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We report the discovery, via a unique high-throughput screening strategy, of a novel bioactive anticancer compound: Thiol Alkylating Compound Inducing Massive Apoptosis (TACIMA)-218. We demonstrate that this molecule engenders apoptotic cell death in genetically diverse murine and human cancer cell lines, irrespective of their p53 status, while sparing normal cells. TACIMA-218 causes oxidative stress in the absence of protective antioxidants normally induced by Nuclear factor erythroid 2–related factor 2 activation. As such, TACIMA-218 represses RNA translation and triggers cell signaling cascade alterations in AKT, p38, and JNK pathways. In addition, TACIMA-218 manifests thiol-alkylating properties resulting in the disruption of redox homeostasis along with key metabolic pathways. When administered to immunocompetent animals as a monotherapy, TACIMA-218 has no apparent toxicity and induces complete regression of pre-established lymphoma and melanoma tumors. In sum, TACIMA-218 is a potent oxidative stress inducer capable of selective cancer cell targeting.

Supplementary data.

Cockayne syndrome group B (CSB) protein has been implicated in the repair of a variety of DNA lesions that induce replication stress. However, little is known about its role at stalled replication forks. Here, we report that CSB is recruited to stalled forks in a manner dependent upon its T1031 phosphorylation by CDK. While dispensable for MRE11 association with stalled forks in wild-type cells, CSB is required for further accumulation of MRE11 at stalled forks in BRCA1/2-deficient cells. CSB promotes MRE11-mediated fork degradation in BRCA1/2-deficient cells. CSB possesses an intrinsic ATP-dependent fork reversal activity in vitro, which is activated upon removal of its N-terminal region that is known to autoinhibit CSB’s ATPase domain. CSB functions similarly to fork reversal factors SMARCAL1, ZRANB3 and HLTF to regulate slowdown in fork progression upon exposure to replication stress, indicative of a role of CSB in fork reversal in vivo. Furthermore, CSB not only acts epistatically with MRE11 to facilitate fork restart but also promotes RAD52-mediated break-induced replication repair of double-strand breaks arising from cleavage of stalled forks by MUS81 in BRCA1/2-deficient cells. Loss of CSB exacerbates chemosensitivity in BRCA1/2-deficient cells, underscoring an important role of CSB in the treatment of cancer lacking functional BRCA1/2.

We report the discovery, via a unique high-throughput screening strategy, of a novel bioactive anticancer compound: Thiol Alkylating Compound Inducing Massive Apoptosis (TACIMA)-218. We demonstrate that this molecule engenders apoptotic cell death in genetically diverse murine and human cancer cell lines, irrespective of their p53 status, while sparing normal cells. TACIMA-218 causes oxidative stress in the absence of protective antioxidants normally induced by Nuclear factor erythroid 2–related factor 2 activation. As such, TACIMA-218 represses RNA translation and triggers cell signaling cascade alterations in AKT, p38, and JNK pathways. In addition, TACIMA-218 manifests thiol-alkylating properties resulting in the disruption of redox homeostasis along with key metabolic pathways. When administered to immunocompetent animals as a monotherapy, TACIMA-218 has no apparent toxicity and induces complete regression of pre-established lymphoma and melanoma tumors. In sum, TACIMA-218 is a potent oxidative stress inducer capable of selective cancer cell targeting.

Study Purpose: Morphometric methods categorize potential osteoporotic vertebral fractures (OVF) on the basis of loss of vertebral height. A particular example is the widely used semiquantitative morphometric tool proposed by Genant (GSQ). A newer morphologic algorithm-based qualitative (mABQ) tool focuses on vertebral end-plate damage in recognizing OVF. We used data from both sexes in the Canadian Multicentre Osteoporosis Study (CaMos) to compare the 2 methods in identifying OVF at baseline and during 10 years of follow-up. Materials and Methods: We obtained lateral thoracic and lumbar spinal radiographs (T4-L4) 3 times, at 5-year intervals, in 828 participants of the population-based CaMos. Logistic regressions were used to study the association of 10-year changes in bone mineral density (BMD) with incident fractures. Results: At baseline, 161 participants had grade 1 and 32 had grade 2 GSQ OVF; over the next 10 years, only 9 of these participants had sustained incident GSQ OVF. Contrastingly, 21 participants at baseline had grade 1 and 48 grade 2 mABQ events; over the next 10 years, 79 subjects experienced incident grade 1 or grade 2 mABQ events. Thus, incident grades 1 and 2 morphologic fractures were 8 times more common than morphometric deformities alone. Each 10-year decrease of 0.01 g/cm2 in total hip BMD was associated with a 4.1% (95% CI: 0.7-7.3) higher odds of having an incident vertebral fracture. Conclusions: This analysis further suggests that morphometric deformities and morphologic fractures constitute distinct entities; morphologic fractures conform more closely to the expected epidemiology of OVF.

