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Proactively identifying where land conversion might occur is critical to targeted and effective conservation planning. Previous efforts to map future habitat loss have largely focused on forested systems and have been limited in their consideration of drivers of loss. We developed a 1-km resolution, global map of land conversion pressure from multiple drivers, referred to as the conversion pressure index (CPI). The CPI combines past rates of anthropogenic change, as measured by temporal human modification maps, with suitability maps for potential future expansion by large-scale development. The CPI thus offers a new way to measure a cumulative gradient of anthropogenic pressure as opposed to categorical land cover change. We find that nearly 23% of land across 200 countries have relatively high conversion pressure, potentially impacting over 460 million ha of intact natural lands. We illustrate how this information can be used to identify areas for proactive conservation to avoid future loss and ensure that national commitments under the Kunming-Montreal Global Biodiversity and Paris Agreement Climate Frameworks are upheld. [ABSTRACT FROM AUTHOR]

Restoring tree cover changes albedo, which is the fraction of sunlight reflected from the Earth's surface. In most locations, these changes in albedo offset or even negate the carbon removal benefits with the latter leading to global warming. Previous efforts to quantify the global climate mitigation benefit of restoring tree cover have not accounted robustly for albedo given a lack of spatially explicit data. Here we produce maps that show that carbon-only estimates may be up to 81% too high. While dryland and boreal settings have especially severe albedo offsets, it is possible to find places that provide net-positive climate mitigation benefits in all biomes. We further find that on-the-ground projects are concentrated in these more climate-positive locations, but that the majority still face at least a 20% albedo offset. Thus, strategically deploying restoration of tree cover for maximum climate benefit requires accounting for albedo change and we provide the tools to do so. Restoring tree cover is a prominent climate solution but can cause global warming due to changes in albedo. This paper maps albedo and carbon changes from restoring tree cover to highlight where the greatest net climate benefits can be achieved. [ABSTRACT FROM AUTHOR]

NDP52 is an autophagy receptor involved in the recognition and degradation of invading pathogens and damaged organelles. Although NDP52 was first identified in the nucleus and is expressed throughout the cell, to date, there is no clear nuclear functions for NDP52. Here, we use a multidisciplinary approach to characterise the biochemical properties and nuclear roles of NDP52. We find that NDP52 clusters with RNA Polymerase II (RNAPII) at transcription initiation sites and that its overexpression promotes the formation of additional transcriptional clusters. We also show that depletion of NDP52 impacts overall gene expression levels in two model mammalian cells, and that transcription inhibition affects the spatial organisation and molecular dynamics of NDP52 in the nucleus. This directly links NDP52 to a role in RNAPII-dependent transcription. Furthermore, we also show that NDP52 binds specifically and with high affinity to double-stranded DNA (dsDNA) and that this interaction leads to changes in DNA structure in vitro. This, together with our proteomics data indicating enrichment for interactions with nucleosome remodelling proteins and DNA structure regulators, suggests a possible function for NDP52 in chromatin regulation. Overall, here we uncover nuclear roles for NDP52 in gene expression and DNA structure regulation. An autophagy receptor, NDP52, is recruited to the nucleus where it can bind DNA. The authors show this promotes changes in chromatin accessibility which supports transcription initiation, providing a direct link between autophagy and transcription regulation. [ABSTRACT FROM AUTHOR]

Human papillomavirus (HPV)-associated cervical cancer is a leading cause of cancer deaths in women. Here we present an integrated multi-omic analysis of 643 cervical squamous cell carcinomas (CSCC, the most common histological variant of cervical cancer), representing patient populations from the USA, Europe and Sub-Saharan Africa and identify two CSCC subtypes (C1 and C2) with differing prognosis. C1 and C2 tumours can be driven by either of the two most common HPV types in cervical cancer (16 and 18) and while HPV16 and HPV18 are overrepresented among C1 and C2 tumours respectively, the prognostic difference between groups is not due to HPV type. C2 tumours, which comprise approximately 20% of CSCCs across these cohorts, display distinct genomic alterations, including loss or mutation of the STK11 tumour suppressor gene, increased expression of several immune checkpoint genes and differences in the tumour immune microenvironment that may explain the shorter survival associated with this group. In conclusion, we identify two therapy-relevant CSCC subtypes that share the same defining characteristics across three geographically diverse cohorts. Human papillomavirus (HPV) is a known cause of cervical cancer. Here, the authors perform a multi-omic analysis using published cervical squamous cell carcinoma cohorts from the USA, Europe, and SubSaharan Africa and identify two cervical squamous cell carcinoma subtypes that display prognostic differences. [ABSTRACT FROM AUTHOR]

