patents on mutational-signature-based clinical algorithms and is a current or past recipient of honoraria from Astra Zeneca, Artios Pharma and the Scottish Genomics Partnership. JJ is an advisory board member of Artios Pharma and receives research funding from Artios Pharma, Cancer Research UK, Dutch Cancer Society and Oncode Institute. All remaining authors have declared no conflicts of interest. CLS acts in an honorary advisory capacity for AstraZeneca, Clovis Oncology, Roche, Eisai Inc, Sierra Oncology, Takeda, MSD.; receives grant/research support from Clovis Oncology, Eisai Inc, Sierra Oncology, Roche, Beigene; travel support from AstraZeneca., (Copyright © 2020 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.)

Epithelial ovarian cancer (EOC) is a complex disease comprising discrete histological and molecular subtypes, for which survival rates remain unacceptably low. Tailored approaches for this deadly heterogeneous disease are urgently needed. Efflux pumps belonging to the ATP-binding cassette (ABC) family of transporters are known for roles in both drug resistance and cancer biology and are also highly targetable. Here we have investigated the association of ABCC4/MRP4 expression to clinical outcome and its biological function in endometrioid and serous tumors, common histological subtypes of EOC. We found high expression of ABCC4/MRP4, previously shown to be directly regulated by c-Myc/N-Myc, was associated with poor prognosis in endometrioid EOC (P = .001) as well as in a subset of serous EOC with a "high-MYCN" profile (C5/proliferative; P = .019). Transient siRNA-mediated suppression of MRP4 in EOC cells led to reduced growth, migration and invasion, with the effects being most pronounced in endometrioid and C5-like serous cells compared to non-C5 serous EOC cells. Sustained knockdown of MRP4 also sensitized endometrioid cells to MRP4 substrate drugs. Furthermore, suppression of MRP4 decreased the growth of patient-derived EOC cells in vivo. Together, our findings provide the first evidence that MRP4 plays an important role in the biology of Myc-associated ovarian tumors and highlight this transporter as a potential therapeutic target for EOC., (© 2020 UICC.)

The United States has the highest incarceration rate in the world. With a substantial number of inmates diagnosed with mental illness, substance use, or both, various diversion strategies have been developed to help decrease and avoid criminalization of individuals with mental illness. This article focuses primarily on the first three Sequential Intercept Model intercept points as related to jail diversion and reviews types of diversion programs, research outcomes for diversion programs, and important components that contribute to successful diversion.

Metabolic-associated fatty liver disease (MAFLD) represents a spectrum of disease states ranging from simple steatosis to non-alcoholic steatohepatitis (NASH). Hepatic macrophages, specifically Kupffer cells (KCs), are suggested to play important roles in the pathogenesis of MAFLD through their activation, although the exact roles played by these cells remain unclear. Here, we demonstrated that KCs were reduced in MAFLD being replaced by macrophages originating from the bone marrow. Recruited macrophages existed in two subsets with distinct activation states, either closely resembling homeostatic KCs or lipid-associated macrophages (LAMs) from obese adipose tissue. Hepatic LAMs expressed Osteopontin, a biomarker for patients with NASH, linked with the development of fibrosis. Fitting with this, LAMs were found in regions of the liver with reduced numbers of KCs, characterized by increased Desmin expression. Together, our data highlight considerable heterogeneity within the macrophage pool and suggest a need for more specific macrophage targeting strategies in MAFLD., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

There is now evidence that gene fusions activating the MAPK pathway are relatively common in pancreatic acinar cell carcinoma with potentially actionable BRAF or RET fusions being found in ~30%. We sought to investigate the incidence of RAF1 fusions in pancreatic malignancies with acinar cell differentiation. FISH testing for RAF1 was undertaken on 30 tumors comprising 25 'pure' acinar cell carcinomas, 2 mixed pancreatic acinar-neuroendocrine carcinomas, 1 mixed acinar cell-low grade neuroendocrine tumor and 2 pancreatoblastomas. RAF1 rearrangements were identified in 5 cases and confirmed by DNA and RNA sequencing to represent oncogenic fusions (GATM-RAF1, GOLGA4-RAF1, PDZRN3-RAF1, HERPUD1-RAF1 and TRIM33-RAF1) and to be mutually exclusive with BRAF and RET fusions, as well as KRAS mutations. Large genome-wide copy number changes were common and included 1q gain and/or 1p loss in all five RAF1 FISH-positive acinar cell carcinomas. RAF1 expression by immunohistochemistry was found in 3 of 5 (60%) of fusion-positive cases and no FISH-negative cases. Phospho-ERK1/2 expression was found in 4 of 5 RAF1-fusion-positive cases. Expression of both RAF1 and phospho-ERK1/2 was heterogeneous and often only detected at the tumor-stroma interface, thus limiting their clinical utility. We conclude that RAF1 gene rearrangements are relatively common in pancreatic acinar cell carcinomas (14.3% to 18.5% of cases) and can be effectively identified by FISH with follow up molecular testing. The combined results of several studies now indicate that BRAF, RET or RAF1 fusions occur in between one third and one-half of these tumors but are extremely rare in other pancreatic malignancies. As these fusions are potentially actionable with currently available therapies, a strong argument can be made to perform FISH or molecular testing on all pancreatic acinar cell carcinomas.