Until recently there has been little evidence available to validate any method by which to make an accurate diagnosis of an osteoporotic vertebral fractures (OVFs) from plain radiographs. In part this reflects a lack of a completely satisfactory "gold standard," but primarily it relates to the absence of well-designed prospective studies in this context. Historically, OVFs were recognized by evidence of macroscopic structural failure in vertebrae using the criteria applied elsewhere in the skeleton. This comprised altered alignment, fragmentation, cortical disruptions, and breaks, among other changes. However, these morphological criteria were replaced by vertebral morphometry, referring to the use of quantitative or quasi-quantitative measurement tools for fracture diagnosis. Vertebral morphometry emerged as an understanding of and treatment for osteoporosis evolved, mainly in response to the need for expeditious assessments of large numbers of spine images for epidemiological and pharmaceutical purposes. Although most of the descriptions of such morphometric tools have stressed that they were not to be applied to clinical diagnosis with respect to individual patients, this constraint has been widely disregarded. Here we review the major attempts to develop a diagnostic strategy for OVF and describe their characteristics in adults and children. Recent evidence suggests that morphometric (quantitative; ie, based on measurement of dimensions and shape description) criteria are inferior to morphologic (qualitative; ie, based on structural integrity) vertebral damage assessment in identifying people with low bone density and at an increased risk of future fracture. Thus there is now an evidentiary basis for suggesting that morphological assessment is the preferred strategy for use in diagnosing OVF from radiographs. © 2019 American Society for Bone and Mineral Research.

Canadian radiology has its roots embedded in Montréal and this is no less true of the Canadian Association of Radiologists Journal, now celebrating its 70th Anniversary with the appointment of a new editor. A journal, Les Rayons-X—a monthly illustrated review published in Montréal and edited by Dr Henri Lasnier– preceded it by 40 years. Les Rayons-X was to last only 7 issues. However, Dr Lasnier clearly recognized the importance of a journal to what was then an emerging specialty. By 1950, the Canadian Association of Radiologists became the first specialty society in Canada to publish a scientific journal. We reflect on some facets of the evolution of the journal from a cottage industry to its adoption by a major publishing house and through the hands of 14 editors. In that time, radiology itself has undergone remarkable changes in its technological infrastructure leading to profound changes in the capacity of radiological practitioners and scientists to diagnose and treat disease. These changes themselves impose some constraints on a general radiology journal. The Association has at times faced substantial challenges that led to questions about its ability to sustain a journal in the face of competing priorities. Those challenges will likely recur in the future, not least in the face of other better-resourced journals. As the Canadian Association of Radiologists has evolved into a distinctive voice in Canadian medicine, we argue that a strong case can be made for preserving a platform for Canadian radiology featuring Canadian observations and perspectives, both scientific and “political.”

A broad spectrum of spontaneous and genotoxin-induced DNA lesions impede replication fork progression. The DNA damage response that acts to promote completion of DNA replication is associated with dynamic changes in chromatin structure that include two distinct processes which operate genome-wide during S-phase. The first, often referred to as histone recycling or parental histone segregation, is characterized by the transfer of parental histones located ahead of replication forks onto nascent DNA. The second, known as de novo chromatin assembly, consists of the deposition of new histone molecules onto nascent DNA. Because these two processes occur at all replication forks, their potential to influence a multitude of DNA repair and DNA damage tolerance mechanisms is considerable. The purpose of this review is to provide a description of parental histone segregation and de novo chromatin assembly, and to illustrate how these processes influence cellular responses to DNA replication roadblocks.

Introduction The current Australian National Cervical Screening Program (NCSP) involves biennial, cytology-based screening of women from the age of 18 years. From December, 2017 this will change to a five-yearly human papilloma virus-based screening commencing at age 25. There is some concern that the new program may delay the opportunistic detection of cervical cancers in women under 25 years. Aim (1) To review all cases of invasive cervical cancer in Queensland women under the age of 25 over the last 28 years. (2) To determine symptoms and screening history prior to diagnosis. Methods A retrospective cohort study was undertaken at the Queensland Centre for Gynaecological Cancer (QCGC) and the Queensland Cancer Registry (QCR) of all women aged between 13 and 25 years diagnosed with cervical cancer in Queensland between 1984 and 2012. Demographic data and symptoms prior to diagnosis were extracted from the QCGC and QCR databases. Results A total of 56 women aged 13–25, were diagnosed with cervical cancer and treated at the QCGC between 1984 and 2012. The commonest reason for the diagnosis of cancer was investigation of abnormal symptoms (n = 22, 39%) rather than routine Pap smear abnormalities (n = 15, 26%). Conclusions Consistent with the world literature, there is a very low incidence of cervical cancer in women under 25 years of age, irrespective of the age of commencement of screening, or the screening interval. Our study lends some support to the proposed commencement age of 25 years in the new NCSP.

