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Multiple Myeloma is an incurable plasma cell malignancy with a poor survival rate that is usually treated with immunomodulatory drugs (iMiDs) and proteosome inhibitors (PIs). The malignant plasma cells quickly become resistant to these agents causing relapse and uncontrolled growth of resistant clones. From whole genome sequencing (WGS) and RNA sequencing (RNA-seq) studies, different high-risk translocation, copy number, mutational, and transcriptional markers can be identified. One of these markers, PHF19, epigenetically regulates cell cycle and other processes and is already studied using RNA-seq. In this study, we generate a large (325,025 cells and 49 patients) single cell multi-omic dataset and jointly quantify ATAC- and RNA-seq for each cell and matched genomic profiles for each patient. We identify an association between one plasma cell subtype with myeloma progression that we call relapsed/refractory plasma cells (RRPCs). These cells are associated with chromosome 1q alterations, TP53 mutations, and higher expression of PHF19. We also identify downstream regulation of cell cycle inhibitors in these cells, possible regulation by the transcription factor (TF) PBX1 on chromosome 1q, and determine that PHF19 may be acting primarily through this subset of cells. Translocations and copy number variations that affect multiple myeloma (MM) have not been investigated at the single cell level. Here, single cell multi-omics reveal the relationship between epigenetic regulation and cytogenetic events that lead to the increase of cell proliferation in MM. [ABSTRACT FROM AUTHOR]

Biallelic TP53 inactivation is the most important high-risk factor associated with poor survival in multiple myeloma. Classical biallelic TP53 inactivation has been defined as simultaneous mutation and copy number loss in most studies; however, numerous studies have demonstrated that other factors could lead to the inactivation of TP53. Here, we hypothesized that novel biallelic TP53 inactivated samples existed in the multiple myeloma population. A random forest regression model that exploited an expression signature of 16 differentially expressed genes between classical biallelic TP53 and TP53 wild-type samples was subsequently established and used to identify novel biallelic TP53 samples from monoallelic TP53 groups. The model reflected high accuracy and robust performance in newly diagnosed relapsed and refractory populations. Patient survival of classical and novel biallelic TP53 samples was consistently much worse than those with mono-allelic or wild-type TP53 status. We also demonstrated that some predicted biallelic TP53 samples simultaneously had copy number loss and aberrant splicing, resulting in overexpression of high-risk transcript variants, leading to biallelic inactivation. We discovered that splice site mutation and overexpression of the splicing factor MED18 were reasons for aberrant splicing. Taken together, our study unveiled the complex transcriptome of TP53, some of which might benefit future studies targeting abnormal TP53. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: Children with diabetes may display cognitive alterations although vascular disorders have not yet appeared. Variations in glucose levels together with relative insulin deficiency in treated type 1 diabetes have been reported to impact brain function indirectly through dysregulation of the hypothalamus–pituitary–adrenal axis. We have recently shown that enhancement of glucocorticoid levels in children with type 1 diabetes is dependent not only on glucocorticoid secretion but also on glucocorticoid tissue concentrations, which is linked to 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) activity. Hypothalamus–pituitary–adrenal axis dysfunction and memory alteration were further dissected in a juvenile rat model of diabetes showing that excess 11β-HSD1 activity within the hippocampus is associated with hippocampal-dependent memory deficits. Here, to investigate the causal relationships between diabetes, 11β-HSD1 activity and hippocampus-dependent memory deficits, we evaluated the beneficial effect of 11β-HSD1 inhibition on hippocampal-related memory in juvenile diabetic rats. We also examined whether diabetes-associated enhancement of hippocampal 11β-HSD1 activity is due to an increase in brain glucose concentrations and/or a decrease in insulin signalling. Methods: Diabetes was induced in juvenile rats by daily i.p. injection of streptozotocin for 2 consecutive days. Inhibition of 11β-HSD1 was obtained by administrating the compound UE2316 twice daily by gavage for 3 weeks, after which hippocampal-dependent object location memory was assessed. Hippocampal 11β-HSD1 activity was estimated by the ratio of corticosterone/dehydrocorticosterone measured by LC/MS. Regulation of 11β-HSD1 activity in response to changes in glucose or insulin levels was determined ex vivo on acute brain hippocampal slices. The insulin regulation of 11β-HSD1 was further examined in vivo using virally mediated knockdown of insulin receptor expression specifically in the hippocampus. Results: Our data show that inhibiting 11β-HSD1 activity prevents hippocampal-related memory deficits in diabetic juvenile rats. A significant increase (53.0±9.9%) in hippocampal 11β-HSD1 activity was found in hippocampal slices incubated in high glucose conditions (13.9 mmol/l) vs normal glucose conditions (2.8 mmol/l) without insulin. However, 11β-HSD1 activity was not affected by variations in insulin concentration either in the hippocampal slices or after a decrease in hippocampal insulin receptor expression. Conclusions/interpretation: Together, these data demonstrate that an increase in 11β-HSD1 activity contributes to memory deficits observed in juvenile diabetic rats and that an excess of hippocampal 11β-HSD1 activity stems from high glucose levels rather than insulin deficiency. 11β-HSD1 might be a therapeutic target for treating cognitive impairments associated with diabetes. [ABSTRACT FROM AUTHOR]