Background: BRCA1/2 mutation status has increasing relevance for ovarian cancer treatments, making traditional coordination of genetic testing by genetic services unsustainable. Consequently alternative models of genetic testing have been developed to improve testing at the initial diagnosis for all eligible women., Methods: A training module to enable mainstreamed genetic testing by oncology healthcare professionals was developed by genetic health professionals. Oncology healthcare professionals completed questionnaires before and 12 months post-training to assess perceived skills, competence and barriers to their coordinating genetic testing for women with high-grade non-mucinous epithelial ovarian cancer. Genetic health professionals were surveyed 12 months post-training to assess perceived barriers to implementation of mainstreaming., Results: 185 oncology healthcare professionals were trained in 42 workshops at 35 Australasian hospitals. Of the 273 tests ordered by oncology healthcare professionals post-training, 241 (93.1%) met national testing guidelines. The number of tests ordered by genetic health professionals reduced significantly (z = 45.0, p = 0.008). Oncology healthcare professionals' perceived barriers to mainstreamed testing decreased from baseline to follow-up (t = 2.39, p = 0.023), particularly perceived skills, knowledge and attitudes. However, only 58% reported either 'always' or 'nearly always' having ordered BRCA testing for eligible patients at 12 months, suggesting oncology healthcare professionals' perceived barriers were not systematically addressed through training., Conclusions: Oncology healthcare professionals have demonstrated a willingness to be involved in the provision of genetic testing in a mainstreaming model. If oncology services are to hold responsibility for coordinating genetic testing, their readiness will require understanding of barriers not addressed by training alone to inform future intervention design., Competing Interests: Declaration of competing interest Bettina Meiser, Kathy Tucker, Maira Kentwell and Margaret Gleeson have held a remunerated consultant role with the company Astrazeneca with respect to this project and together with Michael Friedlander, Yoland Antill, Amy Pearn, Camron Ebzery and Rachel Williams have been remunerated by Astrazeneca for advisory boards and lectures outside this project. Amy Pearn has also held a position with the Genetic Services of Western Australia funded solely by Astrazeneca. Michael Friedlander and Yoland Antill have also received support for investigator initiated clinical trials from Astrazeneca outside the submitted work, and Michael Friedlander reports personal fees from MSD, Lilly, Takeda and Novartis outside the submitted work. Clare Scott has participated in non-remunerated advisory boards on mainstreaming and PARP inhibitor therapy for Astrazeneca, Clovis Oncology and Takeda., (Crown Copyright © 2020. Published by Elsevier Inc. All rights reserved.)

Objective: Research has suggested that increased length of mandated community treatment for individuals with a serious mental disorder leads to better outcomes, but few studies have described whether these outcomes are maintained after treatment ends. The goal of this study was to evaluate the impact of court-mandated treatment on outcomes for individuals found not guilty by reason of insanity (NGRI) and released to the community., Methods: Ninety-three patients who were found to be NGRI participated in this study. Rearrest rates were compared for three groups: patients released to the community with court-mandated treatment (conditional release), patients who were conditionally released but later "restored to sanity" with no further court supervision, and patients released from the hospital to the community by the court with no court-imposed conditions. Patients were followed for an average of 4.83 years after discharge., Results: Nearly half (43.8%) of the patients released to the community without court-mandated supervision were arrested for another offense in the study period, compared with 8.2% of patients released under the supervision of the conditional release program. In contrast, those who were restored to sanity and ultimately released unconditionally had higher arrest rates (25%)., Conclusions: This study suggests that court oversight on an ongoing basis may be necessary to help justice-involved individuals with a serious mental disorder avoid the criminal justice system and remain engaged in community treatment. More research is needed to determine whether these findings can be extrapolated to civil commitment procedures.

BRCA1 gene mutations impair homologous recombination (HR) DNA repair, resulting in cellular senescence and embryonic lethality in mice. Therefore, BRCA1-deficient cancers require adaptations that prevent excessive genomic alterations from triggering cell death. RNF168-mediated ubiquitination of γH2AX at K13/15 (ub-H2AX) serves as a recruitment module for the localization of 53BP1 to DNA break sites. Here, we found multiple BRCA1 -mutant cancer cell lines and primary tumors with low levels of RNF168 protein expression. Overexpression of ectopic RNF168 or a ub-H2AX fusion protein induced cell death and delayed BRCA1 -mutant tumor formation. Cell death resulted from the recruitment of 53BP1 to DNA break sites and inhibition of DNA end resection. Strikingly, reintroduction of BRCA1 or 53BP1 depletion restored HR and rescued the ability of cells to maintain RNF168 and ub-H2AX overexpression. Thus, downregulation of RNF168 protein expression is a mechanism for providing BRCA1-null cancer cell lines with a residual level of HR that is essential for viability. Overall, our work identifies loss of RNF168 ubiquitin signaling as a proteomic alteration that supports BRCA1 -mutant carcinogenesis. We propose that restoring RNF168-ub-H2AX signaling, potentially through inhibition of deubiquitinases, could represent a new therapeutic approach. SIGNIFICANCE: This study explores the concept that homologous recombination DNA repair is not an all-or-nothing concept, but a spectrum, and that where a tumor stands on this spectrum may have therapeutic relevance. See related commentary by Wang and Wulf, p. 2720 ., (©2020 American Association for Cancer Research.)

The phenotypic and functional dichotomy between IRF8 + type 1 and IRF4 + type 2 conventional dendritic cells (cDC1s and cDC2s, respectively) is well accepted; it is unknown how robust this dichotomy is under inflammatory conditions, when additionally monocyte-derived cells (MCs) become competent antigen-presenting cells (APCs). Using single-cell technologies in models of respiratory viral infection, we found that lung cDC2s acquired expression of the Fc receptor CD64 shared with MCs and of IRF8 shared with cDC1s. These inflammatory cDC2s (inf-cDC2s) were superior in inducing CD4 + T helper (Th) cell polarization while simultaneously presenting antigen to CD8 + T cells. When carefully separated from inf-cDC2s, MCs lacked APC function. Inf-cDC2s matured in response to cell-intrinsic Toll-like receptor and type 1 interferon receptor signaling, upregulated an IRF8-dependent maturation module, and acquired antigens via convalescent serum and Fc receptors. Because hybrid inf-cDC2s are easily confused with monocyte-derived cells, their existence could explain why APC functions have been attributed to MCs., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Acquired resistance to PARP inhibitors (PARPi) is a major challenge for the clinical management of high grade serous ovarian cancer (HGSOC). Here, we demonstrate CX-5461, the first-in-class inhibitor of RNA polymerase I transcription of ribosomal RNA genes (rDNA), induces replication stress and activates the DNA damage response. CX-5461 co-operates with PARPi in exacerbating replication stress and enhances therapeutic efficacy against homologous recombination (HR) DNA repair-deficient HGSOC-patient-derived xenograft (PDX) in vivo. We demonstrate CX-5461 has a different sensitivity spectrum to PARPi involving MRE11-dependent degradation of replication forks. Importantly, CX-5461 exhibits in vivo single agent efficacy in a HGSOC-PDX with reduced sensitivity to PARPi by overcoming replication fork protection. Further, we identify CX-5461-sensitivity gene expression signatures in primary and relapsed HGSOC. We propose CX-5461 is a promising therapy in combination with PARPi in HR-deficient HGSOC and also as a single agent for the treatment of relapsed disease.

