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AbstractThe digital transformation of the educational landscape is an integral part of 21st-century learning, yet not all regions have capitalized on the benefits edtech brings. However, Northern Ireland’s (NI’s) education system presents a uniquely opportune environment for embracing edtech, acting as a veritable Goldilocks zone—where conditions appear just right for educational technology’s successful deployment. This work provides a significant expansion to the range and depth of research into educational technologies in NI and important point of reference for schooling, internationally. Notably, the research reveals an urgent need for a robust teacher competence framework. This framework would focus on developing the digital skills of educators, which would, in turn, enhance their digital capital—the skills, knowledge, and attitudes toward digital technologies that enable meaningful engagement in digital activities. The findings also underscore the critical importance of a strategic vision in the application of digital technology in pedagogy.

ABSTRACTSocial work is a demanding profession requiring a range of skills, competencies, and knowledge. Students are expected to learn about these practice related issues through immersion in real world experiences during their practice placement. A cross-sectional, retrospective survey was used to explore Finnish social work students’ (N= 95) experiences of learning activities employed by their supervisors during the practice placement, and the usefulness of these activities for developing professional competence and a sense of social work identity. Findings confirmed that students received a wide range of learning opportunities during their placement, but that there was considerable variation in the regularity of learning activities. The most useful learning activities included a collaborative working relationships and activities involving the student and their practice teacher, such as feedback, reflecting on work, feelings and values, observing others, and being assisted to learn new skills. In contrast, providing theoretical perspectives and linking theory to practice were regarded as least useful. Students with a lower overall learning activity score, were less likely to develop an understanding of social work identity during their placement. These results contribute to a growing evidence base, which can inform social work academics and practice teachers about learning activities that need to be offered to promote practice competence and professional identity of students, in preparation for professionally qualifying.

ATR is a key kinase in the DNA-damage response (DDR) that is synthetic lethal with several other DDR proteins, making it an attractive target for the treatment of genetically selected solid tumors. Herein we describe the discovery of a novel ATR inhibitor guided by a pharmacophore model to position a key hydrogen bond. Optimization was driven by potency and selectivity over the related kinase mTOR, resulting in the identification of camonsertib (RP-3500) with high potency and excellent ADME properties. Preclinical evaluation focused on the impact of camonsertib on myelosuppression, and an exploration of intermittent dosing schedules to allow recovery of the erythroid compartment and mitigate anemia. Camonsertib is currently undergoing clinical evaluation both as a single agent and in combination with talazoparib, olaparib, niraparib, lunresertib, or gemcitabine (NCT04497116, NCT04972110, NCT04855656). A preliminary recommended phase 2 dose for monotherapy was identified as 160 mg QD given 3 days/week.

ABSTRACTThis article discusses a series of interviews with migrants from the North of Ireland to Britain during the Troubles (1969–1998) to explore how they narrate their experiences of movement and settlement by talking about voice and accent. Drawing specifically on two interviews—one with someone who felt her accent caused her to be seen as illiberal and uncivilized, and another who felt he could use his accent situationally and actively, sometimes to his advantage—we argue that accent is a site where interviewees can describe aspects of their memories of migration. Additionally, we argue that existing sociological work on voice, accent, and Irishness in Britain provides useful conceptual framing for this kind of research, but that an oral history methodology makes a more nuanced understanding of accent possible, both in terms of its relationship to individual life trajectories and in terms of the specific histories it relates to (in this instance, the history of the war in both Ireland and Britain).

ABSTRACT:The island of Ireland has been divided for the past century by an international border, now a border between the EU and the UK. While Northern Ireland, part of the UK, and the Republic of Ireland have similar challenges and opportunities in their education systems, and there is evidence that each jurisdiction has learned from the other, the systems have evolved differently and have diverged significantly, and those differences, and the impact and effectiveness of school-level education in both parts of the island, form the focus of this paper. With post-Brexit pressures on the political union within the UK and increased fervour in discussions around trading border locations and constitutional positions, it is timely to examine the challenges, and opportunities, should the two systems converge once again.