Alternative splicing plays a pivotal role in tumorigenesis and proliferation. However, its pattern and pathogenic role has not been systematically analyzed in multiple myeloma or its subtypes. Alternative splicing profiles for 598 newly diagnosed myeloma patients with comprehensive genomic annotation identified primary translocations, 1q amplification, and DIS3 events to have more differentially spliced events than those without. Splicing levels were correlated with expression of splicing factors. Moreover, the non-homologous end joining pathway was an independent factor that was highly associated with splicing frequency as well as an increased number of structural variants. We therefore identify an axis of high-risk disease encompassing expression of the non-homologous end joining pathway, increase structural variants, and increased alternative splicing that are linked together. This indicates a joint pathogenic role for DNA damage response and alternative RNA processing in myeloma. [ABSTRACT FROM AUTHOR]

11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) amplifies tissue glucocorticoid levels and is a pharmaceutical target in diabetes and cognitive decline. Clinical translation of inhibitors is hampered by lack of in vivo pharmacodynamic biomarkers. Our goal was to monitor substrates and products of 11β-HSD1 non-invasively in liver via 19Fluorine magnetic resonance spectroscopy (19F-MRS). Interconversion of mono/poly-fluorinated substrate/product pairs was studied in Wistar rats (male, n = 6) and healthy men (n = 3) using 7T and 3T MRI scanners, respectively. Here we show that the in vitro limit of detection, as absolute fluorine content, was 0.625 μmole in blood. Mono-fluorinated steroids, dexamethasone and 11-dehydrodexamethasone, were detected in phantoms but not in vivo in human liver following oral dosing. A non-steroidal polyfluorinated tracer, 2-(phenylsulfonyl)-1-(4-(trifluoromethyl)phenyl)ethanone and its metabolic product were detected in vivo in rat liver after oral administration of the keto-substrate, reading out reductase activity. Administration of a selective 11β-HSD1 inhibitor in vivo in rats altered total liver 19F-MRS signal. We conclude that there is insufficient sensitivity to measure mono-fluorinated tracers in vivo in man with current dosage regimens and clinical scanners. However, since reductase activity was observed in rats using poly-fluorinated tracers, this concept could be pursued for translation to man with further development. [ABSTRACT FROM AUTHOR]