Objectives: Australia was one of the first countries to make the transition from cytology-based to HPV-based cervical screening.This analysis of the national program’s transition to a new model looks at the lessons learnt that can provide valuable insights to other settings. Type of program: Australia’s National Cervical Screening Program (NCSP). Methods: Following an extensive policy review, in December 2017 the NCSP transitioned from 2-yearly cytology-based screening in women from age 18, to 5-yearly primary HPV screening from age 25. Results: Some changes were more complex than initially anticipated. Building and implementing the National Cancer Screening Register was a more demanding and specialised project than expected. Regulatory requirements for self-collection were unexpectedly onerous, because self-collection was not formally included as an intended use by HPV test manufacturers. This delayed the rollout of a key measure to improve participation and equity. Colposcopy demand was expected to increase substantially but exceeded expectations. Uncertainty about appropriate clinical management or testing outside guideline recommendations may have contributed to the excess demand, highlighting the importance of training providers in the rationale for guidelines as well as the content. Lessons learnt: Although the changes were evidence based, there were nevertheless some concerns among women and healthcare providers, especially about the longer interval and later starting age for screening. These could have been reduced through earlier and more extensively delivered information to healthcare providers, who play a key role in addressing community concerns. Improved coordination of stakeholder support between government and nongovernment organisations may also have extended both the reach and credibility of communication about the program changes. Transitioning a well-established program is challenging, not only because of the changes required, but also because the existing program must continue to function until the transition. Delays may be hard to avoid, but early communication will enable better forward planning, especially by service providers. Since delays can reduce wider confidence in the changes, proactive communication is critical. Achieving high and equitable screening coverage is a key element if Australia and other countries are to succeed in eliminating cervical cancer as a public health problem. Improving screening program confidence and participation remain important ongoing work. Lessons from Australia will provide valuable insights for other countries making similar changes.

Determining whether a low-intensity vertebral fracture in an older person, particularly one with a history of cancer, is due to osteoporosis (OP) or is the result of a metastasis, is a not infrequent clinical problem that has important prognostic and therapeutic implications. The 2 types of fracture are usually indistinguishable on plain radiographs and require higher order imaging for diagnosis. Magnetic resonance imaging is the modality of choice because of its unique ability to depict the bone marrow, which becomes transiently edematous in an acute OP fracture. Preservation of at least part of the normal marrow signal, the visualization of a fracture line parallel to the end plates, the presence of an intravertebral cleft, lack of pedicle involvement, and no extra-osseous mass all favor a benign OP fracture. Absence of the preceding signs, particularly if there is complete replacement of the normal bone marrow and a convex posterior contour of the vertebral body, favors a fracture of malignant origin. Non-routine magnetic resonance sequences using diffusion-weighted imaging and/or chemical shift imaging may be helpful in difficult cases.

The Saccharomyces cerevisiae genome encodes five sirtuins (Sir2 and Hst1–4), which constitute a conserved family of NAD-dependent histone deacetylases. Cells lacking any individual sirtuin display mild growth and gene silencing defects. However, hst3Δ hst4Δ double mutants are exquisitely sensitive to genotoxins, and hst3Δ hst4Δ sir2Δ mutants are inviable. Our published data also indicate that pharmacological inhibition of sirtuins prevents growth of several fungal pathogens, although the biological basis is unclear. Here, we present genome-wide fitness assays conducted with nicotinamide (NAM), a pan-sirtuin inhibitor. Our data indicate that NAM treatment causes yeast to solicit specific DNA damage response pathways for survival, and that NAM-induced growth defects are mainly attributable to inhibition of Hst3 and Hst4 and consequent elevation of histone H3 lysine 56 acetylation (H3K56ac). Our results further reveal that in the presence of constitutive H3K56ac, the Slx4 scaffolding protein and PP4 phosphatase complex play essential roles in preventing hyperactivation of the DNA damage-response kinase Rad53 in response to spontaneous DNA damage caused by reactive oxygen species. Overall, our data support the concept that chromosome-wide histone deacetylation by sirtuins is critical to mitigate growth defects caused by endogenous genotoxins.

Objective Australia's HPV vaccination and HPV-based cervical screening programs are changing the landscape in cervical cancer prevention. We aim to identify areas which can make the biggest further impact on cervical cancer burden. This protocol describes the first stage of a program of work called Pathways-Cervix that aims to generate evidence from modelled evaluations of interventions across the cervical cancer spectrum. Methods Based on evidence from literature reviews and guidance from a multi-disciplinary Scientific Advisory Committee (SAC), the most relevant evaluations for prevention, diagnosis and treatment were identified. Results Priority evaluations agreed by the SAC included: increasing/decreasing and retaining vaccination uptake at the current level; vaccinating older women; increasing screening participation; methods for triaging HPV-positive women; improving the diagnosis of cervical intraepithelial neoplasia (CIN) and cancer; treating cervical abnormalities and cancer; and vaccinating women treated for CIN2/3 to prevent recurrence. Evaluations will be performed using a simulation model, Policy1-Cervix previously used to perform policy evaluations in Australia. Exploratory modelling of interventions using idealised scenarios will initially be conducted in single birth cohorts. If these have a significant impact on findings then evaluations with more realistic assumptions will be conducted. Promising strategies will be investigated further by multi-cohort simulations predicting health outcomes, resource use and cost outcomes. Conclusions Pathways-Cervix will assess the relative benefits of strategies and treatment options in a systematic and health economic framework, producing a list of ‘best buys’ for future decision-making in cervical cancer control.