Chromosome folding has profound impacts on gene regulation, whose evolutionary consequences are far from being understood. Here we explore the relationship between 3D chromatin remodelling in mouse germ cells and evolutionary changes in genome structure. Using a comprehensive integrative computational analysis, we (i) reconstruct seven ancestral rodent genomes analysing whole-genome sequences of 14 species representatives of the major phylogroups, (ii) detect lineage-specific chromosome rearrangements and (iii) identify the dynamics of the structural and epigenetic properties of evolutionary breakpoint regions (EBRs) throughout mouse spermatogenesis. Our results show that EBRs are devoid of programmed meiotic DNA double-strand breaks (DSBs) and meiotic cohesins in primary spermatocytes, but are associated in post-meiotic cells with sites of DNA damage and functional long-range interaction regions that recapitulate ancestral chromosomal configurations. Overall, we propose a model that integrates evolutionary genome reshuffling with DNA damage response mechanisms and the dynamic spatial genome organisation of germ cells. The role of genome folding in the heritability and evolvability of structural variations is not well understood. Here the authors investigate the impact of the three-dimensional genome topology of germ cells in the formation and transmission of gross structural genomic changes detected from comparing whole-genome sequences of 14 rodent species. [ABSTRACT FROM AUTHOR]

Letter to the Editor [ABSTRACT FROM AUTHOR]

Animals are essential genetic tools in scientific research and global resources in agriculture. In both arenas, a single sex is often required in surplus. The ethical and financial burden of producing and culling animals of the undesired sex is considerable. Using the mouse as a model, we develop a synthetic lethal, bicomponent CRISPR-Cas9 strategy that produces male- or female-only litters with one hundred percent efficiency. Strikingly, we observe a degree of litter size compensation relative to control matings, indicating that our system has the potential to increase the yield of the desired sex in comparison to standard breeding designs. The bicomponent system can also be repurposed to generate postnatal sex-specific phenotypes. Our approach, harnessing the technological applications of CRISPR-Cas9, may be applicable to other vertebrate species, and provides strides towards ethical improvements for laboratory research and agriculture. In areas such as animal research and agriculture a single sex is often required in abundance, leading to wasted resources and ethical considerations. Here the authors develop a CRISPR/Cas9 mediated synthetic lethal system that enables the production of single sex offspring that can be repurposed for use in multiple organisms. [ABSTRACT FROM AUTHOR]

Over the course of an individual’s lifetime, normal human cells accumulate mutations1. Here we compare the mutational landscape in 29 cell types from the soma and germline using multiple samples from the same individuals. Two ubiquitous mutational signatures, SBS1 and SBS5/40, accounted for the majority of acquired mutations in most cell types, but their absolute and relative contributions varied substantially. SBS18, which potentially reflects oxidative damage2, and several additional signatures attributed to exogenous and endogenous exposures contributed mutations to subsets of cell types. The rate of mutation was lowest in spermatogonia, the stem cells from which sperm are generated and from which most genetic variation in the human population is thought to originate. This was due to low rates of ubiquitous mutational processes and may be partially attributable to a low rate of cell division in basal spermatogonia. These results highlight similarities and differences in the maintenance of the germline and soma.The authors report the mutational landscape of 29 cell types from microdissected biopsies from 19 organs and explore the mechanisms underlying mutation rates in normal tissues. [ABSTRACT FROM AUTHOR]

Somatic mutations drive the development of cancer and may contribute to ageing and other diseases1,2. Despite their importance, the difficulty of detecting mutations that are only present in single cells or small clones has limited our knowledge of somatic mutagenesis to a minority of tissues. Here, to overcome these limitations, we developed nanorate sequencing (NanoSeq), a duplex sequencing protocol with error rates of less than five errors per billion base pairs in single DNA molecules from cell populations. This rate is two orders of magnitude lower than typical somatic mutation loads, enabling the study of somatic mutations in any tissue independently of clonality. We used this single-molecule sensitivity to study somatic mutations in non-dividing cells across several tissues, comparing stem cells to differentiated cells and studying mutagenesis in the absence of cell division. Differentiated cells in blood and colon displayed remarkably similar mutation loads and signatures to their corresponding stem cells, despite mature blood cells having undergone considerably more divisions. We then characterized the mutational landscape of post-mitotic neurons and polyclonal smooth muscle, confirming that neurons accumulate somatic mutations at a constant rate throughout life without cell division, with similar rates to mitotically active tissues. Together, our results suggest that mutational processes that are independent of cell division are important contributors to somatic mutagenesis. We anticipate that the ability to reliably detect mutations in single DNA molecules could transform our understanding of somatic mutagenesis and enable non-invasive studies on large-scale cohorts.NanoSeq is used to detect mutations in single DNA molecules and analyses show that mutational processes that are independent of cell division are important contributors to somatic mutagenesis. [ABSTRACT FROM AUTHOR]

Malignant rhabdoid tumour (MRT) is an often lethal childhood cancer that, like many paediatric tumours, is thought to arise from aberrant fetal development. The embryonic root and differentiation pathways underpinning MRT are not firmly established. Here, we study the origin of MRT by combining phylogenetic analyses and single-cell mRNA studies in patientderived organoids. Comparison of somatic mutations shared between cancer and surrounding normal tissues places MRT in a lineage with neural crest-derived Schwann cells. Single-cell mRNA readouts of MRT differentiation, which we examine by reverting the genetic driver mutation underpinning MRT, SMARCB1 loss, suggest that cells are blocked en route to differentiating into mesenchyme. Quantitative transcriptional predictions indicate that combined HDAC and mTOR inhibition mimic MRT differentiation, which we confirm experimentally. Our study defines the developmental block of MRT and reveals potential differentiation therapies. [ABSTRACT FROM AUTHOR]