Transformation toward a sustainable future requires an earth stewardship approach to shift society from its current goal of increasing material wealth to a vision of sustaining built, natural, human, and social capital—equitably distributed across society, within and among nations. Widespread concern about earth's current trajectory and support for actions that would foster more sustainable pathways suggests potential social tipping points in public demand for an earth stewardship vision. Here, we draw on empirical studies and theory to show that movement toward a stewardship vision can be facilitated by changes in either policy incentives or social norms. Our novel contribution is to point out that both norms and incentives must change and can do so interactively. This can be facilitated through leverage points and complementarities across policy areas, based on values, system design, and agency. Potential catalysts include novel democratic institutions and engagement of non-governmental actors, such as businesses, civic leaders, and social movements as agents for redistribution of power. Because no single intervention will transform the world, a key challenge is to align actions to be synergistic, persistent, and scalable. [ABSTRACT FROM AUTHOR]

Deciphering Multiple Myeloma evolution in the whole bone marrow is key to inform curative strategies. Here, we perform spatial-longitudinal whole-exome sequencing, including 140 samples collected from 24 Multiple Myeloma patients during up to 14 years. Applying imaging-guided sampling we observe three evolutionary patterns, including relapse driven by a single-cell expansion, competing/co-existing sub-clones, and unique sub-clones at distinct locations. While we do not find the unique relapse sub-clone in the baseline focal lesion(s), we show a close phylogenetic relationship between baseline focal lesions and relapse disease, highlighting focal lesions as hotspots of tumor evolution. In patients with ≥3 focal lesions on positron-emission-tomography at diagnosis, relapse is driven by multiple distinct sub-clones, whereas in other patients, a single-cell expansion is typically seen (p < 0.01). Notably, we observe resistant sub-clones that can be hidden over years, suggesting that a prerequisite for curative therapies would be to overcome not only tumor heterogeneity but also dormancy. Spatially and temporally resolved data can improve our understanding of evolution and treatment resistance in multiple myeloma (MM). Here, the authors analyse spatial and longitudinal heterogeneity in MM patients using multi-region sequencing, and identify subclones associated with relapse and therapy resistance. [ABSTRACT FROM AUTHOR]

Smoldering multiple myeloma (SMM) is a precursor condition of multiple myeloma (MM) with significant heterogeneity in disease progression. Existing clinical models of progression risk do not fully capture this heterogeneity. Here we integrate 42 genetic alterations from 214 SMM patients using unsupervised binary matrix factorization (BMF) clustering and identify six distinct genetic subtypes. These subtypes are differentially associated with established MM-related RNA signatures, oncogenic and immune transcriptional profiles, and evolving clinical biomarkers. Three genetic subtypes are associated with increased risk of progression to active MM in both the primary and validation cohorts, indicating they can be used to better predict high and low-risk patients within the currently used clinical risk stratification models. Existing clinical models cannot fully capture smoldering multiple myeloma (SMM) heterogeneity. Here, integration of 42 genetic alterations from 214 SMM patients using an unsupervised binary matrix factorization clustering approach results in the identification of 6 distinct molecular and clinical subtypes. [ABSTRACT FROM AUTHOR]

Deciphering genomic architecture is key to identifying novel disease drivers and understanding the mechanisms underlying myeloma initiation and progression. In this work, using the CoMMpass dataset, we show that structural variants (SV) occur in a nonrandom fashion throughout the genome with an increased frequency in the t(4;14), RB1, or TP53 mutated cases and reduced frequency in t(11;14) cases. By mapping sites of chromosomal rearrangements to topologically associated domains and identifying significantly upregulated genes by RNAseq we identify both predicted and novel putative driver genes. These data highlight the heterogeneity of transcriptional dysregulation occurring as a consequence of both the canonical and novel structural variants. Further, it shows that the complex rearrangements chromoplexy, chromothripsis and templated insertions are common in MM with each variant having its own distinct frequency and impact on clinical outcome. Chromothripsis is associated with a significant independent negative impact on clinical outcome in newly diagnosed cases consistent with its use alongside other clinical and genetic risk factors to identify prognosis. [ABSTRACT FROM AUTHOR]