The deubiquitinase (DUB) and tumor suppressor BAP1 catalyzes ubiquitin removal from histone H2A Lys-119 and coordinates cell proliferation, but how BAP1 partners modulate its function remains poorly understood. Here, we report that BAP1 forms two mutually exclusive complexes with the transcriptional regulators ASXL1 and ASXL2, which are necessary for maintaining proper protein levels of this DUB. Conversely, BAP1 is essential for maintaining ASXL2, but not ASXL1, protein stability. Notably, cancer-associated loss of BAP1 expression results in ASXL2 destabilization and hence loss of its function. ASXL1 and ASXL2 use their ASXM domains to interact with the C-terminal domain (CTD) of BAP1, and these interactions are required for ubiquitin binding and H2A deubiquitination. The deubiquitination-promoting effect of ASXM requires intramolecular interactions between catalytic and non-catalytic domains of BAP1, which generate a composite ubiquitin-binding interface (CUBI). Notably, the CUBI engages multiple interactions with ubiquitin involving (i) the ubiquitin carboxyl hydrolase catalytic domain of BAP1, which interacts with the hydrophobic patch of ubiquitin, and (ii) the CTD domain, which interacts with a charged patch of ubiquitin. Significantly, we identified cancer-associated mutations of BAP1 that disrupt the CUBI and notably an in-frame deletion in the CTD that inhibits its interaction with ASXL1/2 and DUB activity and deregulates cell proliferation. Moreover, we demonstrated that BAP1 interaction with ASXL2 regulates cell senescence and that ASXL2 cancer-associated mutations disrupt BAP1 DUB activity. Thus, inactivation of the BAP1/ASXL2 axis might contribute to cancer development.

O-GlcNAcylation is a posttranslational modification catalyzed by the O-Linked N-acetylglucosamine (O-GlcNAc) transferase (OGT) and reversed by O-GlcNAcase (OGA). Numerous transcriptional regulators, including chromatin modifying enzymes, transcription factors, and co-factors, are targeted by O-GlcNAcylation, indicating that this modification is central for chromatin-associated processes. Recently, OGT-mediated O-GlcNAcylation was reported to be a novel histone modification, suggesting a potential role in directly coordinating chromatin structure and function. In contrast, using multiple biochemical approaches, we report here that histone O-GlcNAcylation is undetectable in mammalian cells. Conversely, O-GlcNAcylation of the transcription regulators Host Cell Factor-1 (HCF-1) and Ten-Eleven Translocation protein 2 (TET2) could be readily observed. Our study raises questions on the occurrence and abundance of O-GlcNAcylation as a histone modification in mammalian cells and reveals technical complications regarding the detection of genuine protein O-GlcNAcylation. Therefore, the identification of the specific contexts in which histone O-GlcNAcylation might occur is still to be established.

The purpose of this study was to compare the efficacy of gelatin sponge with that of coils for splenic artery embolization in the treatment of blunt splenic injury.A single-center retrospective review was performed with the records of 63 patients (45 men, 18 women; mean age, 45.5 years; range, 16-84 years) with blunt splenic injury treated at a tertiary care trauma center by splenic artery embolization with gelatin sponge (n = 30 patients) or metallic coils (n = 33 patients) between 2005 and 2014. The two groups had comparable median American Association for the Surgery of Trauma grades of IV and comparable angiographic appearances regarding active extravasation and pseudoaneurysm formation at preembolization splenic arteriography (p = 0.32). Clinical outcomes and procedure-related outcomes were evaluated.The success rates were similar in the two groups: splenic artery embolization failed in 6.6% (2/30) of patients in the gelatin sponge group and 12.1% (4/33) in the coil embolization group (p = 0.45; 95% CI, -30.1% to 19.2%). Major complications occurred in six patients (20.0%) in the gelatin sponge group and in six patients (18.1%) in the coil group (p = 0.85; 95% CI, -23.0% to 26.6%). Minor complications occurred in three patients (10.0%) in the gelatin sponge group and seven patients (21.2%) in the coil group (p = 0.21; 95% CI, -35.4% to 14.0%). Procedure time was significantly shorter in the gelatin sponge group (median, 32 minutes; interquartile range, 18-48 minutes) than in the coil group (median, 53 minutes; interquartile range, 30-76 minutes) (p = 0.01).Splenic artery embolization with gelatin sponge appears to be as effective and as safe as coil embolization and can be completed in a shorter time.