To constrain global warming, we must strongly curtail greenhouse gas emissions and capture excess atmospheric carbon dioxide1,2. Regrowing natural forests is a prominent strategy for capturing additional carbon3, but accurate assessments of its potential are limited by uncertainty and variability in carbon accumulation rates2,3. To assess why and where rates differ, here we compile 13,112 georeferenced measurements of carbon accumulation. Climatic factors explain variation in rates better than land-use history, so we combine the field measurements with 66 environmental covariate layers to create a global, one-kilometre-resolution map of potential aboveground carbon accumulation rates for the first 30 years of natural forest regrowth. This map shows over 100-fold variation in rates across the globe, and indicates that default rates from the Intergovernmental Panel on Climate Change (IPCC)4,5 may underestimate aboveground carbon accumulation rates by 32 per cent on average and do not capture eight-fold variation within ecozones. Conversely, we conclude that maximum climate mitigation potential from natural forest regrowth is 11 per cent lower than previously reported3 owing to the use of overly high rates for the location of potential new forest. Although our data compilation includes more studies and sites than previous efforts, our results depend on data availability, which is concentrated in ten countries, and data quality, which varies across studies. However, the plots cover most of the environmental conditions across the areas for which we predicted carbon accumulation rates (except for northern Africa and northeast Asia). We therefore provide a robust and globally consistent tool for assessing natural forest regrowth as a climate mitigation strategy. A one-kilometre-resolution map of aboveground carbon accumulation rates of forest regrowth shows 100-fold variation across the globe, with rates 32% higher on average than IPCC estimates. [ABSTRACT FROM AUTHOR]

All normal somatic cells are thought to acquire mutations, but understanding of the rates, patterns, causes and consequences of somatic mutations in normal cells is limited. The uterine endometrium adopts multiple physiological states over a lifetime and is lined by a gland-forming epithelium1,2. Here, using whole-genome sequencing, we show that normal human endometrial glands are clonal cell populations with total mutation burdens that increase at about 29 base substitutions per year and that are many-fold lower than those of endometrial cancers. Normal endometrial glands frequently carry 'driver' mutations in cancer genes, the burden of which increases with age and decreases with parity. Cell clones with drivers often originate during the first decades of life and subsequently progressively colonize the epithelial lining of the endometrium. Our results show that mutational landscapes differ markedly between normal tissues—perhaps shaped by differences in their structure and physiology—and indicate that the procession of neoplastic change that leads to endometrial cancer is initiated early in life. Whole-genome sequencing of normal human endometrial glands shows that most are clonal cell populations and frequently carry cancer driver mutations that occur early in life, and that parity has a protective effect. [ABSTRACT FROM AUTHOR]

A catalytic membrane reactor with a Au–Pd catalyst, impregnated at the inner side of the membrane, was studied in the catalytic oxidation of benzyl alcohol in flow. The reactor comprised of four concentric sections. The liquid substrate flowed in the annulus created by an inner tube and the membrane. The membrane consisted of 3 layers of α-alumina and a titania top layer with 5 nm average pore size. Oxygen was fed on the outer side of the membrane, and its use allowed the controlled contact of the liquid and the gas phase. Experiments revealed excellent stability of the impregnated membrane and selectivities to benzaldehyde were on average > 95%. Increasing the pressure of the gas phase and decreasing liquid flowrates and benzyl alcohol concentration resulted in an increased conversion, while selectivities to benzaldehyde remained constant and in excess of 95%. [ABSTRACT FROM AUTHOR]

The colorectal adenoma–carcinoma sequence has provided a paradigmatic framework for understanding the successive somatic genetic changes and consequent clonal expansions that lead to cancer1. However, our understanding of the earliest phases of colorectal neoplastic changes—which may occur in morphologically normal tissue—is comparatively limited, as for most cancer types. Here we use whole-genome sequencing to analyse hundreds of normal crypts from 42 individuals. Signatures of multiple mutational processes were revealed; some of these were ubiquitous and continuous, whereas others were only found in some individuals, in some crypts or during certain periods of life. Probable driver mutations were present in around 1% of normal colorectal crypts in middle-aged individuals, indicating that adenomas and carcinomas are rare outcomes of a pervasive process of neoplastic change across morphologically normal colorectal epithelium. Colorectal cancers exhibit substantially increased mutational burdens relative to normal cells. Sequencing normal colorectal cells provides quantitative insights into the genomic and clonal evolution of cancer. Genome sequencing of hundreds of normal colonic crypts from 42 individuals sheds light on mutational processes and driver mutations in normal colorectal epithelial cells. [ABSTRACT FROM AUTHOR]