The increasing frequency of extreme events, exogenous and endogenous, poses challenges for our societies. The current pandemic is a case in point; but "once-in-a-century" weather events are also becoming more common, leading to erosion, wildfire and even volcanic events that change ecosystems and disturbance regimes, threaten the sustainability of our life-support systems, and challenge the robustness and resilience of societies. Dealing with extremes will require new approaches and large-scale collective action. Preemptive measures can increase general resilience, a first line of protection, while more specific reactive responses are developed. Preemptive measures also can minimize the negative effects of events that cannot be avoided. In this paper, we first explore approaches to prevention, mitigation and adaptation, drawing inspiration from how evolutionary challenges have made biological systems robust and resilient, and from the general theory of complex adaptive systems. We argue further that proactive steps that go beyond will be necessary to reduce unacceptable consequences. [ABSTRACT FROM AUTHOR]

10.1579/0044-7447(2007)36[639:CHANS]2.0.CO;2 20 Reyers B, Folke C, Moore M-L, Biggs R, Galaz V. Social-ecological systems resilience for navigating the dynamics of the Anthropocene. The topic resilience was selected as one of those and resulted in a 74 pages report 'Resilience and Sustainable Development: Building Adaptive Capacity in a World of Transformations' (Folke et al. [10]). The network engaged pioneering resilience thinkers and triggered interesting and path breaking work on resilience, including the by now classic Panarchy book edited by Gunderson and Holling in 2002. 10.1038/s41893-018-0210-1 7 Elmqvist T, Folke C, Nyström M, Peterson G, Bengtsson J, Walker B, Norberg J. Response diversity, ecosystem change, and resilience. [Extracted from the article]

Poly(ADP-ribose)ylation (PARylation) by PAR polymerase 1 (PARP1) and PARylation removal by poly(ADP-ribose) glycohydrolase (PARG) critically regulate DNA damage responses; yet, conflicting reports obscure PARG biology and its impact on cancer cell resistance to PARP1 inhibitors. Here, we found that PARG expression is upregulated in many cancers. We employed chemical library screening to identify and optimize methylxanthine derivatives as selective bioavailable PARG inhibitors. Multiple crystal structures reveal how substituent positions on the methylxanthine core dictate binding modes and inducible-complementarity with a PARG-specific tyrosine clasp and arginine switch, supporting inhibitor specificity and a competitive inhibition mechanism. Cell-based assays show selective PARG inhibition and PARP1 hyperPARylation. Moreover, our PARG inhibitor sensitizes cells to radiation-induced DNA damage, suppresses replication fork progression and impedes cancer cell survival. In PARP inhibitor-resistant A172 glioblastoma cells, our PARG inhibitor shows comparable killing to Nedaplatin, providing further proof-of-concept that selectively inhibiting PARG can impair cancer cell survival. PARG catalyzes the removal of poly(ADP-ribose) (PAR) from target proteins and executes critical functions in the DNA damage response. Here the authors provide structural and biological insight with small molecule PARG inhibitors and show that PARG inhibition sensitizes cells to ionizing radiation and kills cancer cells through replication fork defects. [ABSTRACT FROM AUTHOR]

The purpose of this study was to characterize the phenotypic presentation, clinical course, and outcomes of epibulbar dermoids (EpDs) which are the most common congenital eye tumor in children. Sixty-eight dermoids were identified in 58 eyes of 48 patients of Seattle Children's Hospital between 1981 and 2014 via electronic medical record search. Patients were organized into: 'EpD-Only' [patients without other congenital anomalies ( n = 13)], 'EpD-CFM' [patients with a craniofacial microsomia (CFM) diagnosis ( n = 25)], and 'EpD-Other' [patients with other congenital anomalies ( n = 10)]. All EpD in the EpD-Only group were unilateral and singular, while the EpD-CFM group had six cases with multiple unilateral EpD and five cases with bilateral EpD. In the EpD-Only group, 69 % of EpD were left sided, whereas in the EpD-CFM group, there was no side predisposition. Among both groups, the majority of EpD were limbal or lipodermoids in the inferotemporal quadrant of the eye. Surgery was more common and at a younger age in the EpD-CFM group than the EpD-Only group (56 vs. 38 %, 5.2 vs. 7.0 years). Follow-up surgeries occurred only in the EpD-CFM group (21 %). EpDs were most commonly associated with preauricular tags, congenital heart defects, genitourinary, and nervous system anomalies. Whereas the location and type of EpDs did not significantly differ between the groups, the phenotype in the EpD-Only group appears to be less complex. This may indicate an important difference between EpDs in isolation and those within CFM. Additional studies will further characterize these phenotypes and outcomes. [ABSTRACT FROM AUTHOR]