Dendritic cells function in the immune system to instruct adaptive immune cells to respond accordingly to different threats. While conventional dendritic cells can be subdivided into two main subtypes, termed cDC1s and cDC2s, it is clear that further heterogeneity exists within these subtypes, particularly for cDC2s. Understanding the signals involved in specifying each of these lineages and subtypes thereof is crucial to (i) enable us to determine their specific functions and (ii) put us in a position to be able to target these cells to promote or prevent a specific function in any given disease setting. Although we still have much to learn regarding the specification of these cells, here we review the most recent advances in our understanding of this and highlight some of the next questions for the future., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

While CNS microglia have been extensively studied, relatively little is known about macrophages populating the peripheral nervous system. Here we performed ontogenic, transcriptomic and spatial characterization of sciatic nerve macrophages (snMacs). Using multiple fate-mapping systems, we show that snMacs do not derive from the early embryonic precursors colonizing the CNS, but originate primarily from late embryonic precursors and become replaced by bone-marrow-derived macrophages over time. Using single-cell transcriptomics, we identified a tissue-specific core signature of snMacs and two spatially separated snMacs: Relmα + Mgl1 + snMacs in the epineurium and Relmα - Mgl1 - snMacs in the endoneurium. Globally, snMacs lack most of the core signature genes of microglia, with only the endoneurial subset expressing a restricted number of these genes. In response to nerve injury, the two resident snMac populations respond differently. Moreover, and unlike in the CNS, monocyte-derived macrophages that develop during injury can engraft efficiently in the pool of resident peripheral nervous system macrophages.

The increasing prevalence of obesity is accompanied by a rising incidence in metabolic syndrome and related pathologies such as non-alcoholic fatty liver disease. Macrophages are hypothesized to play central roles in these diseases, through their role as inflammatory mediators and as such are thought to be potential targets for future therapies. Recently, single cell technologies have revealed significant heterogeneity within the macrophage pool in both liver and adipose tissue in obesity. Thus current efforts are focused on dissecting this heterogeneity and understanding the distinct functions of the individual subsets. In this review, we discuss the current knowledge regarding macrophage heterogeneity, ontogeny and functions in the context of obese adipose tissue and fatty liver disease and attempt to align the distinct populations described to date., (Copyright © 2020 Remmerie, Martens and Scott.)

Objective: Positive and negative influences from teammates (e.g., supportive teammate friendships, modelling of teammates' disordered eating) have been associated with athletes' eating/exercise psychopathology. However, research is yet to explore how an athlete's psychological well-being and gender may impact upon these relationships. This study aimed to explore whether psychological well-being mediates the relationship between teammate influences and eating/exercise psychopathology, and to determine whether gender moderates the significant mediation effects identified., Method: Athletes (N = 195, mean age 18.35 years, n = 110 female, n = 81 lean sport athletes) completed a survey three times over an 8-month period exploring teammate influences, psychological well-being (self-esteem, anxiety, depression) and eating/exercise psychopathology. Mediation and moderated-mediation analyses were conducted., Results: Higher levels of anxiety significantly mediated the positive relationships between bulimia modelling and teammate pressure with eating and exercise psychopathology. Higher levels of depression significantly mediated the positive relationship between teammate pressure and body dissatisfaction, and the negative relationship between supportive friendships and body dissatisfaction. Higher levels of self-esteem mediated both inverse relationships between supportive friendships and a lower drive for thinness (fully) and body dissatisfaction (partially). Gender did not significantly moderate any mediation relationships., Discussion: Male and female athletes with poor psychological well-being (i.e., high levels of anxiety or depression) are more susceptible to negative teammate influences, while athletes with good psychological well-being (i.e., high self-esteem) reap the protective benefits of supportive teammate friendships. Understanding the circumstances under which teammates are influential is vital for the development of targeted intervention and prevention strategies to reduce athlete eating and exercise psychopathology., (© 2020 Wiley Periodicals, Inc.)

Gynaecological carcinosarcomas are the most lethal gynaecological malignancies that are often highly resistant to standard chemotherapy. They are composed of both carcinomatous and sarcomatous components and are associated with high rates of metastatic disease. Due to their rarity, molecular studies have been carried out on relatively few tumours, revealing a broad spectrum of heterogeneity. In this review, we have collated the gene mutations, gene expression, epigenetic regulation and protein expression reported by a number of studies on gynaecological carcinosarcomas. Based on these results, we describe potential therapeutics that may demonstrate efficacy and present any pre-clinical studies that have been carried out. We also describe the pre-clinical models currently available for future research to assess the potential of molecularly matched therapies. Interestingly, over-expression of many biomarkers in carcinosarcoma tumours often doesn't correlate with a worse prognosis. Therefore, we propose that profiling the mutational landscape, gene expression, and gene amplification/deletion may better indicate potential treatment strategies and predict response, thus improving outcomes for women with this rare, aggressive disease., (Crown Copyright © 2019. Published by Elsevier Ltd. All rights reserved.)