Firefighters in the line of duty are exposed to many hazardous air toxics released from burning vegetation and other materials that may cause severe health risks. Current literature does not consider complex mixtures and cumulative impacts of these air toxics when assessing firefighter exposure risk. This study aims to determine if cumulative exposure to mixtures of air toxics will put firefighters at risk in the context of current firefighter exposure regulations. This was tested using CO exposure and air toxics data collected during prescribed burns. Personal CO monitors were deployed to 122 firefighters at 31 prescribed burns across Australian temperate forests. CO concentrations were used to determine equivalent exposures for air toxics using their emission ratio, which were then used to calculate cumulative exposure. Average personal monitor CO exposure was 9.2 ppm across all burns, with 1-min maximum ranging between 0.3 and 703 ppm. Work safe Australia exposure standards were exceeded for 6 firefighters out of 122. Five individual firefighters had average cumulative exposures exceeding 100% exposure limit. Six toxicological classes were identified to be the most hazardous, causing eye disorders, upper and lower respiratory disorders, skin disorders and cancer. Across these classes, three toxins contributed significantly to the cumulative exposure; respirable particles (< 3 μm), formaldehyde and acrolein. Using the cumulative exposure methodology as described here and a reduction in the CO exposure standards to account for the numerous air toxics emitted during a fire would supply decision makers with a tool to better identify exposure risks.

Bees are important pollinators and are essential for the reproduction of many plants in natural and agricultural ecosystems. However, bees can have adverse ecological effects when introduced to areas outside of their native geographic ranges. Dozens of non-native bee species are currently found in North America and have raised concerns about their potential role in the decline of native bee populations. Osmia taurusSmith (Hymenoptera: Megachilidae) is a mason bee native to eastern Asia that was first reported in the United States in 2002. Since then, this species has rapidly expanded throughout the eastern part of North America. Here, we present a comprehensive review of the natural history of O. taurus, document its recent history of spread through the United States and Canada, and discuss the evidence suggesting its potential for invasiveness. In addition, we compare the biology and history of colonization of O. taurusto O. cornifrons(Radoszkowski), another non-native mason bee species now widespread in North America. We highlight gaps of knowledge and future research directions to better characterize the role of O. taurusin the decline of native Osmiaspp. Panzer and the facilitation of invasive plant-pollinator mutualisms.

Amplification of the CCNE1locus on chromosome 19q12 is prevalent in multiple tumour types, particularly in high-grade serous ovarian cancer, uterine tumours and gastro-oesophageal cancers, where high cyclin E levels are associated with genome instability, whole-genome doubling and resistance to cytotoxic and targeted therapies1–4. To uncover therapeutic targets for tumours with CCNE1amplification, we undertook genome-scale CRISPR–Cas9-based synthetic lethality screens in cellular models of CCNE1amplification. Here we report that increasing CCNE1dosage engenders a vulnerability to the inhibition of the PKMYT1 kinase, a negative regulator of CDK1. To inhibit PKMYT1, we developed RP-6306, an orally bioavailable and selective inhibitor that shows single-agent activity and durable tumour regressions when combined with gemcitabine in models of CCNE1amplification. RP-6306 treatment causes unscheduled activation of CDK1 selectively in CCNE1-overexpressing cells, promoting early mitosis in cells undergoing DNA synthesis. CCNE1overexpression disrupts CDK1 homeostasis at least in part through an early activation of the MMB–FOXM1 mitotic transcriptional program. We conclude that PKMYT1 inhibition is a promising therapeutic strategy for CCNE1-amplified cancers.