The 2013 Minamata Convention seeks to reduce anthropogenic emissions of mercury (Hg) and enhance public awareness of Hg exposure and impacts. The treaty also requires countries to increase monitoring of Hg in the environment in order to reduce human exposure and examine the efficacy of the treaty over time. Campos dos Goytacazes, Brazil, is located in a watershed with a history of significant Hg deposition from gold mining and sugarcane farming. This study provides previously unpublished data on the presence of Hg in certain fish in Campos and the awareness of mercury contamination among the local population. We analyzed Hg concentrations in five commonly consumed fish species by the residents of Campos and found concentrations to be elevated in some species, to vary significantly among species, and to correlate with trophic levels likely due to biomagnification. A sample survey of people in Campos found that education levels negatively correlated with knowledge of the presence of Hg in fish and the negative health effects of both Hg and heavy metal contamination in general. These findings have potential importance for understanding Hg levels in the environment, underscore the necessity for public awareness and education efforts regarding Hg contamination (as called for in the new Convention), and provide baseline measures for the presence of Hg in fish in Campos and public awareness related to this presence. These data can be compared to future studies to examine the efficacy of the Convention and other efforts to reduce Hg emissions and exposure to Hg in this part of Brazil. [ABSTRACT FROM AUTHOR]

Aims: Disrupted intermediary metabolism may contribute to the adverse pregnancy outcomes in women with very severe obesity. Our aim was to study metabolism in such pregnancies. Methods: We recruited a longitudinal cohort of very severely obese ( n = 190) and lean ( n = 118) glucose-tolerant women for anthropometric and metabolic measurements at early, mid and late gestation and postpartum. In case-control studies of very severely obese and lean women we measured glucose and glycerol turnover during low- and high-dose hyperinsulinaemic-euglycaemic clamps (HEC) at early and late pregnancy and in non-pregnant women (each n = 6-9) and body fat distribution by MRI in late pregnancy ( n = 10/group). Results: Although greater glucose, insulin, NEFA and insulin resistance (HOMA-IR), and greater weight and % fat mass (FM) was observed in very severely obese vs lean participants, the degree of worsening was attenuated in the very severely obese individuals with advancing gestation, with no difference in triacylglycerol (TG) concentrations between very severely obese and lean women at term. Enhanced glycerol production was observed in early pregnancy only in very severely obese individuals, with similar intrahepatic FM in very severely obese vs lean women by late gestation. Offspring from obese mothers were heavier ( p = 0.04). Conclusions/interpretation: Pregnancies complicated by obesity demonstrate attenuation in weight gain and insulin resistance compared with pregnancies in lean women. Increased glycerol production is confined to obese women in early pregnancy and obese and lean individuals have similar intrahepatic FM by term. When targeting maternal metabolism to treat adverse pregnancy outcomes, therapeutic intervention may be most effective applied early in pregnancy. [ABSTRACT FROM AUTHOR]