Objective: Mucinous ovarian carcinoma (MOC) is an uncommon ovarian cancer histotype that responds poorly to conventional chemotherapy regimens. Although long overall survival outcomes can occur with early detection and optimal surgical resection, recurrent and advanced disease are associated with extremely poor survival. There are no current guidelines specifically for the systemic management of recurrent MOC. We analyzed data from a large cohort of women with MOC to evaluate the potential for clinical utility from a range of systemic agents., Methods: We analyzed gene copy number (n = 191) and DNA sequencing data (n = 184) from primary MOC to evaluate signatures of mismatch repair deficiency and homologous recombination deficiency, and other genetic events. Immunohistochemistry data were collated for ER, CK7, CK20, CDX2, HER2, PAX8 and p16 (n = 117-166)., Results: Molecular aberrations noted in MOC that suggest a match with current targeted therapies include amplification of ERBB2 (26.7%) and BRAF mutation (9%). Observed genetic events that suggest potential efficacy for agents currently in clinical trials include: KRAS/NRAS mutations (66%), TP53 missense mutation (49%), RNF43 mutation (11%), ARID1A mutation (10%), and PIK3CA/PTEN mutation (9%). Therapies exploiting homologous recombination deficiency (HRD) may not be effective in MOC, as only 1/191 had a high HRD score. Mismatch repair deficiency was similarly rare (1/184)., Conclusions: Although genetically diverse, MOC has several potential therapeutic targets. Importantly, the lack of response to platinum-based therapy observed clinically corresponds to the lack of a genomic signature associated with HRD, and MOC are thus also unlikely to respond to PARP inhibition., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest. ADF, NT and DDLB have received research grant funding from AstraZeneca, unrelated to the contents on this manuscript. DDLB also reports funding from Roche-Genentech and BeiGene, also unrelated. CG reports funding from AstraZeneca, Roche, Clovis, Tesaro, Foundation One, Nucana, Aprea, Novartis, Chugai, and MSD, all outside the submitted work. CLS reports non-financial support and/or other support from Clovis Oncology, Roche, Eisai Australia, Beigene, Sierra Oncology, and AstraZeneca, all outside the submitted work., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)

Inflammatory signaling pathways are tightly regulated to avoid chronic inflammation and the development of disease. OTULIN is a deubiquitinating enzyme that controls inflammation by cleaving linear ubiquitin chains generated by the linear ubiquitin chain assembly complex. Here, we show that ablation of OTULIN in liver parenchymal cells in mice causes severe liver disease which is characterized by liver inflammation, hepatocyte apoptosis, and compensatory hepatocyte proliferation, leading to steatohepatitis, fibrosis, and hepatocellular carcinoma (HCC). Genetic ablation of Fas-associated death domain (FADD) completely rescues and knockin expression of kinase inactive receptor-interacting protein kinase 1 (RIPK1) significantly protects mice from developing liver disease, demonstrating that apoptosis of OTULIN-deficient hepatocytes triggers disease pathogenesis in this model. Finally, we demonstrate that type I interferons contribute to disease in hepatocyte-specific OTULIN-deficient mice. Our study reveals the critical importance of OTULIN in protecting hepatocytes from death, thereby preventing the development of chronic liver inflammation and HCC., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Despite intensive research and constant medical progress, sepsis remains one of the most urgent unmet medical needs of today. Most studies have been focused on the inflammatory component of the disease; however, recent advances support the notion that sepsis is accompanied by extensive metabolic perturbations. During times of limited caloric intake and high energy needs, the liver acts as the central metabolic hub in which PPARα is crucial to coordinate the breakdown of fatty acids. The role of hepatic PPARα in liver dysfunction during sepsis has hardly been explored. We demonstrate that sepsis leads to a starvation response that is hindered by the rapid decline of hepatic PPARα levels, causing excess free fatty acids, leading to lipotoxicity, and glycerol. In addition, treatment of mice with the PPARα agonist pemafibrate protects against bacterial sepsis by improving hepatic PPARα function, reducing lipotoxicity and tissue damage. Since lipolysis is also increased in sepsis patients and pemafibrate protects after the onset of sepsis, these findings may point toward new therapeutic leads in sepsis., (© 2020 The Authors. Published under the terms of the CC BY 4.0 license.)

Purpose: Rare cancers are challenging for researchers, as clinicians and scientists have difficulty recruiting sufficient patient cases to power studies appropriately. Likewise, patients often are frustrated by a lack of specific information or evidence base for their cancer and, although eager to participate in research, have limited opportunities. We established CART-WHEEL.org, an online patient-entered database, to directly engage patients in the research process, collect rare cancer data, and facilitate their entry into additional research., Patients and Methods: Patients access CART-WHEEL.org directly online. Clinical information is collected from users via a streamlined questionnaire developed collaboratively with consumer groups to ensure accessibility and relevance. Data collected include the following: patient demographics, comorbidities, and risk factors and tumor diagnostic, biomarker, and treatment history. Patients can download a medical summary for personal use; consent for research use of data; and indicate willingness to be contacted about other research or clinical trials. We describe data collected to date and its validation, and we provide examples of how CART-WHEEL.org can facilitate rare cancer research., Results: From January 2010 to March 2018, 558 patients provided consent and entered their rare cancer data. One hundred distinct rare tumor types and patients from 22 countries were included. Validation of data entered by 21 patients with sarcoma against a hospital database demonstrated accuracy sufficient to facilitate future research in key fields, such as tumor site (95%) and histopathologic diagnosis (90%). Examples of CART-WHEEL-based disease-specific projects, subsequent recruitment to other rare cancer projects, and rare cancer patient cases of interest are described., Conclusions: Online platforms like CART-WHEEL.org can engage consumers directly, facilitating collection of patient-entered rare cancer data for hypothesis generation, and connect patients with researchers to enable specific rare cancer research and clinical trials.