Background: Public health crises in primary care and psychiatry have prompted development of innovative, integrated care models, yet undergraduate medical education is not currently designed to prepare future physicians to work within such systems.Aim: To implement an integrated primary care-psychiatry clerkship for third-year medical students.Setting: Undergraduate medical education, amid institutional curriculum reform.Participants: Two hundred thirty-seven medical students participated in the clerkship in academic years 2015-2017.Program Description: Educators in psychiatry, internal medicine, and pediatrics developed a 12-week integrated Biopsychosocial Approach to Health (BAH)/Primary Care-Psychiatry Clerkship. The clerkship provides students clinical experience in primary care, psychiatry, and integrated care settings, and a longitudinal, integrated didactic series covering key areas of interface between the two disciplines.Program Evaluation: Students reported satisfaction with the clerkship overall, rating it 3.9-4.3 on a 1-5 Likert scale, but many found its clinical curriculum and administrative organization disorienting. Students appreciated the conceptual rationale integrating primary care and psychiatry more in the classroom setting than in the clinical setting.Conclusions: While preliminary clerkship outcomes are promising, further optimization and evaluation of clinical and classroom curricula are ongoing. This novel educational paradigm is one model for preparing students for the integrated healthcare system of the twenty-first century. [ABSTRACT FROM AUTHOR]

This paper describes the function of a software tool for identifying urban agglomerations in low-information settings using free, open data. The framework outlined here is designed to work using polygon data. This paper describes the advantages and disadvantages of using polygon-based geographies in regional analysis, discusses the practical and ethical challenges of distinguishing urban from rural regions, and discusses the relevance of this tool in the analysis of global city regions. It also describes the logical structure of our polygon-based software tool and directs interested readers to the source code. We finally examine the agglomeration results for Sri Lanka and compare them with published urbanization figures. We conclude that there are very large disparities between our model's outputs and the urbanization estimates from the United Nations and that our tools can be used as a less discretionary way to identify actual levels of urbanization. We hope that other analysts will continue to refine the progression toward a less discretionary model of identifying urban regions. [ABSTRACT FROM AUTHOR]

Platinum-based doublet chemotherapy with or without bevacizumab is the standard of care for the initial management of advanced and metastatic non-small cell lung cancer (NSCLC) without a targetable molecular abnormality. However, the majority of patients with NSCLC will ultimately develop resistance to initial platinum-based chemotherapy, and many remain candidates for subsequent lines of therapy. Randomised trials over the past 10-15 years have established pemetrexed (non-squamous histology), docetaxel, erlotinib and gefitinib as approved second-line agents in NSCLC without targetable driver mutations or rearrangements. Trials comparing these agents with other chemotherapy, evaluating the addition of an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) to chemotherapy or the addition of another targeted agent to erlotinib or gefitinib have all failed to demonstrate an improvement in overall survival for patients with NSCLC. In contrast, recent data comparing therapy with novel monoclonal antibodies against programmed cell death 1 (PD-1) or PD ligand (PD-L1) pathway versus standard chemotherapy following platinum failure have demonstrated significant improvements in overall survival. Therapy with nivolumab or pembrolizumab would now be considered standard second-line therapy in patients without contraindication to immune checkpoint inhibitors. Atezolizumab also appears promising in this setting. [ABSTRACT FROM AUTHOR]

Background: We examined clinical outcomes in a population-based cohort of EGFR mutant advanced NSCLC patients, exploring the potential role of factors including tumour EGFR mutation fraction and cellularity in predicting outcomes.Methods: A cohort of patients with EGFR mutant advanced NSCLC was identified (N =2 93); clinical outcomes, pathologic and treatment details were collected. Tumour response was determined from radiology and clinical notes. Association between demographic and pathologic variables EGFR TKI response, time to treatment failure (TTF) and overall survival (OS) was examined using logistic regression and proportional hazards regression. EGFR TKI response rates were summarised by percent mutation fraction to explore their association.Results: Higher mutation fraction was associated with greater EGFR TKI response rate (odds ratio 1.58, 95% CI = 1.21-2.07, P = 0.0008), longer TTF (hazard ratio 0.80, 95% CI = 0.68-0.92, P = 0.003) and better OS (hazard ratio 0.81, 95% CI = 0.67-0.99, P = 0.04). However, even in patients with ⩽ 5% mutation fraction, response rate was 34%. Females had longer TTF (P = 0.02).Conclusions: EGFR mutation fraction in tumour samples was significantly associated with response, TTF and OS. Despite this, no lower level of mutation fraction was detected for which EGFR TKI should be withheld in those with activating EGFR mutations. [ABSTRACT FROM AUTHOR]

The simultaneous sequencing of a single cell's genome and transcriptome offers a powerful means to dissect genetic variation and its effect on gene expression. Here we describe G&T-seq, a method for separating and sequencing genomic DNA and full-length mRNA from single cells. By applying G&T-seq to over 220 single cells from mice and humans, we discovered cellular properties that could not be inferred from DNA or RNA sequencing alone. [ABSTRACT FROM AUTHOR]

