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Multiple strategies are continuously being explored to expand the drug target repertoire in solid tumors. We devised a novel computational workflow for transcriptome‐wide gene expression outlier analysis that allows the systematic identification of both overexpression and underexpression events in cancer cells. Here, it was applied to expression values obtained through RNA sequencing in 226 colorectal cancer (CRC) cell lines that were also characterized by whole‐exome sequencing and microarray‐based DNA methylation profiling. We found cell models displaying an abnormally high or low expression level for 3533 and 965 genes, respectively. Gene expression abnormalities that have been previously associated with clinically relevant features of CRC cell lines were confirmed. Moreover, by integrating multi‐omics data, we identified both genetic and epigenetic alternations underlying outlier expression values. Importantly, our atlas of CRC gene expression outliers can guide the discovery of novel drug targets and biomarkers. As a proof of concept, we found that CRC cell lines lacking expression of the MTAP gene are sensitive to treatment with a PRMT5‐MTA inhibitor (MRTX1719). Finally, other tumor types may also benefit from this approach. [ABSTRACT FROM AUTHOR]

Purpose: Several types of structural heart intervention (SHI) use information from multiple imaging modalities to complete an interventional task. For example, in transcatheter aortic valve replacement (TAVR), placement and deployment of a bioprosthetic aortic valve in the aorta is primarily guided by x‐ray fluoroscopy (XRF), and echocardiography provides visualization of cardiac anatomy and blood flow. However, simultaneous interpretation of independent x‐ray and echo displays remains a challenge for the interventionalist. The purpose of this work was to develop a novel echo/x‐ray co‐registration solution in which volumetric transthoracic echo (TTE) is transformed to the x‐ray coordinate system by tracking the three‐dimensional (3D) pose of a probe fiducial attachment from its appearance in two‐dimensional (2D) x‐ray images. Methods: A fiducial attachment for a commercial TTE probe consisting of rings of high‐contrast ball bearings was designed and fabricated. The 3D pose (position and orientation) of the fiducial attachment is estimated from a 2D x‐ray image using an algorithm in which a virtual point cloud model of the attachment is iteratively rotated, translated, and forward‐projected onto the image until the average sum‐of‐squares of grayscale values at the projected points is minimized. Fiducial registration error (FRE) and target registration error (TRE) of this approach were evaluated in phantom studies using TAVR‐relevant gantry orientations and four standard acoustic windows for the TTE probe. A patient study was conducted to assess the clinical suitability of the fiducial attachment prototype during TTE imaging of patients undergoing SHI. TTE image quality for the task of guiding a transcatheter procedure was evaluated in a reviewer study. Results: The 3D FRE ranged from 0.32 ± 0.03 mm (mean ± SD) to 1.31 ± 0.05 mm, depending on C‐arm orientation and probe acoustic window. The 3D TRE ranged from 1.06 ± 0.03 mm to 2.42 ± 0.06 mm. Fiducial pose estimation was stable when >75% of the fiducial markers were visible in the x‐ray image. A panel of reviewers graded the presentation of heart valves in TTE images from 48 SHI patients. While valve presentation did not differ significantly between acoustic windows (P > 0.05), the mitral valve did achieve a significantly higher image quality compared to the aortic and tricuspid valves (P < 0.001). Overall, reviewers perceived sufficient image quality in 76.5% of images of the mitral valve, 54.9% of images of the aortic valve, and 48.6% of images of the tricuspid valve. Conclusions: Fiducial‐based tracking of a commercial TTE probe is compatible with clinical SHI workflows and yields 3D target registration error of less than 2.5 mm for a variety of x‐ray gantry geometries and echo probe acoustic windows. Although TTE image quality with respect to target valve anatomy was sufficient for the majority of cases examined, prescreening of patients for sufficient TTE quality would be helpful. [ABSTRACT FROM AUTHOR]