The efficient transfer of energy between organic and inorganic semiconductors is a widely sought after property, but has so far been limited to the transfer of spin-singlet excitons. Here we report efficient resonant-energy transfer of molecular spin-triplet excitons from organic semiconductors to inorganic semiconductors. We use ultrafast optical absorption spectroscopy to track the dynamics of triplets, generated in pentacene through singlet exciton fission, at the interface with lead selenide (PbSe) nanocrystals. We show that triplets transfer to PbSe rapidly (<1 ps) and efficiently, with 1.9 triplets transferred for every photon absorbed in pentacene, but only when the bandgap of the nanocrystals is close to resonance (±0.2 eV) with the triplet energy. Following triplet transfer, the excitation can undergo either charge separation, allowing photovoltaic operation, or radiative recombination in the nanocrystal, enabling luminescent harvesting of triplet exciton energy in light-emitting structures. [ABSTRACT FROM AUTHOR]

Cushing's syndrome, caused by increased production of cortisol, leads to metabolic dysfunction including visceral adiposity, hypertension, hyperlipidaemia and type 2 diabetes. The similarities with the metabolic syndrome are striking and major efforts have been made to find obesity-associated changes in the regulation of glucocorticoid action and synthesis, both at a systemic level and tissue level. Obesity is associated with tissue-specific alterations in glucocorticoid metabolism, with increased activity of the glucocorticoid-regenerating enzyme 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1) in subcutaneous adipose tissue and decreased conversion of cortisone to cortisol, interpreted as decreased 11βHSD1 activity, in the liver. In addition, genetic manipulation of 11βHSD1 activity in rodents can either induce (by overexpression of Hsd11b1, the gene encoding 11βHSD1) or prevent (by knocking out Hsd11b1) obesity and metabolic dysfunction. Taken together with earlier evidence that non-selective inhibitors of 11βHSD1 enhance insulin sensitivity, these results led to the hypothesis that inhibition of 11βHSD1 might be a promising target for treatment of the metabolic syndrome. Several selective 11βHSD1 inhibitors have now been developed and shown to improve metabolic dysfunction in patients with type 2 diabetes, but the small magnitude of the glucose-lowering effect has precluded their further commercial development. This review focuses on the role of 11βHSD1 as a tissue-specific regulator of cortisol exposure in obesity and type 2 diabetes in humans. We consider the potential of inhibition of 11βHSD1 as a therapeutic strategy that might address multiple complications in patients with type 2 diabetes, and provide our thoughts on future directions in this field. [ABSTRACT FROM AUTHOR]

Fuelled by the obesity epidemic, there is considerable interest in the developmental origins of white adipose tissue (WAT) and the stem and progenitor cells from which it arises. Whereas increased visceral fat mass is associated with metabolic dysfunction, increased subcutaneous WAT is protective. There are six visceral fat depots: perirenal, gonadal, epicardial, retroperitoneal, omental and mesenteric, and it is a subject of much debate whether these have a common developmental origin and whether this differs from that for subcutaneous WAT. Here we show that all six visceral WAT depots receive a significant contribution from cells expressing Wt1 late in gestation. Conversely, no subcutaneous WAT or brown adipose tissue arises from Wt1-expressing cells. Postnatally, a subset of visceral WAT continues to arise from Wt1-expressing cells, consistent with the finding that Wt1 marks a proportion of cell populations enriched in WAT progenitors. We show that all visceral fat depots have a mesothelial layer like the visceral organs with which they are associated, and provide several lines of evidence that Wt1-expressing mesothelium can produce adipocytes. These results reveal a major ontogenetic difference between visceral and subcutaneous WAT, and pinpoint the lateral plate mesoderm as a major source of visceral WAT. They also support the notion that visceral WAT progenitors are heterogeneous, and suggest that mesothelium is a source of adipocytes. [ABSTRACT FROM AUTHOR]