Patients with colorectal cancer (CRC) face a number of challenges leading up to diagnosis; however, research is limited regarding their specific needs during the pre-diagnosis period. A multicenter cross-sectional survey was conducted to elicit information about the CRC experience during the pre-diagnosis phase. Across the three sites, 104 eligible patients were approached, and 82 patients completed the survey, for a total response rate of 78.9 %. The needs most identified by participants during the pre-diagnosis period were informational (31.6 %) and emotional (20.3 %) needs; social needs were rated as the least important need for these patients (7 %). The majority (84.0 %) reported that these needs were met. Participants reported feeling shocked or overwhelmed on learning of their diagnosis (57.1 %) and high levels of anxiety during this time (40.0 %). The majority (77.9 %) of participants reported that they were not directed to any resources to help address their anxiety. Informational and emotional needs are identified as the most important needs during the pre-diagnosis phase, and for most these needs are being met; however, some participants are experiencing high levels of anxiety without access to appropriate resources. Further work is required to understand the optimal mechanisms to address identified needs during this pre-diagnosis period and to assess the potential benefits and costs of addressing these needs. [ABSTRACT FROM AUTHOR]

Purpose: This study aimed to describe the perceptions of women with early stage breast cancer regarding their involvement in treatment decision making (TDM). Methods: Eligible women with early stage breast cancer were recruited immediately after their first consultation with a specialist. Semistructured personal interviews were held prior to treatment. Interviews were audiotaped, transcribed, and analyzed. Results: Nineteen women with early stage breast cancer considering surgery ( n = 6) or adjuvant therapy ( n = 13) participated. Women described being involved in various stages of TDM and interacting with informal networks and specialists. Women's descriptions suggest that (1) the concept of involvement in TDM may have a broader meaning for patients than strictly their decisional role and (2) inclusion of significant others in TDM contributes to the patient's sense of involvement. Conclusions: Conceptualization and measurement of patient involvement in TDM have often been framed within the context of the medical encounter and the patient's perceived or actual role in this process. Our findings raise questions about what involvement means to patients with early stage breast cancer and suggest that the focus on patient involvement in TDM within the medical encounter may be too narrow to capture the meaning of involvement from the patient's perspective. [ABSTRACT FROM AUTHOR]

Patients with lung cancer have numerous and varying needs spanning across the cancer trajectory; however, only limited research has focused specifically on the pre-diagnosis phase. A multicentre cross-sectional survey was conducted to explore the experience of lung cancer patients during the pre-diagnosis phase. High levels of anxiety were reported by many participants (45.6 %). Informational (32.1 %), and emotional (24.1 %) needs were reported as most important; the majority (89.0 %) reported these needs were met. Most participants sought information throughout, with many (38.6 %) rating their oncology health care providers to be the best source of information. The majority (70.0 %) reported that they were not directed to any resources to help address their anxiety. During pre-diagnosis, informational and emotional needs appear most important, and for the majority, these were reportedly met. Although many experienced high levels of anxiety, few were directed to resources to address it. [ABSTRACT FROM AUTHOR]

Trans-acting genetic variants have a substantial, albeit poorly characterized, role in the heritable determination of gene expression. Using paired purified primary monocytes and B cells, we identify new predominantly cell type-specific cis and trans expression quantitative trait loci (eQTLs), including multi-locus trans associations to LYZ and KLF4 in monocytes and B cells, respectively. Additionally, we observe a B cell-specific trans association of rs11171739 at 12q13.2, a known autoimmune disease locus, with IP6K2 (P = 5.8 × 10?15), PRIC285 (P = 3.0 × 10?10) and an upstream region of CDKN1A (P = 2 × 10?52), suggesting roles for cell cycle regulation and peroxisome proliferator-activated receptor ? (PPAR?) signaling in autoimmune pathogenesis. We also find that specific human leukocyte antigen (HLA) alleles form trans associations with the expression of AOAH and ARHGAP24 in monocytes but not in B cells. In summary, we show that mapping gene expression in defined primary cell populations identifies new cell type-specific trans-regulated networks and provides insights into the genetic basis of disease susceptibility. [ABSTRACT FROM AUTHOR]