Background: Studies continue to show that women who give birth in the private maternity sector are less likely to receive depression screening and psychosocial assessment as a routine component of maternity care. However, examples of successfully implemented routine psychosocial assessment programs are beginning to emerge, and there is great value in better understanding the factors that can contribute to the successful delivery of emotional health care in this context. Aim: The aim of this study was to identify factors that facilitated successful implementation of antenatal psychosocial assessment in a private hospital setting. Methods: This study employed a qualitative research design. Semi‐structured interviews were used to explore the views and experiences of health professionals involved in implementation of the program at the participating site. Results: Nine health professionals participated in the study (three midwives, three obstetricians, two managers and one mental health worker). Factors that facilitated successful implementation of the program were reflected in five key themes: (i) multidisciplinary support for the program; (ii) training and clinical supervision; (iii) allocation of sufficient resources; (iv) availability of local referral pathways; and (v) normalisation of the process. Conclusion: This study shows that barriers to implementation of perinatal depression screening and psychosocial assessment are surmountable and will provide confidence to other services, that routine 'mental health assessment' as required under updated Medical Benefits Scheme items for obstetric services, can be successfully implemented and sustained in private hospital settings. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) is the third leading cause of cancer‐related deaths worldwide. Therapies that take advantage of defects in DNA repair pathways have been explored in the context of breast, ovarian, and other tumor types, but not yet systematically in CRC. At present, only immune checkpoint blockade therapies have been FDA approved for use in mismatch repair‐deficient colorectal tumors. Here, we discuss how systematic identification of alterations in DNA repair genes could provide new therapeutic opportunities for CRCs. Analysis of The Cancer Genome Atlas Colon Adenocarcinoma (TCGA‐COAD) and Rectal Adenocarcinoma (TCGA‐READ) PanCancer Atlas datasets identified 141 (out of 528) cases with putative driver mutations in 29 genes associated with DNA damage response and repair, including the mismatch repair and homologous recombination pathways. Genetic defects in these pathways might confer repair‐deficient characteristics, such as genomic instability in the absence of homologous recombination, which can be exploited. For example, inhibitors of poly(ADP)‐ribose polymerase are effectively used to treat cancers that carry mutations in BRCA1 and/or BRCA2 and have shown promising results in CRC preclinical studies. HR deficiency can also occur in cells with no detectable BRCA1/BRCA2 mutations but exhibiting BRCA‐like phenotypes. DNA repair‐targeting therapies, such as ATR and CHK1 inhibitors (which are most effective against cancers carrying ATM mutations), can be used in combination with current genotoxic chemotherapies in CRCs to further improve therapy response. Finally, therapies that target alternative DNA repair mechanisms, such as thiopurines, also have the potential to confer increased sensitivity to current chemotherapy regimens, thus expanding the spectrum of therapy options and potentially improving clinical outcomes for CRC patients. Clinical samples from colorectal cancer patients can be assessed for DNA repair deficiency in two ways: (a) Identification of molecular biomarkers associated with repair defects and (b) Functional ex vivo assays that measure repair proficiency. These data can predict response to therapies that target repair pathways (red), further sensitizing cells to current genotoxic agents (black), and potentially improving clinical outcomes. [ABSTRACT FROM AUTHOR]

Background: There is limited information relating to routine depression screening and psychosocial assessment programs in private maternity settings in Australia. Aims: To describe the psychosocial profile of a sample of private maternity patients who participated in a depression screening and psychosocial risk assessment program as part of routine antenatal care, and to explore women's experience of receiving this component of pregnancy care. Materials and methods: We conducted a retrospective medical records audit of 455 consecutive women having a routine psychosocial assessment and referral. Assessment was undertaken using the Edinburgh Postnatal Depression Scale (EPDS) and the Antenatal Risk Questionnaire (ANRQ) for psychosocial risk; 101 women completed a feedback survey about their experience of receiving routine psychosocial care. Results: Of the 87.7% of women who completed both EPDS and ANRQ, 4.3% scored 13 or more on the EPDS. On the ANRQ, 25.3% of women endorsed one risk factor, 11.6% two risk factors and 10.5% three or more risk factors. Elevated EPDS scores were associated with major stresses in the last 12 months, high trait anxiety and significant past mental health issue/s. Acceptability of depression screening and psychosocial risk assessment was high. Conclusions: This study highlights the need for, and acceptability of, depression and psychosocial assessment in the private maternity sector. These findings are particularly timely given the provision of new Medicare Benefits Scheme items for obstetricians to undertake psychosocial assessment (both antenatally and postnally) in line with recommended clinical best practice. [ABSTRACT FROM AUTHOR]