Background Coronary artery calcification (CAC) is highly prevalent among dialysis patients and is associated with increased cardiovascular and all cause mortality. Magnesium (Mg) inhibits vascular calcification in animal and in-vitro studies but whether the same effect occurs in humans is uncertain. Methods A single centre cross-sectional study of 80 prevalent peritoneal dialysis (PD) patients; on PD only for a minimum of 3 months. A radiologist blinded to patient status calculated their abdominal aortic calcification (AAC) scores on lateral lumbar spine radiographs, a validated surrogate for CAC. Results Eighty patients provided informed consent and underwent lumbar spine radiography. The mean serum Mg was 0.8 mmol/L (standard deviation 0.2) and mean AAC score 8.9 (minimum 0, maximum 24). A higher serum Mg level was associated with a lower AAC score (R 2 = 0.06, unstandardized coefficient [B] = −7.81, p = 0.03), and remained after adjustment for age, serum phosphate, serum parathyroid hormone, low-density lipoprotein cholesterol, smoking history, and diabetes (model adjusted R 2 = 0.36, serum Mg and AAC score B = −11.44, p = 0.00). This translates to a 0.1 mmol/L increase in serum Mg being independently associated with a 1.1-point decrease in AAC score. Conclusions Our findings suggest that Mg may inhibit vascular calcification. If this association is replicated across larger studies with serial Mg and vascular calcification measurements, interventions that increase serum Mg and their effect on vascular calcification warrant further investigation in the PD population. Electronic supplementary material The online version of this article (doi:10.1186/s12882-017-0549-y) contains supplementary material, which is available to authorized users.

The tumor suppressor BAP1 interacts with chromatin-associated proteins and regulates cell proliferation, but its mechanism of action and regulation remain poorly defined. We show that the ubiquitin-conjugating enzyme UBE2O multi-monoubiquitinates the nuclear localization signal of BAP1, thereby inducing its cytoplasmic sequestration. This activity is counteracted by BAP1 autodeubiquitination through intramolecular interactions. Significantly, we identified cancer-derived BAP1 mutations that abrogate autodeubiquitination and promote its cytoplasmic retention, indicating that BAP1 autodeubiquitination ensures tumor suppression. The antagonistic relationship between UBE2O and BAP1 is also observed during adipogenesis, whereby UBE2O promotes differentiation and cytoplasmic localization of BAP1. Finally, we established a putative targeting consensus sequence of UBE2O and identified numerous chromatin remodeling factors as potential targets, several of which tested positive for UBE2O-mediated ubiquitination. Thus, UBE2O defines an atypical ubiquitin-signaling pathway that coordinates the function of BAP1 and establishes a paradigm for regulation of nuclear trafficking of chromatin-associated proteins.

Antibodies that recognize specific histone modifications are invaluable tools to study chromatin structure and function. There are numerous commercially available antibodies that recognize a remarkable diversity of histone modifications. Unfortunately, many of them fail to work in certain applications or lack the high degree of specificity required of these reagents. The production of affinity-purified polyclonal antibodies against histone modifications demands a little effort but, in return, provides extremely valuable tools that overcome many of the concerns and limitations of commercial antibodies. We present a series of protocols and guidelines for the production and use of large amounts of polyclonal antibodies that recognize modifications of canonical histones. Our protocols can be applied to obtain antibodies that occur in histone variants and proteins other than histones. In addition, some of our protocols are compatible with the production of monoclonal or recombinant antibodies.

Antibodies that recognize specific histone modifications are invaluable tools to study chromatin structure and function. There are numerous commercially available antibodies that recognize a remarkable diversity of histone modifications. Unfortunately, many of them fail to work in certain applications or lack the high degree of specificity required of these reagents. The production of affinity-purified polyclonal antibodies against histone modifications demands a little effort but, in return, provides extremely valuable tools that overcome many of the concerns and limitations of commercial antibodies. We present a series of protocols and guidelines for the production and use of large amounts of polyclonal antibodies that recognize modifications of canonical histones. Our protocols can be applied to obtain antibodies that occur in histone variants and proteins other than histones. In addition, some of our protocols are compatible with the production of monoclonal or recombinant antibodies.