Congenital adrenal hyperplasia (CAH) is a genetic disorder caused by defective steroidogenesis that results in glucocorticoid deficiency; the most common underlying mutation is in the gene that encodes 21-hydroxylase. Life-saving glucocorticoid treatment was introduced in the 1950s, and the number of adult patients is now growing; however, no consensus has been reached on the management of CAH beyond childhood. Adult patients are prescribed a variety of glucocorticoids, including hydrocortisone, prednisone, prednisolone, dexamethasone and combinations of these drugs taken in either a circadian or reverse circadian regimen. Despite these personalized treatments, biochemical control of CAH is only achieved in approximately one-third of patients. Some patients have a poor health status, with an increased incidence of obesity and osteoporosis, and impaired fertility and quality of life. The majority of poor health outcomes seem to relate to inadequate treatment rather than the genotype of the patient. Patients receiving high doses of glucocorticoids and the more potent synthetic long-acting glucocorticoids are at an increased risk of obesity, insulin resistance and a reduced quality of life. Further research is required to optimize the treatment of adult patients with CAH and improve health outcomes. [ABSTRACT FROM AUTHOR]

Singlet exciton fission, the spin-conserving process that produces two triplet excited states from one photoexcited singlet state, is a means to circumvent the Shockley-Queisser limit in single-junction solar cells. Although the process through which singlet fission occurs is not well characterized, some local order is thought to be necessary for intermolecular coupling. Here, we report a triplet yield of 200% and triplet formation rates approaching the diffusion limit in solutions of bis(triisopropylsilylethynyl (TIPS)) pentacene. We observe a transient bound excimer intermediate, formed by the collision of one photoexcited and one ground-state TIPS-pentacene molecule. The intermediate breaks up when the two triplets separate to each TIPS-pentacene molecule. This efficient system is a model for future singlet-fission materials and for disordered device components that produce cascades of excited states from sunlight. [ABSTRACT FROM AUTHOR]

To identify variants for multiple myeloma risk, we conducted a genome-wide association study with validation in additional series totaling 4,692 individuals with multiple myeloma (cases) and 10,990 controls. We identified four risk loci at 3q26.2 (rs10936599, P = 8.70 × 10−14), 6p21.33 (rs2285803, PSORS1C2, P = 9.67 × 10−11), 17p11.2 (rs4273077, TNFRSF13B, P = 7.67 × 10−9) and 22q13.1 (rs877529, CBX7, P = 7.63 × 10−16). These data provide further evidence for genetic susceptibility to this B-cell hematological malignancy, as well as insight into the biological basis of predisposition. [ABSTRACT FROM AUTHOR]

Inhibition of the enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) has been proposed as a novel therapeutic target for the treatment of type 2 diabetes mellitus. Over 170 new compounds targeting 11β-HSD1 have been developed. This article reviews the current published literature on compounds that have reached phase II clinical trials in patients with type 2 diabetes, and summarises the preclinical evidence that such agents may be useful for associated conditions, including peripheral vascular disease, coronary artery disease and cognitive decline. In clinical trials, 11β-HSD1 inhibitors have been well tolerated and have improved glycaemic control, lipid profile and blood pressure, and induced modest weight loss. The magnitude of the effects are small relative to other agents, so that further development of 11β-HSD1 inhibitors for the primary therapeutic indication of type 2 diabetes has stalled. Ongoing programmes are focused on additional benefits for cognitive function and other cardiovascular risk factors. [ABSTRACT FROM AUTHOR]

A number of specific chromosomal abnormalities define the subgroups of multiple myeloma. In a meta-analysis of two genome-wide association studies of multiple myeloma including a total of 1,661 affected individuals, we investigated risk for developing a specific tumor karyotype. The t(11;14)(q13;q32) translocation in which CCND1 is placed under the control of the immunoglobulin heavy chain enhancer was strongly associated with the CCND1 c.870G>A polymorphism (P = 7.96 × 10−11). These results provide a model in which a constitutive genetic factor is associated with risk of a specific chromosomal translocation. [ABSTRACT FROM AUTHOR]