Psychosis is a unique and significant risk factor associated with violent and suicidal behavior and warrants special consideration. This article presents a careful review of the literature on violence risk and psychosis and suicide risk and psychosis as it pertains to youth or those who have been newly diagnosed with or are at high risk for psychotic disorders. Each topic is covered in reference to general considerations and specific psychotic symptoms (eg, hallucinations, delusions, paranoia). The reader can refer to practical boxes to assist in identifying relevant risk factors and examples of questions to ask the patient and family., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Teammates have a powerful influence on athletes' eating attitudes/behaviours, but less is known about the relative importance of teammate influence mechanisms. The primary aim of this study was to explore the relationships and predictive associations between teammate influences (e.g., modelling of teammates' disordered eating; supportive teammate friendships) and athletes' eating and exercise attitudes and behaviours. A further aim was to identify the presence of any gender differences. Athletes (N = 1172, mean age 24 years, n = 727 female) completed a survey exploring multiple teammate influences, eating and exercise attitudes and behaviours, and psychological wellbeing (anxiety, depression, self-esteem). Many significant relationships were identified between teammate influences and eating/exercise psychopathology. Stepwise regression analysis revealed that a perceived pressure from teammates to lose weight/change shape and perceptions that teammates engaged in disordered eating practices were the best predictors of higher eating and exercise psychopathology. Supportive teammate friendships was the best predictor of lower eating psychopathology and higher levels of healthy exercise behaviours. Encouragement/discouragement to eat healthily were also significant predictors. Teammate influences explained more variance in exercise than eating psychopathology, and total variance explained by teammates was higher for females compared to males. Teammates may have a positive and negative influence on the eating and exercise attitudes/behaviours of athletes; however, gender differences are apparent. Understanding teammate influences on the eating and exercise practices of athletes is important for the development of team-based interventions to reduce or prevent disordered eating and exercise. Future research should explore these relationships longitudinally, considering the role of moderating factors (e.g., sport type, stage of season)., (Copyright © 2019. Published by Elsevier Ltd.)

Purpose: The ALLOCATE study was designed as a pilot to demonstrate the feasibility and clinical utility of real-time targeted molecular profiling of patients with recurrent or advanced ovarian cancer for identification of potential targeted therapies., Patients and Methods: A total of 113 patients with ovarian cancer of varying histologies were recruited from two tertiary hospitals, with 99 patient cases suitable for prospective analysis. Targeted molecular and methylation profiling of fresh biopsy and archived tumor samples were performed by screening for mutations or copy-number variations in 44 genes and for promoter methylation of BRCA1 and RAD51C ., Results: Somatic genomic or methylation events were identified in 85% of all patient cases, with potentially actionable events with defined targeted therapies (including four resistance events) detected in 60% of all patient cases. On the basis of these findings, six patients received molecularly guided therapy, three patients had unsuspected germline cancer-associated BRCA1 / 2 mutations and were referred for genetic counseling, and two intermediate differentiated (grade 2) serous ovarian carcinomas were reclassified as low grade, leading to changes in clinical management. Additionally, secondary reversion mutations in BRCA1 / 2 were identified in fresh biopsy samples of two patients, consistent with clinical platinum/poly (ADP-ribose) polymerase inhibitor resistance. Timely reporting of results if molecular testing is done at disease recurrence, as well as early referral for patients with platinum-resistant cancers, were identified as factors that could improve the clinical utility of molecular profiling., Conclusion: ALLOCATE molecular profiling identified known genomic and methylation alterations of the different ovarian cancer subtypes and was deemed feasible and useful in routine clinical practice. Better patient selection and access to a wider range of targeted therapies or clinical trials will further enhance the clinical utility of molecular profiling.

Macrophages are strongly adapted to their tissue of residence. Yet, little is known about the cell-cell interactions that imprint the tissue-specific identities of macrophages in their respective niches. Using conditional depletion of liver Kupffer cells, we traced the developmental stages of monocytes differentiating into Kupffer cells and mapped the cellular interactions imprinting the Kupffer cell identity. Kupffer cell loss induced tumor necrosis factor (TNF)- and interleukin-1 (IL-1) receptor-dependent activation of stellate cells and endothelial cells, resulting in the transient production of chemokines and adhesion molecules orchestrating monocyte engraftment. Engrafted circulating monocytes transmigrated into the perisinusoidal space and acquired the liver-associated transcription factors inhibitor of DNA 3 (ID3) and liver X receptor-α (LXR-α). Coordinated interactions with hepatocytes induced ID3 expression, whereas endothelial cells and stellate cells induced LXR-α via a synergistic NOTCH-BMP pathway. This study shows that the Kupffer cell niche is composed of stellate cells, hepatocytes, and endothelial cells that together imprint the liver-specific macrophage identity., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: To ascertain the preferences of perianesthesia nurses regarding peripheral nerve blocks (PNBs) and their impact on patient recovery after total joint replacement (TJR)., Design: Survey of perianesthesia nurses at a single medical center., Methods: Fifty-nine perianesthesia nurses completed a 23-question survey on PNBs for TJR., Findings: Most agreed PNBs improved patients' pain after knee, hip, and shoulder TJR (35 [92.1%], 35 [92.1%], and 34 [91.9%], respectively). Most felt lower extremity PNBs increased risk of falling (26 [70.3%]), whereas 7 of 35 (20.0%) felt patients fell more after spinal anesthesia than after general anesthesia. Respondents preferred a block to opioid-based analgesia if they were to have lower extremity TJR or total shoulder replacement (100% [30/30 and 33/33])., Conclusions: The perianesthesia nurses surveyed felt PNBs improved pain control and patient recovery despite a perceived risk of falling for lower extremity TJR, and they preferred PNB when considering TJR surgery for themselves., (Copyright © 2019 American Society of PeriAnesthesia Nurses. Published by Elsevier Inc. All rights reserved.)