The mechanism of action of valproate (VPA), a widely prescribed short chain fatty acid with anticonvulsant and anticancer properties, remains poorly understood. Here, the yeast Saccharomyces cerevisiae was used as model to investigate the biological consequences of VPA exposure. We found that low pH strongly potentiates VPA-induced growth inhibition. Transcriptional profiling revealed that under these conditions, VPA modulates the expression of genes involved in diverse cellular processes including protein folding, cell wall organisation, sexual reproduction, and cell cycle progression. We further investigated the impact of VPA on selected processes and found that this drug: i) activates markers of the unfolded protein stress response such as Hac1 mRNA splicing; ii) modulates the cell wall integrity pathway by inhibiting the activation of the Slt2 MAP kinase, and synergizes with cell wall stressors such as micafungin and calcofluor white in preventing yeast growth; iii) prevents activation of the Kss1 and Fus3 MAP kinases of the mating pheromone pathway, which in turn abolishes cellular responses to alpha factor; and iv) blocks cell cycle progression and DNA replication. Overall, our data identify heretofore unknown biological responses to VPA in budding yeast, and highlight the broad spectrum of cellular pathways influenced by this chemical in eukaryotes.

Background Australia’s National Cervical Screening Program currently recommends cytological screening every 2 years for women aged 18–69 years. Human papillomavirus (HPV) vaccination was implemented in 2007 with high population coverage, and falls in high-grade lesions in young women have been reported extensively. This decline prompted a major review of the National Cervical Screening Program and new clinical management guidelines, for which we undertook this analysis. Methods We did eff ectiveness modelling and an economic assessment of potential new screening strategies, using a model of HPV transmission, vaccination, natural history, and cervical screening. First, we evaluated 132 screening strategies, including those based on cytology and primary HPV testing. Second, after a recommendation was made to adopt primary HPV screening with partial genotyping and direct referral to colposcopy of women positive for HPV16/18, we evaluated the fi nal eff ect of HPV screening after incorporating new clinical guidelines for women positive for HPV. Both evaluations considered both unvaccinated and vaccinated cohorts. Findings Strategies entailing HPV testing every 5 years and either partial genotyping for HPV16/18 or cytological co-testing were the most effective. One of the most effective and cost-effective strategies comprised primary HPV screening with referral of women positive for oncogenic HPV16/18 direct to colposcopy, with refl excytological triage for women with other oncogenic types and direct referral for those in this group with high-grade cytological findings. After incorporating detailed clinical guidelines recommendations, this strategy is predicted to reduce cervical cancer incidence and mortality by 31% and 36%, respectively, in unvaccinated cohorts, and by 24% and 29%, respectively, in cohorts offered vaccination. Furthermore, this strategy is predicted to reduce costs by up to 19% for unvaccinated cohorts and 26% for cohorts offered vaccination, compared with the current programme. Interpretation Primary HPV screening every 5 years with partial genotyping is predicted to be substantially more effective and potentially cost-saving compared with the current cytology-based screening programme undertaken every 2 years. These findings underpin the decision to transition to primary HPV screening with partial genotyping in the Australian National Cervical Screening Program, which will occur in May, 2017. The fi rst component of this evaluation was funded by the Medical Services Advisory Committee Australia (MSAC application 1122). The Department of Health (Australia) funded Cancer Council Australia to develop the renewed clinical management guidelines for prevention of cervical cancer; Cancer Council NSW (J-BL, KTS, MAS, MH, Y-JK, XMX, MC, LSV, and KC) was subcontracted to perform some of this work as part of the technical team, and some modelling work undertaken for this contract is included in the submitted paper. Development of the model used in the evaluation was funded by a range of further sources including the NHMRC (project grants APP440200 and APP1007518), the Medical Services Advisory Committee, Department of Health Australia, Cancer Council Australia and Cancer Council NSW, the New Zealand Ministry of Health, and the UK Health Technologies Assessment (HTA). KC receives salary support from NHMRC Australia (Career Development Fellowship APP1082989). We thank the Renewal Steering Committee and the Cervical Cancer Screening Guidelines Working Party (of which IH is Chair) for their guidance in development of the clinical management pathways incorporated into the model. We also thank Robert Walker for assistance in the development of the dynamic HPV model and running strategies in the dynamic HPV model

Rivaling or cooperating with other post-translational modifications, ubiquitination plays central roles in regulating numerous cellular processes. Not surprisingly, gain- or loss-of-function mutations in several components of the ubiquitin system are causally linked to human pathologies including cancer. The covalent attachment of ubiquitin to target proteins occurs in sequential steps and involves ubiquitin ligases (E3s) which are the most abundant enzymes of the ubiquitin system. Although often associated with proteasomal degradation, ubiquitination is also involved in regulatory events in a proteasome-independent manner. Moreover, ubiquitination is reversible and specific proteases, termed deubiquitinases (DUBs), remove ubiquitin from protein substrates. While we now appreciate the importance of ubiquitin signaling in coordinating a plethora of physio-pathological processes, the molecular mechanisms are not fully understood. This review summarizes current findings on the critical functions exerted by E3s and DUBs in transcriptional control, particularly chromatin remodeling and transcription initiation/elongation.