Based on the clinical features of myeloma and related malignancies of plasma cells, it has been possible to generate a model system of myeloma progression from a normal plasma cell through smouldering myeloma to myeloma and then plasma cell leukaemia. Using this model system we can study at which points the genetic alterations identified through whole-tumour molecular analyses function in the initiation and progression of myeloma. Further genetic complexity, such as intraclonal heterogeneity, and insights into the molecular evolution and intraclonal dynamics in this model system are crucial to our understandings of tumour progression, treatment resistance and the use of currently available and future treatments. [ABSTRACT FROM AUTHOR]

Increasing ecotourism activity in Argentine Patagonia has led to concerns about the effects of ecotourism on wildlife populations. Penguin breeding colonies are popular tourist destinations. While some species of penguins habituate to human visits, others exhibit negative effects due to disturbance. We studied the effects of tourism on Magellanic Penguins ( Spheniscus magellanicus) at San Lorenzo colony located on the Peninsula Valdes, Chubut, Argentina. We measured behavioural, physiological, and reproductive parameters in birds nesting in tourist-visited and non-visited areas. San Lorenzo has 11 years of visitation history and a low intensity of visitors (~10,000 annually). After 15 min of a simulated tourist visit, penguins in the tourist area showed fewer alternate head turns and lower plasma levels of the stress hormone corticosterone than penguins in a non-visited area. However, penguins showed similar baseline levels of corticosterone between areas as well as similar levels of integrated corticosterone expressed after an acute stressor. Penguin breeding success and chick growth were similar between areas. We compared these findings to results previously published from Punta Tombo, a colony with a longer history (+50 years) and high intensity of annual visitors (>120,000 people). Many (reproductive and behavioural parameters), but not all (physiological parameters), of our findings are similar. That a physiological difference exists may suggest that the previous history of human visitation plays an important role in the response of the birds. Thus, the continuous monitoring of tourist activity is important, as a history of visitation disturbance seems to have an effect on how birds respond to tourists. [ABSTRACT FROM AUTHOR]

To identify risk variants for multiple myeloma, we conducted a genome-wide association study of 1,675 individuals with multiple myeloma and 5,903 control subjects. We identified risk loci for multiple myeloma at 3p22.1 (rs1052501 in ULK4; odds ratio (OR) = 1.32; P = 7.47 × 10?9) and 7p15.3 (rs4487645, OR = 1.38; P = 3.33 × 10?15). In addition, we observed a promising association at 2p23.3 (rs6746082, OR = 1.29; P = 1.22 × 10?7). Our study identifies new genomic regions associated with multiple myeloma risk that may lead to new etiological insights. [ABSTRACT FROM AUTHOR]

The ubiquitin proteasome pathway plays a critical role in regulating many processes in the cell which are important for tumour cell growth and survival. Inhibition of proteasome function has emerged as a powerful strategy for anti-cancer therapy. Clinical validation of the proteasome as a therapeutic target was achieved with bortezomib and has prompted the development of a second generation of proteasome inhibitors with improved pharmacological properties. This review summarises the main mechanisms of action of proteasome inhibitors in cancer, the development of proteasome inhibitors as therapeutic agents and the properties and progress of next generation proteasome inhibitors in the clinic. [ABSTRACT FROM AUTHOR]

This paper explores the consequences of changes in a system’s resilience on the sustainability of resource allocation decisions, as measured by Inclusive Wealth (IW) (Arrow et al. in Environ Resour Econ 26:647–685, 2003). We incorporate an estimate of resilience in IW by taking account of known or suspected thresholds that can lead to irreversible (or practically irreversible) changes in the productivity and value of assets and hence social welfare. These thresholds allow us to identify policies or projects that may be leading to an increased risk of decline in capital stocks (the wealth of the region). Such risks are not reflected through usual measures of current system performance, e.g. agricultural production. We use the Goulburn-Broken Catchment in south-eastern Australia as a case study to explore the significance and practicality of including resilience in inclusive wealth estimates. [ABSTRACT FROM AUTHOR]