Thiopurines are part of a clinical regimen used for the treatment of autoimmune disorders and childhood acute lymphoblastic leukemia. However, despite these successes, there are also unintended consequences such as therapy‐induced cancer in long‐term survivors. Therefore, a better understanding of cellular responses to thiopurines will lead to improved and personalized treatment strategies. RAD51D is an important component of homologous recombination (HR), and our previous work established that mammalian cells defective for RAD51D are more sensitive to the thiopurine 6‐thioguanine (6TG) and have dramatically increased numbers of multinucleated cells and chromosome instability. 6TG is capable of being incorporated into telomeres, and interestingly, RAD51D contributes to telomere maintenance, although the precise function of RAD51D at the telomeres remains unclear. We sought here to investigate: (1) the activity of RAD51D at telomeres, (2) the contribution of RAD51D to protect against 6TG‐induced telomere damage, and (3) the fates of Rad51d‐deficient cells following 6TG treatment. These results demonstrate that RAD51D is required for maintaining the telomeric 3′ overhangs. As measured by γ‐H2AX induction and foci formation, 6TG induced DNA damage in Rad51d‐proficient and Rad51d‐deficient cells. However, the extent of γ‐H2AX telomere localization following 6TG treatment was higher in Rad51d‐deficient cells than in Rad51d‐proficient cells. Using live‐cell imaging of 6TG‐treated Rad51d‐deficient cells, two predominant forms of mitotic catastrophe were found to contribute to the formation of multinucleated cells, failed division and restitution. Collectively, these findings provide a unique window into the role of the RAD51D HR protein during thiopurine induction of mitotic catastrophe. Environ. Mol. Mutagen. 59:38–48, 2018. © 2017 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Background Psychosocial assessment and depression screening are recommended for all pregnant and postnatal women in Australia. However, women who give birth in private maternity settings remain less likely to participate in psychosocial assessment programs, making it difficult to comment on the potential resource implications. Aims To describe the psychosocial profile of a sample of women who had recently given birth in a private hospital and to examine the acceptability and feasibility of introducing psychosocial assessment as a routine component of maternity care. Materials and Methods Two hundred and twenty participants were recruited in a four-month period from a private tertiary hospital located in Murdoch, Western Australia. All participants completed the Edinburgh Depression Scale ( EDS) and a Antenatal Risk Questionnaire ( ANRQ) prior to discharge via an iPad. Results The mean total score for the EDS was 4.77 ( SD = 3.93), with 5% of women scoring above the recommended cut-off of 13 or more. The mean total score for the ANRQ was 17.73 ( SD = 10.72). 45.0% of all women endorsed no significant risk factors. The proportion of women scoring above the recommended ANRQ cut-off of 23 or more was 32.3%. Approximately 11% of women were referred for additional support or treatment. Acceptability of the ANRQ was high at 97.3%. Conclusions This study describes the psychosocial profile of a sample of women who recently gave birth in an Australian private maternity hospital and demonstrates that with additional resources, the implementation of psychosocial assessment as a routine component of maternity care was feasible and highly acceptable in this setting. [ABSTRACT FROM AUTHOR]

Background There exists little evidence that routine assessment of current or past mental health in the perinatal period positively impacts on rates of referral for emotional health issues. This study aimed to evaluate the impact of this early intervention approach on reported referrals for emotional health issues during pregnancy and the first postpartum year. Method A subsample of women ( N = 1,804) drawn from the Australian Longitudinal Study on Women's Health participated in the study. Results Multivariate analyses showed that predictors of being given a referral for emotional health issues during pregnancy and the postnatal period, respectively, included assessment of past mental health (Adjusted Odds Ratio [AOR] = 4.40, p < 0.001, and A OR = 5.69, p < 0.001), assessment of current mental health (A OR = 2.47, p < 0.001, and A OR = 2.72, p < 0.001), and reported experience of significant emotional distress (A OR = 2.58, p < 0.001, and A OR = 2.83, p < 0.001). The odds of receiving a referral were up to 16 times greater for women who were asked about both their past and current mental health than for women who did not receive any form of mental health assessment. Conclusions This study highlights that enquiry into risk factors such as past history (in addition to current mental health) enhances initiation of referrals. Importantly, results suggest that enquiry about current mental health is associated with appropriate rates of referral rather than a nonspecific inflation of referrals. In line with Australia's Clinical Practice Guidelines for Perinatal Mental Health, the value of a comprehensive approach to mental health assessment to aid decision making around referral for further assessment or care is particularly evident. [ABSTRACT FROM AUTHOR]

This study prospectively examined the separate and combined influences of maternal prenatal anxiety disorder and postnatal caregiving sensitivity on infants' salivary cortisol responses to the still-face procedure. Effects were assessed by measuring infant salivary cortisol upon arrival at the laboratory, and at 15-, 25-, and 40-min following the still-face procedure. Maternal symptoms of anxiety during the last 6 months of pregnancy were assessed using clinical diagnostic interview. Data analyses using linear mixed models were based on 88 women and their 7-month-old infants. Prenatal anxiety and maternal sensitivity emerged as independent, additive moderators of infant cortisol reactivity, F (3, 180) = 3.29, p = .02, F (3, 179) = 2.68, p = .05 respectively. Results were independent of maternal prenatal depression symptoms, and postnatal symptoms of anxiety and depression. Infants' stress-induced cortisol secretion patterns appear to relate not only to exposure to maternal prenatal anxiety, but also to maternal caregiving sensitivity, irrespective of prenatal psychological state. © 2009 Wiley Periodicals, Inc. Dev Psychobiol 51: 625–637, 2009 [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to an article on postnatal depression which was published in the September 7, 2009 issue.