This study aimed to evaluate the use of a shared electronic primary health care record (EHR) to assist with medicines reconciliation in the hospital from admission to discharge.: This is a prospective cross-sectional, comparison evaluation for 2 phases, in a short-term elderly admissions ward in the United Kingdom. In phase 1, full reconciliation of the medication history was attempted, using conventional methods, before accessing the EHR, and then the EHR was used to verify the reconciliation. In phase 2, the EHR was the initial method of retrieving the medication history-validated by conventional methods.: Where reconciliation was led by conventional methods, and before any access to the EHR was attempted, 28 (28%) of hospital prescriptions were found to contain errors. Of 99 prescriptions subsequently checked using the EHR, only 50 (50%) matched the EHR. Of the remainder, 25% of prescriptions contained errors when verified by the EHR. However, 26% of patients had an incorrect list of current medications on the EHR.Using the EHR as the primary method of reconciliation, 33 (32%) of 102 prescriptions matched the EHR. Of those that did not match, 39 (38%) of prescriptions were found to contain errors. Furthermore, 37 (36%) of patients had an incorrect list of current medications on the EHR.The most common error type on the discharge prescription was drug omission; and on the EHR, wrong drug. Common potentially serious errors were related to unidentified allergies and adverse drug reactions.: The EHR can reduce medication errors. However, the EHR should be seen as one of a range of information sources for reconciliation; the primary source being the patient or their carer. Both primary care and hospital clinicians should have read-and-write access to the EHR to reduce errors at care transitions. We recommend further evaluation studies.

Background Bilateral oophorectomy is commonly performed at the time of hysterectomy for benign disease. Indications for oophorectomy vary, but in most cases relatively little high-quality information is available to inform the surgeon or patient regarding the relative risks and benefits of ovarian conservation or removal. This review will address the common clinical situations when oophorectomy may be performed and will evaluate the evidence for risk and benefit in each of these circumstances. The aim of this review is to bring together the evidence regarding oophorectomy in pre- and post-menopausal women and to highlight the areas needing further study. Methods We searched the published literature for studies related to outcomes following surgical menopause, risk-reducing surgery for ovarian cancer, surgical treatment for endometriosis, bilateral oophorectomy for benign disease and treatment for premenstrual syndrome/premenstrual dysphoric disorder. Results Rates of oophorectomy at the time of hysterectomy for benign disease appear to be increasing. There is good evidence to support bilateral salpingoophorectomy (BSO) as a risk-reducing surgery for women at high risk of ovarian cancer, but relatively little evidence to support oophorectomy or BSO in other circumstances. There is growing evidence from observational studies that surgical menopause may impact negatively on future cardiovascular, psychosexual, cognitive and mental health. Conclusion Clinicians and patients should fully consider the relative risks and benefits of oophorectomy on an individual basis prior to surgery.

Adult-type granulosa cell tumors (GCTs) of the ovary are generally low-grade malignancies, but late metastases are relatively common. Limited data suggest that recurrent GCTs may exhibit altered morphology and/or biologic behavior, but few studies have directly compared primary and recurrent tumors in individual patients. Fourteen GCTs in which histologic material was available from both the primary tumor and one or more metastases were reviewed, and the mitotic index (MI) and Ki-67 labelling index (KI) were evaluated using carefully specified methodology. The findings were also correlated with the time interval to tumor recurrence. The median interval to first recurrence was 6.6 years (range: 2.2 to 12.2 yr). There were only minor differences in tumor morphology between the primary and metastatic GCTs. None of the cases exhibited high-grade (sarcomatoid) transformation. There was a wide range in MI and KI in the GCTs and no consistent correlation was seen between these indices in the paired primary and recurrent neoplasms. There was also no association between the MI and the KI and the time interval to metastasis. In conclusion, metastatic GCTs generally maintain their morphologic features even after multiple recurrences over many years. Cellular proliferation in GCT is variable, and there is no uniform alteration in proliferation indices between paired primary and metastatic lesions. Therefore, data derived from the analysis of primary GCT may not always be applicable to recurrent tumors. These findings may have implications for management including the potential response of GCT to adjuvant therapies.

Frozen section is a reliable technique in gynecologic pathology and is widely used to guide intraoperative management in patients presenting with ovarian masses. However, there are limited data regarding the diagnostic accuracy of frozen section in specific subtypes of ovarian neoplasia. Our impression that primary clear cell carcinoma (CCC) causes disproportionate diagnostic difficulty led us to review the intraoperative and final histopathologic reports from a consecutive series of 44 CCC that were subject to frozen-section assessment and to compare the results with a similar number of primary serous and endometrioid carcinomas. The original intraoperative slides from those CCC with discordant diagnoses were also reviewed. Review of the diagnostic reports showed that CCC was less frequently specifically identified than serous or endometrioid carcinomas on frozen section (44% cases compared with 55% and 65%, respectively), although the differences were not statistically significant. Difficulties in distinguishing primary ovarian carcinoma from tumors metastatic to the ovary occurred in a minority of cases of all histologic subtypes, but was slightly more frequent in CCC. Two CCC were misdiagnosed as borderline epithelial tumors and 1 case as a dysgerminoma. Review of the frozen-section slides from the CCC with discrepant intraoperative diagnoses showed features suggestive or indicative of the correct diagnosis in 7 (39%) of 18 cases.