Mucinous ovarian carcinoma (MOC) is a unique subtype of ovarian cancer with an uncertain etiology, including whether it genuinely arises at the ovary or is metastatic disease from other organs. In addition, the molecular drivers of invasive progression, high-grade and metastatic disease are poorly defined. We perform genetic analysis of MOC across all histological grades, including benign and borderline mucinous ovarian tumors, and compare these to tumors from other potential extra-ovarian sites of origin. Here we show that MOC is distinct from tumors from other sites and supports a progressive model of evolution from borderline precursors to high-grade invasive MOC. Key drivers of progression identified are TP53 mutation and copy number aberrations, including a notable amplicon on 9p13. High copy number aberration burden is associated with worse prognosis in MOC. Our data conclusively demonstrate that MOC arise from benign and borderline precursors at the ovary and are not extra-ovarian metastases.

While the roles of parenchymal microglia in brain homeostasis and disease are fairly clear, other brain-resident myeloid cells remain less well understood. By dissecting border regions and combining single-cell RNA-sequencing with high-dimensional cytometry, bulk RNA-sequencing, fate-mapping and microscopy, we reveal the diversity of non-parenchymal brain macrophages. Border-associated macrophages (BAMs) residing in the dura mater, subdural meninges and choroid plexus consisted of distinct subsets with tissue-specific transcriptional signatures, and their cellular composition changed during postnatal development. BAMs exhibited a mixed ontogeny, and subsets displayed distinct self-renewal capacity following depletion and repopulation. Single-cell and fate-mapping analysis both suggested that there is a unique microglial subset residing on the apical surface of the choroid plexus epithelium. Finally, gene network analysis and conditional deletion revealed IRF8 as a master regulator that drives the maturation and diversity of brain macrophages. Our results provide a framework for understanding host-macrophage interactions in both the healthy and diseased brain.

ZEB1 and ZEB2 are zinc-finger E homeobox-binding transcription factors best known for their role in driving epithelial to mesenchymal transition. However, in recent years our understanding of these two transcription factors has broadened, and it is now clear that they are expressed by a variety of immune cells of both myeloid and lymphoid lineages, including dendritic cells, macrophages, monocytes, B, T, and NK cells. In these cells, ZEBs function to regulate important transcriptional networks necessary for cell differentiation, maintenance, and function. Here, we review the current understanding of ZEB regulation across immune cell lineages, particularly in mice, highlighting present gaps in our knowledge. We also speculate on important questions for the future., (Copyright © 2019 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Competing Interests: Conflict-of-interest disclosure: The authors declare no competing financial interests.

A key resistance mechanism to platinum-based chemotherapies and PARP inhibitors in BRCA -mutant cancers is the acquisition of BRCA reversion mutations that restore protein function. To estimate the prevalence of BRCA reversion mutations in high-grade ovarian carcinoma (HGOC), we performed targeted next-generation sequencing of circulating cell-free DNA (cfDNA) extracted from pretreatment and postprogression plasma in patients with deleterious germline or somatic BRCA mutations treated with the PARP inhibitor rucaparib. BRCA reversion mutations were identified in pretreatment cfDNA from 18% (2/11) of platinum-refractory and 13% (5/38) of platinum-resistant cancers, compared with 2% (1/48) of platinum-sensitive cancers ( P = 0.049). Patients without BRCA reversion mutations detected in pretreatment cfDNA had significantly longer rucaparib progression-free survival than those with reversion mutations (median, 9.0 vs. 1.8 months; HR, 0.12; P < 0.0001). To study acquired resistance, we sequenced 78 postprogression cfDNA, identifying eight additional patients with BRCA reversion mutations not found in pretreatment cfDNA. SIGNIFICANCE: BRCA reversion mutations are detected in cfDNA from platinum-resistant or platinum-refractory HGOC and are associated with decreased clinical benefit from rucaparib treatment. Sequencing of cfDNA can detect multiple BRCA reversion mutations, highlighting the ability to capture multiclonal heterogeneity. This article is highlighted in the In This Issue feature, p. 151 ., (©2018 American Association for Cancer Research.)

Autoimmune myocarditis often leads to dilated cardiomyopathy (DCM). Although T cell reactivity to cardiac self-antigen is common in the disease, it is unknown which antigen presenting cell (APC) triggers autoimmunity. Experimental autoimmune myocarditis (EAM) was induced by immunizing mice with α-myosin loaded bone marrow APCs cultured in GM-CSF. APCs found in such cultures include conventional type 2 CD11b + cDCs (GM-cDC2s) and monocyte-derived cells (GM-MCs). However, only α-myosin loaded GM-cDC2s could induce EAM. We also studied antigen presenting capacity of endogenous type 1 CD24 + cDCs (cDC1s), cDC2s, and MCs for α-myosin-specific TCR-transgenic TCR-M CD4 + T cells. After EAM induction, all cardiac APCs significantly increased and cDCs migrated to the heart-draining mediastinal lymph node (LN). Primarily cDC2s presented α-myosin to TCR-M cells and induced Th1/Th17 differentiation. Loss of IRF4 in Irf4 fl / fl .Cd11cCre mice reduced MHCII expression on GM-cDC2s in vitro and cDC2 migration in vivo . However, partly defective cDC2 functions in Irf4 fl / fl .Cd11cCre mice did not suppress EAM. MCs were the largest APC subset in the inflamed heart and produced pro-inflammatory cytokines. Targeting APC populations could be exploited in the design of new therapies for cardiac autoimmunity.