This article from the Arctic Studies Center Newsletter discusses the experiences of two interns, Lola Page and Adele Roulston, who worked with researchers Igor Krupnik and Stephen Loring on various projects. Adele Roulston's internship with Dr. Loring involved tasks such as compiling an index for a manuscript, organizing photographs, and creating a map of a specific region in the Northwest Territories. She also learned archaeological skills and worked with artifacts from the Aleutian Islands and Labrador. Roulston expresses gratitude for the opportunity and highlights the valuable experiences she gained for her future career in museum anthropology. [Extracted from the article]

This article explores the relations among childhood innocence, queerness, and nation-building in Rosemary Manning’s boarding school narrative, The Chinese Garden (1962). Recent scholarship by Lee Edelman and Kathryn Bond Stockton has questioned the innocence we invest in the figure of the child, and how this innocence has become a precondition for generating heteronormative models of nation-building and imagined futures. Analyzing the boarding school community in The Chinese Garden, this article examines how the figure of the child is used to confirm the compulsory narrative of nation-building even as it queers the very concepts of place and belonging. In the narrative, set in 1928, the year of the publication of The Well of Loneliness, the protagonist witnesses an erotic relationship between two girls without wanting to acknowledge what is happening; it examines both the yearning for innocence and a desire for sexual knowledge within a context of repressive normalization and antihomosexual panic. The Chinese Garden is also a fictional autobiography, foregrounding Manning’s own resistance to her pre-Stonewall historical present, and her fascination with the queer past.

Presents a speech given by Heather Roulston Ettinger, principal of Roulson Company, delivered to the Akron Community Foundation on April 13, 2000. The issue of women and philanthropy; The progress of women over time; Women in the corporate world; Statistics on wealth owned by women in the United States; How women approach their charitable giving.

This article discusses the recently launched curriculum for nursing associates and the authors' involvement in the development of a medicine management module. This required recognition of the challenges in an ever-changing healthcare environment with, in this instance, limited guidance from the Nursing and Midwifery Council and associated professional organisations and with multiple stakeholders to satisfy. Curriculum development therefore required consideration of the concerns of service users and providers regarding the integration of this new, poorly understood role, its potential effect on skill mix and lack of knowledge regarding proposed regulation.

Supplemental Digital Content is available in the text.Triple-negative breast cancer (TNBC) is typically aggressive, difficult to treat, and commonly metastasizes to the visceral organs and soft tissues, including the lungs and the brain. Taxanes represent the most effective and widely used therapeutic class in metastatic TNBC but possess limiting adverse effects that often result in a delay, reduction, or cessation of their use. DZ-2384 is a candidate microtubule-targeting agent with a distinct mechanism of action and strong activity in several preclinical cancer models, with reduced toxicities. DZ-2384 is highly effective in patient-derived taxane-sensitive and taxane-resistant xenograft models of TNBC at lower doses and over a wider range relative to paclitaxel. When comparing compound exposure at minimum effective doses relative to safe exposure levels, the therapeutic window for DZ-2384 is 14–32 compared with 2.0 and less than 2.8 for paclitaxel and docetaxel, respectively. DZ-2384 is effective at reducing brain metastatic lesions when used at maximum tolerated doses and is equivalent to paclitaxel. Drug distribution experiments indicate that DZ-2384 is taken up more efficiently by tumor tissue but at equivalent levels in the brain compared with paclitaxel. Selective DZ-2384 uptake by tumor tissue may in part account for its wider therapeutic window compared with taxanes. In view of the current clinical efforts to combine chemotherapy with immune checkpoint inhibitors, we demonstrate that DZ-2384 acts synergistically with anti-CTLA-4 immunotherapy in a syngeneic murine model. These results demonstrate that DZ-2384 has a superior pharmacologic profile over currently used taxanes and is a promising therapeutic agent for the treatment of metastatic TNBC.