Purpose: To present an updated survival analysis of an open-label, parallel-group, phase IIB trial of BLP25 liposome vaccine (L-BLP25) in patients with stage IIIB or IV non-small-cell lung cancer (NSCLC). Methods: Patients were randomized to either L-BLP25 plus best supportive care (BSC) or BSC alone. Patients in the L-BLP25 arm received subcutaneous vaccinations of L-BLP25 930 μg weekly for 8 weeks, followed by maintenance vaccinations at 6-week intervals. Results: Median survival time was 4.2 months longer in patients receiving L-BLP25 plus BSC ( n = 88) than in those receiving BSC alone ( n = 83; 17.2 months vs. 13.0 months, respectively; hazard ratio [HR] 0.745, 95% confidence interval [CI] 0.533-1.042). The 3-year survival rate was 31% in patients receiving L-BLP25 plus BSC and 17% in those receiving BSC ( P = 0.035). In the stratified subset of patients with stage IIIB loco-regional (LR) disease, median survival time was 17.3 months longer in patients receiving L-BLP25 plus BSC ( n = 35) than in those receiving BSC ( n = 30; 30.6 months vs. 13.3 months, respectively; HR 0.548, 95% CI 0.301-0.999). In this subgroup, 3-year survival was 49% in patients receiving L-BLP25 plus BSC and 27% in those receiving BSC ( P = 0.070). Conclusions: Confirming the initial results, further follow-up continues to show that survival time for patients with stage IIIB/IV NSCLC was longer with L-BLP25 plus BSC compared with BSC alone, with the greatest difference seen in patients with stage IIIB LR disease. [ABSTRACT FROM AUTHOR]

Acute myeloid leukemia (AML) is a molecularly diverse malignancy with a poor prognosis whose largest subgroup is characterized by somatic mutations in NPM1, which encodes nucleophosmin. These mutations, termed NPM1c, result in cytoplasmic dislocation of nucleophosmin and are associated with distinctive transcriptional signatures, yet their role in leukemogenesis remains obscure. Here we report that activation of a humanized Npm1c knock-in allele in mouse hemopoietic stem cells causes Hox gene overexpression, enhanced self renewal and expanded myelopoiesis. One third of mice developed delayed-onset AML, suggesting a requirement for cooperating mutations. We identified such mutations using a Sleeping Beauty transposon, which caused rapid-onset AML in 80% of mice with Npm1c, associated with mutually exclusive integrations in Csf2, Flt3 or Rasgrp1 in 55 of 70 leukemias. We also identified recurrent integrations in known and newly discovered leukemia genes including Nf1, Bach2, Dleu2 and Nup98. Our results provide new pathogenetic insights and identify possible therapeutic targets in NPM1c+ AML. [ABSTRACT FROM AUTHOR]

The combination of density functional theory (DFT) calculations and kinetic analyses is a very useful approach to study surface reactions in heterogeneous catalysis. The present paper reviews some recent work applying this approach to Fischer–Tropsch (FT) synthesis. Emphasis is placed on the following fundamental issues in FT synthesis: (i) reactive sites for both hydrogenation and C–C coupling reactions; (ii) reaction mechanisms including carbene mechanism, CO-insertion mechanism and hydroxyl-carbene mechanism; (iii) selectivity with a focus on CH4 selectivity, α-olefin selectivity and chain growth probability; and (iv) activity. [ABSTRACT FROM AUTHOR]

Numerous attributes render the domestic dog a highly pertinent model for cancer-associated gene discovery. We performed microarray-based comparative genomic hybridization analysis of 60 spontaneous canine intracranial tumors to examine the degree to which dog and human patients exhibit aberrations of ancestrally related chromosome regions, consistent with a shared pathogenesis. Canine gliomas and meningiomas both demonstrated chromosome copy number aberrations (CNAs) that share evolutionarily conserved synteny with those previously reported in their human counterpart. Interestingly, however, genomic imbalances orthologous to some of the hallmark aberrations of human intracranial tumors, including chromosome 22/ NF2 deletions in meningiomas and chromosome 1p/19q deletions in oligodendrogliomas, were not major events in the dog. Furthermore, and perhaps most significantly, we identified highly recurrent CNAs in canine intracranial tumors for which the human orthologue has been reported previously at low frequency but which have not, thus far, been associated intimately with the pathogenesis of the tumor. The presence of orthologous CNAs in canine and human intracranial cancers is strongly suggestive of their biological significance in tumor development and/or progression. Moreover, the limited genetic heterogenity within purebred dog populations, coupled with the contrasting organization of the dog and human karyotypes, offers tremendous opportunities for refining evolutionarily conserved regions of tumor-associated genomic imbalance that may harbor novel candidate genes involved in their pathogenesis. A comparative approach to the study of canine and human intracranial tumors may therefore provide new insights into their genetic etiology, towards development of more sophisticated molecular subclassification and tailored therapies in both species. [ABSTRACT FROM AUTHOR]

The male-specific region of the Y chromosome is evolutionarily predisposed to accumulate genes important for spermatogenesis. Recent work in this laboratory identified two novel Y-linked transcripts that were upregulated in the testis in response to deletions on the chromosome arm Yq. This article reports the further characterisation of these two transcripts and their comparison to related X and autosomal genes. Both map to chromosome arm Yp, outside the Sxr b deletion interval, both are present in at least two copies on the Y, and both are expressed specifically in spermatids. Given the testicular phenotype of mice with deletions on the Y chromosome, both genes are therefore likely to function in spermatid differentiation. AK006152 is a novel mouse-specific gene with a single potential open reading frame, and it is unusual in that there appears to be no X-linked relative. H2al2y is a novel histone in the H2A superfamily and has multiple X-linked relatives and a single autosomal relative in mouse. The presence of a single X-linked copy in rat suggests that H2al amplification is mouse-specific, with the alternative explanation being an earlier amplification followed by gene loss. A phylogenetic analysis of H2al genes together with other H2A genes indicates that H2al is most closely related to the mammalian-specific H2A.Bbd family of histones. Interestingly, Ka/ Ks analysis indicates that the X and Y members of the H2al family may be under positive selection in mouse, while the autosomal copy is under purifying selection and presumably retains the ancestral function. [ABSTRACT FROM AUTHOR]