To compare the efficacy of spherical polyvinyl alcohol (PVA) particles versus conventional PVA particles for uterine artery embolization (UAE).Of 149 patients with 1-year follow-up after UAE, 96 received conventional PVA particles and 53 received spherical PVA particles. Severity of symptoms was ranked on an 11-point numeric rating scale (0-10). The changes in severity of symptoms after embolization, blood hemoglobin level, and the size of the dominant tumor depicted by ultrasonography were used to assess the efficacy of the two types of particles. The number of hysterectomies and myomectomies in each group was also recorded as evidence of UAE failure.On 1-year follow-up, patients treated with conventional PVA showed average numeric rating scale score improvements of 4.6 in menorrhagia, 2.9 in dysmenorrhea, 3.7 in pressure sensation, and 3.4 in urinary frequency. With spherical PVA, the average improvements were 3.0 in menorrhagia, 2.4 in dysmenorrhea, 3.1 in pressure sensation, and 2.0 in urinary frequency. Except in dysmenorrhea, all differences were significant (P.001). With conventional PVA, there was an 8-mg/mL increase in blood hemoglobin level versus a 3-mg/mL increase with spherical PVA (P.05). With conventional PVA, there was a 28-mm (34%) average reduction in diameter of the dominant tumor versus a 15.7-mm (19%) reduction with spherical PVA (P = .01). Eight of 96 patients (8%) treated with conventional PVA underwent hysterectomy or myomectomy during the entire length of the study, versus six of 53 patients (11%) treated with spherical PVA (P = .6). No patient underwent multiple embolizations.In comparison with conventional PVA particles, UAE with the use of spherical PVA particles resulted in less fibroid tumor shrinkage and less improvement in clinical symptoms.

No consensus exists which patients with surgical stage 1 epithelial ovarian should receive postoperative chemotherapy. The purpose of this study was to evaluate the prognostic impact of preoperative CA-125 and to establish a prognostic index to identify patients in different risk categories.Data of 600 surgically staged patients with FIGO stage 1 EOC treated in eleven gynecological cancer centers in Australia, the USA and Europe were analyzed. Eligible patients include those with invasive EOC where a preoperative CA-125 was obtained and standard surgical staging performed. Overall survival (OS) was chosen as study endpoint. Preoperative CA-125 values were compared with other prognostic factors, and univariate and multivariate Cox models were calculated.Two hundred and one patients (33.5%) had preoperative CA-125or =30 U/ml and CA-125 levelsor =30 U/ml were associated with lower grade, sub-stage 1A and mucinous histologic cell type. Patients with elevated CA-125 levels were more likely to receive chemotherapy. OS probability was 95% and 85% for patients with pretreatment CA-125or =30 U/ml and30 U/ml, respectively (p 0.003). Multivariate analysis confirmed preoperative serum CA-12530 U/ml (OR 2.7) and age at diagnosis70 years (OR 2.6) as the only independent predictors for overall survival.Pretreatment of CA-125or =30 U/ml dominates over histologic cell type, sub-stage and grade to identify a subgroup of FIGO stage 1 patients with a genuinely good prognosis with extremely good survival and who could possibly be spared with adjuvant chemotherapy.

While analyzing dual-energy X-ray absorptiometry (DXA) examinations, we observed that, on occasion, the Ward region of interest (ROI) was positioned either unexpectedly or differently between successive examinations. When this occurred, it appeared to be either a marker of a compromised examination or of incident disease. This prompted a systematic inquiry. It became apparent that, while in general seeking the region of least areal density, the Ward ROI is positioned differently by the machines available to us from 2 particular manufacturers (General Electric Co. and Hologic Inc.). Three reviews were thus undertaken: (1) a prospective systematic examination of 200 unselected consecutive DXA examinations made with a General Electric Co. machine, 80 having had follow-up examinations and 245 made with a Hologic Inc. device; (2) a prospective systematic examination of 625 consecutive, unselected DXA examinations that were repeat examinations; and (3) a retrospective examination of a file of 86 cases collected for pedagogical purposes, predominantly made with a Hologic Inc. device. The commonest cause of an unusual position of the Ward area was compromised patient positioning or change in body habitus. Changes between examinations were, in addition if less often, apt to reflect physiological change or disease. Unusual positioning or a change in position of the Ward ROI is easily observed. It does not occur frequently, but, when it does, it may be useful in directing attention to either technical factors or incidental diseases. Observation of the position of the Ward ROI may thus be a quality assurance, and occasionally a diagnostic, tool.