Teachers of qualitative research tasked with conveying the complexity and diversity of paradigmatic difference to novice researchers face challenges, including how to convey complexity without misrepresenting topics, facilitating respectful and ethical dialogue among students, and finding sufficient time within the curriculum to examine multiple paradigms. This special issue presents articles that consider how teachers of qualitative inquiry envision and enact the teaching of qualitative research from a Big Tent perspective. These authors’ explorations of ways to pursue work with/across/within/against differences in worldviews and practices assume that this knowledge is critical for the preparation of the next generation of qualitative researchers who will engage in complex topics of inquiry that contribute to policy development and building just and equitable societies, as well as making theoretical and methodological advances.

This article reflects on how teachers of qualitative research methods might facilitate and promote dialogue across paradigmatic and disciplinary difference. Using the musical concept of polyphony, together with phenomenologist Alfred Schutz's ideas on intersubjectivity and transcendence (1962, 1996), the article discusses possible ways of thinking about breakdowns in understanding in classroom encounters across theoretical and paradigmatic difference. Schutz was intensely interested in examining how intersubjectivity is accomplished by members of society and, with Luckmann (Schutz & Luckmann, 1973, 1989), reflected on the boundaries of understanding that people encounter that involve “little,” “medium,” and “great” transcendencies. Using these ideas, the article examines approaches that teachers of qualitative inquiry might use with students to examine paradigmatic and theoretical difference.

Southeast Asia experiences frequent fires in fuel‐rich tropical peatlands, leading to extreme episodes of regional haze with high concentrations of fine particulate matter (PM2.5) impacting human health. In a study published recently, the first field measurements of PM2.5emission factors for tropical peat fires showed larger emissions than from other fuel types. Here we report even higher PM2.5emission factors, measured at newly ignited peat fires in Malaysia, suggesting that current estimates of fine particulate emissions from peat fires may be underestimated by a factor of 3 or more. In addition, we use both field and laboratory measurements of burning peat to provide the first mechanistic explanation for the high variability in PM2.5emission factors, demonstrating that buildup of a surface ash layer causes the emissions of PM2.5to decrease as the peat fire progresses. This finding implies that peat fires are more hazardous (in terms of aerosol emissions) when first ignited than when still burning many days later. Varying emission factors for PM2.5also have implications for our ability to correctly model the climate and air quality impacts downwind of the peat fires. For modelers able to implement a time‐varying emission factor, we recommend an emission factor for PM2.5from newly ignited tropical peat fires of 58 g of PM2.5per kilogram of dry fuel consumed (g/kg), reducing exponentially at a rate of 9%/day. If the age of the fire is unknown or only a single value may be used, we recommend an average value of 24 g/kg. This paper provides evidence that peat fire emissions of fine particulates are much larger than for other fires when the peat is newly ignited but decrease rapidly as the fire progresses. This is important because it means that newly ignited fires are particularly detrimental to ambient air quality in impacted regions. In this study we show that emissions of PM2.5from Malaysian peat fires are likely 3 times larger than previously assumedWe show that the emissions of fine particulate matter from peat fires in the field decrease rapidly with the age of the fireWe show that the likely cause is the accumulation of an ash layer as the peat burns below the surface

ABSTRACTPractice learning is integral to the curriculum for qualifying social work students. Accreditation standards require regular student supervision and exposure to specific learning activities. Most agencies offer high-quality placements, but organizational cutbacks may affect supervision and restrict the development of competence and professional identity. Undergraduate social work students in Northern Ireland universities (n=396) were surveyed about the usefulness of the learning activities they received on placement for developing practice competence and professional social work identity. Results suggest that students most valued regular supervision, constructive feedback, observing social workers, and thinking critically about the social work role. Differences were reported across placements with students feeling disadvantaged in agencies where there was no clear social work role.