Using single-cell RNA sequencing of both immune and non-immune cells in the developing lung, Cohen et al. map candidate cell-cell interactions during alveolar macrophage development. This revealed potential cross-talk between epithelial cells, ILC2s, basophils, and the developing macrophages, which were validated both in vitro and in vivo., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Two studies show that adding NOTCH ligands to Flt3L cultures increases the yield of cDC1s from mouse and human progenitors. Moreover, these NOTCH-DCs more closely resemble in vivo DCs transcriptionally and functionally. This will be extremely valuable for studying DCs in vitro and for further developing autologous DC-based antitumor vaccinations., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Accurately identifying patients with high-grade serous ovarian carcinoma (HGSOC) who respond to poly(ADP-ribose) polymerase inhibitor (PARPi) therapy is of great clinical importance. Here we show that quantitative BRCA1 methylation analysis provides new insight into PARPi response in preclinical models and ovarian cancer patients. The response of 12 HGSOC patient-derived xenografts (PDX) to the PARPi rucaparib was assessed, with variable dose-dependent responses observed in chemo-naive BRCA1/2-mutated PDX, and no responses in PDX lacking DNA repair pathway defects. Among BRCA1-methylated PDX, silencing of all BRCA1 copies predicts rucaparib response, whilst heterozygous methylation is associated with resistance. Analysis of 21 BRCA1-methylated platinum-sensitive recurrent HGSOC (ARIEL2 Part 1 trial) confirmed that homozygous or hemizygous BRCA1 methylation predicts rucaparib clinical response, and that methylation loss can occur after exposure to chemotherapy. Accordingly, quantitative BRCA1 methylation analysis in a pre-treatment biopsy could allow identification of patients most likely to benefit, and facilitate tailoring of PARPi therapy.

Background: This review focuses on non-dispensing services from pharmacists, i.e. pharmacists in community, primary or ambulatory-care settings, to non-hospitalised patients, and is an update of a previously-published Cochrane Review., Objectives: To examine the effect of pharmacists' non-dispensing services on non-hospitalised patient outcomes., Search Methods: We searched CENTRAL, MEDLINE, Embase, two other databases and two trial registers in March 2015, together with reference checking and contact with study authors to identify additional studies. We included non-English language publications. We ran top-up searches in January 2018 and have added potentially eligible studies to 'Studies awaiting classification'., Selection Criteria: Randomised trials of pharmacist services compared with the delivery of usual care or equivalent/similar services with the same objective delivered by other health professionals., Data Collection and Analysis: We used standard methodological procedures of Cochrane and the Effective Practice and Organisation of Care Group. Two review authors independently checked studies for inclusion, extracted data and assessed risks of bias. We evaluated the overall certainty of evidence using GRADE., Main Results: We included 116 trials comprising 111 trials (39,729 participants) comparing pharmacist interventions with usual care and five trials (2122 participants) comparing pharmacist services with services from other healthcare professionals. Of the 116 trials, 76 were included in meta-analyses. The 40 remaining trials were not included in the meta-analyses because they each reported unique outcome measures which could not be combined. Most trials targeted chronic conditions and were conducted in a range of settings, mostly community pharmacies and hospital outpatient clinics, and were mainly but not exclusively conducted in high-income countries. Most trials had a low risk of reporting bias and about 25%-30% were at high risk of bias for performance, detection, and attrition. Selection bias was unclear for about half of the included studies.Compared with usual care, we are uncertain whether pharmacist services reduce the percentage of patients outside the glycated haemoglobin target range (5 trials, N = 558, odds ratio (OR) 0.29, 95% confidence interval (CI) 0.04 to 2.22; very low-certainty evidence). Pharmacist services may reduce the percentage of patients whose blood pressure is outside the target range (18 trials, N = 4107, OR 0.40, 95% CI 0.29 to 0.55; low-certainty evidence) and probably lead to little or no difference in hospital attendance or admissions (14 trials, N = 3631, OR 0.85, 95% CI 0.65 to 1.11; moderate-certainty evidence). Pharmacist services may make little or no difference to adverse drug effects (3 trials, N = 590, OR 1.65, 95% CI 0.84 to 3.24) and may slightly improve physical functioning (7 trials, N = 1329, mean difference (MD) 5.84, 95% CI 1.21 to 10.48; low-certainty evidence). Pharmacist services may make little or no difference to mortality (9 trials, N = 1980, OR 0.79, 95% CI 0.56 to 1.12, low-certaintly evidence).Of the five studies that compared services delivered by pharmacists with other health professionals, no studies evaluated the impact of the intervention on the percentage of patients outside blood pressure or glycated haemoglobin target range, hospital attendance and admission, adverse drug effects, or physical functioning., Authors' Conclusions: The results demonstrate that pharmacist services have varying effects on patient outcomes compared with usual care. We found no studies comparing services delivered by pharmacists with other healthcare professionals that evaluated the impact of the intervention on the six main outcome measures. The results need to be interpreted cautiously because there was major heterogeneity in study populations, types of interventions delivered and reported outcomes.There was considerable heterogeneity within many of the meta-analyses, as well as considerable variation in the risks of bias.

Heterogeneity between different macrophage populations has become a defining feature of this lineage. However, the conserved factors defining macrophages remain largely unknown. The transcription factor ZEB2 is best described for its role in epithelial to mesenchymal transition; however, its role within the immune system is only now being elucidated. We show here that Zeb2 expression is a conserved feature of macrophages. Using Clec4f-cre, Itgax-cre, and Fcgr1-cre mice to target five different macrophage populations, we found that loss of ZEB2 resulted in macrophage disappearance from the tissues, coupled with their subsequent replenishment from bone-marrow precursors in open niches. Mechanistically, we found that ZEB2 functioned to maintain the tissue-specific identities of macrophages. In Kupffer cells, ZEB2 achieved this by regulating expression of the transcription factor LXRα, removal of which recapitulated the loss of Kupffer cell identity and disappearance. Thus, ZEB2 expression is required in macrophages to preserve their tissue-specific identities., (Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.)