This paper examines a southern Ontario kettle-hole peatland (Spongy Lake) to determine its hydrogeological linkage with local and regional water tables. The water table in the peat deposit and lake are perched 6 m above the regional aquifer, and there are strong lateral and downward hydraulic gradients. The horizontal hydraulic gradient (Δh/Δz) measured at the edge of the peatland ranged between 0.15 and 0.23 and the vertical gradient reached -1.24 (i.e., downward flow). At depths less than 1.0 m, saturated hydraulic conductivity (Ks) ranged from 10-7 to 10-5 m s-1 and increased in magnitude with proximity to the peat surface. In an intermediate zone (1.0-4.0 m depth), Ks values ranged from 10-8 to 10-7 m s-1, while deeper clay materials had Ks values ranging from 10-9 to 10-8 m s-1. A clay layer directly below the deep peat limits downward seepage of water (one to two orders of magnitude less than evaporation). During periods of relatively high water, most seepage loss occurs laterally at the interface between mineral sediment and the peat. Spongy Lake is an important recharge zone for the regional aquifer, and the hydrologic and ecological integrity of the system should be protected. [ABSTRACT FROM AUTHOR]

Visual improvement following octreotide for growth hormone secreting pituitary macroadenomas is uncommon without tumour shrinkage. A 45-year old lady presented with blurred vision for 12 months. Visual assessment revealed a bitemporal hemianopia and CT scan demonstrated a large pituitary tumour with lateral and suprasellar extension. Acromegaly was confirmed by 75 g glucose tolerance testing. Primary transsphenoidal surgery was performed with normalisation of visual acuity and fields of vision. Post-operatively she had anterior pituitary hormone deficiency. As GH and IGF-1 levels remained elevated she underwent external pituitary irradiation. CT scanning demonstrated tumour shrinkage associated with a modest fall in GH levels. IGF-1 levels remained elevated falling to the age-related upper limit of normal after 5 years. At regular review she had stable visual acuity and fields of vision. She presented as an emergency 7 years from presentation with reduced vision and recurrence of bitemporal hemianopia. An MRI demonstrated a large pituitary adenoma. We therefore undertook a carefully monitored trial of octreotide with great caution with daily reassessment of acuity and fields. A decision was made to proceed to surgery in the event of deterioration or lack of improvement after a short trial over 5–7 days. We observed normalisation of visual acuity and perimetry within 3 days. She then commenced long-acting octreotide (Sandostatin LAR) 20 mg every 28 days. MRI after 1 week showed shrinkage of the tumour by a few millimetres. Five months later repeat MRI failed to show any further improvement in tumour size. However she remains well 29 months from treatment with normal vision and is being monitored carefully as her chosen form of therapy. Somatostatin analogues may be effective as therapy in a selected group of patients with acromegaly and visual loss who are not suitable for pituitary surgery. If used in this way the drug must be given cautiously with frequent detailed ongoing visual assessments. In this present case there has been a restoration of vision but the long-term outlook remains guarded without significant tumor shrinkage. [ABSTRACT FROM AUTHOR]

Objective: To develop and implement an evidence-based medicine (EBM) curriculum and determine its effectiveness in improving residents' EBM behaviors and skills.Design: Description of the curriculum and a multifaceted evaluation, including a pretest-posttest controlled trial.Setting: University-based primary care internal medicine residency program.Participants: Second- and third-year internal medicine residents (N = 34).Interventions: A 7-week EBM curriculum in which residents work through the steps of evidence-based decisions for their own patients. Based on adult learning theory, the educational strategy included a resident-directed tutorial format, use of real clinical encounters, and specific EBM facilitating techniques for faculty.Measurements and Main Results: Behaviors and self-assessed competencies in EBM were measured with questionnaires. Evidence-based medicine skills were assessed with a 17-point test, which required free text responses to questions based on a clinical vignette and a test article. After the intervention, residents participating in the curriculum (case subjects) increased their use of original studies to answer clinical questions, their examination of methods and results sections of articles, and their self-assessed EBM competence in three of five domains of EBM, while the control subjects did not. The case subjects significantly improved their scores on the EBM skills test (8.5 to 11.0, p = .001), while the control subjects did not (8.5 to 7.1, p = .09). The difference in the posttest scores of the two groups was 3.9 points (p = .001, 95% confidence interval 1.9, 5.9).Conclusions: An EBM curriculum based on adult learning theory improves residents' EBM skills and certain EBM behaviors. The description and multifaceted evaluation can guide medical educators involved in EBM training. [ABSTRACT FROM AUTHOR]