Renal cell carcinomas with MITF aberrations demonstrate a wide morphologic spectrum, highlighting the need to consider these entities within the differential diagnosis of renal tumors encountered in clinical practice. Herein, we describe our experience with application of clinical fluorescence in situ hybridization (FISH) assays for detection of TFE3 and TFEB gene aberrations from 85 consecutive renal cell carcinoma cases submitted to our genitourinary FISH service. Results from 170 FISH assays performed on these tumors were correlated with available clinicopathologic findings. Ninety-eight percent of renal tumors submitted for FISH evaluation were from adult patients. Thirty-one (37%) tumors were confirmed to demonstrate MITF aberrations (21 TFE3 translocation, 4 TFEB translocation, and 6 TFEB amplification cases). Overall, renal cell carcinomas with MITF aberrations demonstrated morphologic features overlapping with clear cell, papillary, or clear cell papillary renal cell carcinomas. Renal cell carcinomas with MITF aberrations were significantly more likely to demonstrate dual (eosinophilic and clear) cytoplasmic tones (P=0.030), biphasic TFEB translocation renal cell carcinoma-like morphology (P=0.002), psammomatous calcifications (P=0.002), and nuclear pseudoinclusions (P=0.001) than renal cell carcinomas without MITF aberrations. Notably, 7/9 (78%) renal cell carcinomas exhibiting subnuclear clearing and linear nuclear array (6 of which showed high World Health Organization/International Society of Urological Pathology nucleolar grade) demonstrated TFE3 translocation, an association that was statistically significant when compared with renal cell carcinomas without MITF aberrations (P=0.009). In this cohort comprising consecutive cases, TFEB-amplified renal cell carcinomas were more commonly identified than renal cell carcinomas with TFEB translocations, and four (67%) of these previously unreported TFEB-amplified renal cell carcinomas demonstrated oncocytic and papillary features with a high World Health Organization/International Society of Urological Pathology nucleolar grade. In summary, TFE3 and TFEB FISH evaluation aids in identification and accurate classification of renal cell carcinomas with MITF aberrations, including TFEB-amplified renal cell carcinoma, which may demonstrate aggressive behavior.

Renal cell carcinomas with MITF aberrations demonstrate a wide morphologic spectrum, highlighting the need to consider these entities within the differential diagnosis of renal tumors encountered in clinical practice. Herein, we describe our experience with application of clinical fluorescence in situhybridization (FISH) assays for detection of TFE3and TFEBgene aberrations from 85 consecutive renal cell carcinoma cases submitted to our genitourinary FISH service. Results from 170 FISH assays performed on these tumors were correlated with available clinicopathologic findings. Ninety-eight percent of renal tumors submitted for FISH evaluation were from adult patients. Thirty-one (37%) tumors were confirmed to demonstrate MITF aberrations (21 TFE3translocation, 4 TFEBtranslocation, and 6 TFEBamplification cases). Overall, renal cell carcinomas with MITF aberrations demonstrated morphologic features overlapping with clear cell, papillary, or clear cell papillary renal cell carcinomas. Renal cell carcinomas with MITF aberrations were significantly more likely to demonstrate dual (eosinophilic and clear) cytoplasmic tones (P=0.030), biphasic TFEBtranslocation renal cell carcinoma-like morphology (P=0.002), psammomatous calcifications (P=0.002), and nuclear pseudoinclusions (P=0.001) than renal cell carcinomas without MITF aberrations. Notably, 7/9 (78%) renal cell carcinomas exhibiting subnuclear clearing and linear nuclear array (6 of which showed high World Health Organization/International Society of Urological Pathology nucleolar grade) demonstrated TFE3translocation, an association that was statistically significant when compared with renal cell carcinomas without MITF aberrations (P=0.009). In this cohort comprising consecutive cases, TFEB-amplified renal cell carcinomas were more commonly identified than renal cell carcinomas with TFEBtranslocations, and four (67%) of these previously unreported TFEB-amplified renal cell carcinomas demonstrated oncocytic and papillary features with a high World Health Organization/International Society of Urological Pathology nucleolar grade. In summary, TFE3and TFEBFISH evaluation aids in identification and accurate classification of renal cell carcinomas with MITF aberrations, including TFEB-amplified renal cell carcinoma, which may demonstrate aggressive behavior.