Distinct macrophage populations throughout the body display highly heterogeneous transcriptional and epigenetic programs. Recent research has highlighted that these profiles enable the different macrophage populations to perform distinct functions as required in their tissue of residence, in addition to the prototypical macrophage functions such as in innate immunity. These 'extra' tissue-specific functions have been termed accessory functions. One such putative accessory function is lipid metabolism, with macrophages in the lung and liver in particular being associated with this function. As it is now appreciated that cell metabolism not only provides energy but also greatly influences the phenotype and function of the cell, here we review how lipid metabolism affects macrophage phenotype and function and the specific roles played by macrophages in the pathogenesis of lipid-related diseases. In addition, we highlight the current questions limiting our understanding of the role of macrophages in lipid metabolism., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Female gametes are stored in the ovary in structures called primordial follicles, the supply of which is non-renewable. It is well established that DNA-damaging cancer treatments can deplete the ovarian reserve of primordial follicles, causing premature ovarian failure and infertility. The precise mechanisms underlying this chemotherapy-driven follicle loss are unclear, and this has limited the development of targeted ovarian-protective agents. To address this fundamental knowledge gap, we used gene deletion mouse models to examine the role of the DNA damage-induced pro-apoptotic protein, PUMA, and its transcriptional activator TAp63, in primordial follicle depletion caused by treatment with cyclophosphamide or cisplatin. Cyclophosphamide caused almost complete destruction of the primordial follicle pool in adult wild-type (WT) mice, and a significant destructive effect was also observed for cisplatin. In striking contrast, Puma -/- mice retained 100% of their primordial follicles following either genotoxic treatment. Furthermore, elimination of PUMA alone completely preserved fertility in cyclophosphamide-treated mice, indicating that oocytes rescued from DNA damage-induced death can repair themselves sufficiently to support reproductive function and offspring health. Primordial follicles were also protected in TAp63 -/- mice following cisplatin treatment, but not cyclophosphamide, suggesting mechanistic differences in the induction of apoptosis and depletion of the ovarian reserve in response to these different chemotherapies. These studies identify PUMA as a crucial effector of apoptosis responsible for depletion of primordial follicles following exposure to cyclophosphamide or cisplatin, and this indicates that inhibition of PUMA may be an effective ovarian-protective strategy during cancer treatment in women.

Microglia, the mononuclear phagocytes of the central nervous system (CNS), are important for the maintenance of CNS homeostasis, but also critically contribute to CNS pathology. Here we demonstrate that the nuclear factor kappa B (NF-κB) regulatory protein A20 is crucial in regulating microglia activation during CNS homeostasis and pathology. In mice, deletion of A20 in microglia increases microglial cell number and affects microglial regulation of neuronal synaptic function. Administration of a sublethal dose of lipopolysaccharide induces massive microglia activation, neuroinflammation, and lethality in mice with microglia-confined A20 deficiency. Microglia A20 deficiency also exacerbates multiple sclerosis (MS)-like disease, due to hyperactivation of the Nlrp3 inflammasome leading to enhanced interleukin-1β secretion and CNS inflammation. Finally, we confirm a Nlrp3 inflammasome signature and IL-1β expression in brain and cerebrospinal fluid from MS patients. Collectively, these data reveal a critical role for A20 in the control of microglia activation and neuroinflammation.

Genomic instability and mutations are fundamental aspects of human malignancies, leading to progressive accumulation of the hallmarks of cancer. For some time, it has been clear that key mutations may be used as both prognostic and predictive biomarkers, the best-known examples being the presence of germline BRCA1 or BRCA2 mutations, which are not only associated with improved prognosis in ovarian cancer, but are also predictive of response to poly(ADP-ribose) polymerase (PARP) inhibitors. Although biomarkers as specific and powerful as these are rare in human malignancies, next-generation sequencing and improved bioinformatic analyses are revealing mutational signatures, i.e. broader patterns of alterations in the cancer genome that have the power to reveal information about underlying driver mutational processes. Thus, the cancer genome can act as a stratification factor in clinical trials and, ultimately, will be used to drive personalized treatment decisions. In this review, we use ovarian high-grade serous carcinoma (HGSC) as an example of a disease of extreme genomic complexity that is marked by widespread copy number alterations, but that lacks powerful driver oncogene mutations. Understanding of the genomics of HGSC has led to the routine introduction of germline and somatic BRCA1/2 testing, as well as testing of mutations in other homologous recombination genes, widening the range of patients who may benefit from PARP inhibitors. We will discuss how whole genome-wide analyses, including loss of heterozygosity quantification and whole genome sequencing, may extend this paradigm to allow all patients to benefit from effective targeted therapies. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd., (Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.)

Kupffer cells (KCs) and monocyte-derived macrophages are implicated in non-alcoholic steatohepatitis (NASH) pathogenesis but their functions remain unclear due to the lack of specific markers to distinguish between the different cell types. Additionally, it is unclear if multiple subsets of KCs are present during NASH. Here, we characterized the liver macrophage subsets during methionine/choline deficient (MCD) diet-induced NASH and recovery. We observed a significant reduced contribution of Ly6C lo Clec4F + Tim4 + KCs to the hepatic macrophage pool in MCD fed mice, which normalized during recovery. Ly6C lo Clec4F - Tim4 - monocyte-derived macrophages increased during MCD feeding and returned to baseline during recovery. Ly6C lo Clec4F + Tim4 - monocyte-derived KCs developed during initial recovery but did not self-renew as their numbers were reduced after full recovery. Initial recovery from MCD diet feeding was further characterized by increased proportions of Ki-67 + proliferating KCs. In conclusion, the hepatic macrophage pool undergoes substantial albeit transient changes during NASH and recovery, with the KC pool being maintained by proliferation and differentiation of short-lived monocyte-derived KCs., (Copyright © 2017. Published by Elsevier Inc.)