Objective: To evaluate a primary care internal medicine curriculum, the authors surveyed four years (1983-1986) of graduates of the primary care and traditional internal medicine residency programs at their institution concerning the graduates' preparation.Design: Mailed survey of alumni of a residency training program.Setting: Teaching hospital alumni.Subjects/methods: Of 91 alumni of an internal medicine training program for whom addresses had been found, 82 (90%) of the residents (20 primary care and 62 traditional) rated on a five-point Likert scale 82 items for both adequacy of preparation for practice and importance of training. These items were divided into five groups: traditional medical disciplines (e.g., cardiology), allied disciplines (e.g., orthopedics), areas related to medical practice (e.g., patient education), basic skills and knowledge (e.g., history and physical), and technical procedures.Main Results: Primary care residents were more likely to see themselves as primary care physicians versus subspecialists (84% versus 45%). The primary care graduates felt significantly better prepared in the allied disciplines and in areas related to medical practice (p less than 0.01). There was no significant difference overall in perceptions of preparation in the traditional medical disciplines, basic skills and knowledge, and procedures. The same results were obtained when the authors looked only at graduates from the two programs who spent more than 50% of their time as primary care physicians versus subspecialists. There was no significant difference between the two groups in the perceived importance of these areas to current practice.Conclusions: These results suggest that the primary care curriculum has prepared residents in areas particularly relevant to primary care practice. Additionally, these individuals feel as well prepared as do their colleagues in the traditional medical disciplines, basic skills and knowledge, and procedural skills. [ABSTRACT FROM AUTHOR]

Alkylating agents have been reported to yield response rates of up to 20% in hormone-refractory prostate cancer. Melphalan was studied in four small trials in which the drug was given orally. In this phase II trial, melphalan (30 mg/m2) was given intravenously every 28 days to 27 patients with hormone-refractory prostate cancer. Pharmacokinetic sampling was performed so as to describe the clearance of melphalan in this population and in an attempt to carry out pharmacodynamic modeling for toxicity and response. Prostate-specific antigen (PSA) was also assessed prospectively. No objective responses to this regimen were documented. The median survival for patients on this trial was 11.5 months. There was no correlation between drug clearance and measured creatinine clearance and no relationship between systemic exposure and toxicity. A decrease of > 50% in serum PSA that was sustained for > 6 weeks was documented in two patients, most notably in one patient who has survived for more than 29 months. Intravenous melphalan is not an active agent in hormone-refractory prostate cancer. [ABSTRACT FROM AUTHOR]

We report an alternative approach to transcriptome sequencing for the Illumina Genome Analyzer, in which the reverse transcription reaction takes place on the flowcell. No amplification is performed during the library preparation, so PCR biases and duplicates are avoided, and because the template is poly(A)+ RNA rather than cDNA, the resulting sequences are necessarily strand-specific. The method is compatible with paired- or single-end sequencing. [ABSTRACT FROM AUTHOR]

This report describes the use of thrombin to treat a type II endoleak which was causing continued abdominal aortic aneurysm expansion in a patient who had undergone endovascular repair. A small quantity of thrombin was injected into the leak by a percutaneous approach directly into the aneurysm sac using color doppler ultrasound. The procedure was successful and required only a few minutes to perform. We believe this procedure is an alternative to some of the more complex and technically challenging means of treating this lesion. [ABSTRACT FROM AUTHOR]

Beta 1-3, 1-4 glucans (“beta-glucans”) are one of the key components of the cell wall of cereals, complementing the main structural component cellulose. Beta-glucans are also an important source of soluble fibre in foods containing oats with claims of other beneficial nutritional properties such as plasma cholesterol lowering in humans. Key to the function of beta-glucans is their molecular weight and because of their high polydispersity - molecular weight distribution. Analytical ultracentrifugation provides a matrix-free approach (not requiring separation columns or media) to polymer molecular weight distribution determination. The sedimentation coefficient distribution is converted to a molecular weight distribution via a power law relation using an established procedure known as the Extended Fujita approach. We establish and apply the power law relation and Extended Fujita method for the first time to a series of native and processed oat beta-glucans. The application of this approach to beta-glucans from other sources is considered. [ABSTRACT FROM AUTHOR]

A 43-year-old woman presented with a several-month history of transient ischemic attacks 7 years following surgery for a malignant carotid body tumor. Angiography revealed a pseudoaneurysm at the distal vein graft anastomosis and a stenosis related to the proximal anastomosis. Due to the extensive previous surgery an endovascular approach was advocated and the pseudoaneurysm was successfully excluded using a covered stent (Wallgraft). This is, to our knowledge, the first time such an approach has been used following carotid body tumor excision. [ABSTRACT FROM AUTHOR]

Evaluates the case report of Kasthuri concerning the percutaneous ultrasound-guided thrombin injection of edoleaks. Claim of the author that the thrombin injection technique is new to them; Recurrence of type 2 endoleak.