Finches are sociable birds and are highly recommended for novice bird owners. The most common type of finches are the zebra and society finches. They feed mostly on seeds and can easily get accustomed to new surroundings. The more brightly-colored finches such as the rainbow-colored Lady Gouldian require more care. The young ones do not acclimatize easily and have delicate health. Exotic finches such as cordons, gold-breasted and tricolor nuns need live insect food supplements to their regular seed diet.

AbstractThe moth Symmetrischema lavernella(Chambers) (Lepidoptera: Gelechiidae) has two feeding strategies on its host plant PhysalisLinnaeus (Solanaceae): a fruitworm that feeds on developing ovules in a fruit and a budworm that consumes a floral bud. The fruitworm strategy occurs when a neonate caterpillar enters the ovary of a flower bud above a size threshold (~4 mm in Physalis heterophyllaNees), consumes the developing ovules, and pupates in the fruit. In P. heterophylla, occupancy of the ovary by S. lavernellacauses fruit development to occur in the absence of pollination, indicating that the caterpillar initiates developmental pathways associated with pollination. The budworm strategy occurs in buds below ~4 mm, involves consumption of the ovary and immature anthers, and results in pupation inside the uninflated calyx. The two strategies co-occur on plants, determined by the sizes of the available buds at the time of oviposition. The most prominent natural enemy of S. lavernellausing the fruitworm strategy was the frugivorous caterpillar Heliothis subflexa(Guenée) (Lepidoptera: Noctuidae), also a specialist of Physalis. The larger Heliothis subflexafeeds on the fruit externally, consumes S. lavernella, and caused 31.3% of fruitworm mortality in field surveys. Parasitoids included wasps (Hymenoptera) of the families Braconidae, Ichneumonidae, and Chalcididae.

Corporate finance consultancies in Leeds, England, are working with more clients who have a presence in national or world markets. The local mergers and acquisitions marketplace has expanded rapidly during 1996 and 1997. Deals completed during 1996 and 1997 have often involved clients who have a national or international presence. Leeds consultancies are being introduced to contracts by company branches elsewhere in the country.

Excitotoxicity, a neuronal death process in neurological disorders such as stroke, is initiated by the overstimulation of ionotropic glutamate receptors. Although dysregulation of proteolytic signaling networks is critical for excitotoxicity, the identity of affected proteins and mechanisms by which they induce neuronal cell death remain unclear. To address this, we used quantitative N-terminomics to identify proteins modified by proteolysis in neurons undergoing excitotoxic cell death. We found that most proteolytically processed proteins in excitotoxic neurons are likely substrates of calpains, including key synaptic regulatory proteins such as CRMP2, doublecortin-like kinase I, Src tyrosine kinase and calmodulin-dependent protein kinase IIβ (CaMKIIβ). Critically, calpain-catalyzed proteolytic processing of these proteins generates stable truncated fragments with altered activities that potentially contribute to neuronal death by perturbing synaptic organization and function. Blocking calpain-mediated proteolysis of one of these proteins, Src, protected against neuronal loss in a rat model of neurotoxicity. Extrapolation of our N-terminomic results led to the discovery that CaMKIIα, an isoform of CaMKIIβ, undergoes differential processing in mouse brains under physiological conditions and during ischemic stroke. In summary, by identifying the neuronal proteins undergoing proteolysis during excitotoxicity, our findings offer new insights into excitotoxic neuronal death mechanisms and reveal potential neuroprotective targets for neurological disorders.

Purpose: The purpose of this paper is to present considerations for developing a writing community for doctoral students. Design/methodology/approach: The paper reflects on data from a self-study of a writing seminar in which the authors were involved. The authors examined students’ writing samples and peer-review comments, email correspondence, online discussion board postings, meeting minutes and participants’ reflections on their participation in the seminar. Findings: While doctoral students described benefits from their participation in the writing seminar, the paper provides a cautionary tale concerning the challenges that can arise in the development and delivery of interventions that focus on developing writing communities involving doctoral students. Research limitations/implications: This article draws on findings from an examination of a writing intervention to consider potential challenges that faculty and students face in developing writing communities. Findings may not apply to other kinds of settings, and they are limited by the small number of participants involved. Practical implications: The paper discusses strategies that might be used to inform faculty in the development of writing communities for doctoral students. Social implications: The authors’ experiences in developing and delivering a writing seminar highlight the importance of the process of trust-building for students to perceive the value of feedback from others so that they can respond to the technical demands of doctoral writing. Originality/value: There is a growing body of work on the value of writing interventions for doctoral students such as retreats and writing groups. These are frequently facilitated by faculty whose area of expertise is in teaching writing. This paper contributes understanding to what is needed for faculty who are not writing instructors to facilitate groups of this sort. Participants must demonstrate a sufficient level of competence as writers to review others’ work; develop trusting, collegial relationships with one another; and be willing to contribute to others’ development and make a commitment to accomplishing the required tasks.

Chromosomal abnormalities are important for the risk stratification of acute lymphoblastic leukemia/lymphoma (ALL). However, approximately 30% of pediatric and 50% of adult patients lack abnormalities with clinical relevance by traditional cytogenetic analysis. We integrated cytogenetic, fluorescence in situhybridization, and whole-genome single-nucleotide polymorphism array results from 60 consecutive clinical ALL cases. By cytogenetic and/or fluorescence in situhybridization analyses, recurring abnormalities with clinical relevance were observed in 33 B-cell ALL (B-ALL), including t(9;22), hyperdiploidy, KMT2Atranslocation, ETV6-RUNX1, intrachromosomal amplification of chromosome 21, near haploidy or low hypodiploidy, and t(8;22). Single-nucleotide polymorphism array analysis found additional aberrations with prognostic or therapeutic implication in 21 B-ALL and two T-cell ALL, including IKZF1deletion, intrachromosomal amplification of chromosome 21 (one case with a normal karyotype), low hypodiploidy (two cases with a normal karyotype), and one case each with fusion genes ETV6-NTRK3, CRLF2-P2RY8, NUP214-ABL1, and SET-NUP214. IKZF1deletion was noted in nine B-ALL with t(9;22), one B-ALL with t(4;11), five B-ALL with a normal karyotype, and three B-ALL with nonrecurring karyotypic abnormalities. Combining single-nucleotide polymorphism array with chromosome and fluorescence in situhybridization assays, the detection rate for clinically significant abnormal results increased from 56% to 75%. Whole-genome single-nucleotide polymorphism array analysis detects cytogenetically undetectable clinically significant aberrations and should be routinely applied at diagnosis of ALL.

Forward-looking information about climate risks is critical for decision makers, but the provision and accuracy of such information is limited. Innovative prediction-market designs could provide a mechanism to enhance applied climate research in an incentive-compatible way.

Nice coverage of the 2007 Mr. Olympia in the December 2007 issue of FLEX. I would like to see more direct comparisons of all eight mandatory poses between the top [...]

Tumor markers are used to monitor patients with certain types of cancer, but their usefulness as a screening tool for diagnosis of early-stage disease is limited. Tests are described by their sensitivity and specificity. The sensitivity of a test measures its ability to show a positive result when the disease is present; specificity measures the test's ability to show negative results in the absence of the disease. Both measures are independent of the incidence of the disease. When screening for a disease, the incidence of disease will be very low. The most important factor in test evaluation for the clinician is positive predictive value. This is the percentage of positive results that are truly positive. Positive predictive value provides the odds that the elevated level of the marker is actually due to the disease. As the incidence of disease changes, so does the positive predictive value; if the disease prevalence is low, the positive predictive value is reduced. Screening is effective if there is a high incidence of the disease in the group being screened. Unless tests have 100 percent sensitivity and 100 percent specificity, a low incidence of disease will reduce the positive predictive value. It is suggested that more emphasis be placed on identifying potential high-risk groups which could then be appropriately monitored. (Consumer Summary produced by Reliance Medical Information, Inc.)

Former general practitioner Mirfield, West Yorkshire (b Londonderry 1915; q Queen's University, Belfast, 1938; MD), died 7 December 2003. During the second world war Jim Roulston was a captain in [...]

Combinations of ataxia telangiectasia- and Rad3-related kinase inhibitors (ATRis) and poly(ADP-ribose) polymerase inhibitors (PARPis) synergistically kill tumor cells through modulation of complementary DNA repair pathways, but their tolerability is limited by hematological toxicities. To address this, we performed a genome-wide CRISPR-Cas9 screen to identify genetic alterations that hypersensitize cells to a combination of the ATRi RP-3500 with PARPi, including deficiency in RNase H2, RAD51paralog mutations, or the “alternative lengthening of telomeres” telomere maintenance mechanism. We show that RP-3500 and PARPi combinations kill cells carrying these genetic alterations at doses sub-therapeutic as single agents. We also demonstrate the mechanism of combination hypersensitivity in RNase H2-deficient cells, where we observe an irreversible replication catastrophe, allowing us to design a highly efficacious and tolerable in vivodosing schedule. We present a comprehensive dataset to inform development of ATRi and PARPi combinations and an experimental framework applicable to other drug combination strategies.

Follicular lymphoma (FL) constitutes the second most common non-Hodgkin lymphoma in the western world. FL carries characteristic recurrent structural genomic aberrations. However, information regarding the coding genome in FL is still evolving. Here, we describe the results of massively parallel exome sequencing and single nucleotide polymorphism 6.0 array genomic profiling of 11 highly purified FL cases, and 1 transformed FL case and the validation of selected mutations in 102 FL cases. We report the identification of 15 novel recurrently mutated genes in FL. These include frequent mutations in the linker histone genes HIST1H1 B-E(27%) and mutations in OCT2(also known as POU2F2; 8%), IRF8(6%), and ARID1A(11%). A subset of the mutations in HIST1H1 B-Eaffected binding to DNMT3B, and mutations in HIST1H1 B-Eand in EZH2or ARID1Awere largely mutually exclusive, implicating HIST1H1 B-Ein epigenetic deregulation in FL. Mutations in OCT2 (POU2F2)affected its transcriptional and functional properties as measured through luciferase assays, the biological analysis of stably transduced cell lines, and global expression profiling. Finally, multiple novel mutated genes located within regions of acquired uniparental disomy in FL are identified. In aggregate, these data substantially broaden our understanding of the genomic pathogenesis of FL.

Follicular lymphoma (FL) constitutes the second most common non-Hodgkin lymphoma in the western world. FL carries characteristic recurrent structural genomic aberrations. However, information regarding the coding genome in FL is still evolving. Here, we describe the results of massively parallel exome sequencing and single nucleotide polymorphism 6.0 array genomic profiling of 11 highly purified FL cases, and 1 transformed FL case and the validation of selected mutations in 102 FL cases. We report the identification of 15 novel recurrently mutated genes in FL. These include frequent mutations in the linker histone genes HIST1H1 B-E (27%) and mutations in OCT2 (also known as POU2F2; 8%), IRF8 (6%), and ARID1A (11%). A subset of the mutations in HIST1H1 B-E affected binding to DNMT3B, and mutations in HIST1H1 B-E and in EZH2 or ARID1A were largely mutually exclusive, implicating HIST1H1 B-E in epigenetic deregulation in FL. Mutations in OCT2 (POU2F2) affected its transcriptional and functional properties as measured through luciferase assays, the biological analysis of stably transduced cell lines, and global expression profiling. Finally, multiple novel mutated genes located within regions of acquired uniparental disomy in FL are identified. In aggregate, these data substantially broaden our understanding of the genomic pathogenesis of FL.