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Random forest regression (RF) is an extremely popular tool for the analysis of high-dimensional data. Nonetheless, its benefits may be lessened in sparse settings due to weak predictors, and a pre-estimation dimension reduction (targeting) step is required. We show that proper targeting controls the probability of placing splits along strong predictors, thus providing an important complement to RF's feature sampling. This is supported by simulations using representative finite samples. Moreover, we quantify the immediate gain from targeting in terms of increased strength of individual trees. Macroeconomic and financial applications show that the bias-variance trade-off implied by targeting, due to increased correlation among trees in the forest, is balanced at a medium degree of targeting, selecting the best 10--30\% of commonly applied predictors. Improvements in predictive accuracy of targeted RF relative to ordinary RF are considerable, up to 12-13\%, occurring both in recessions and expansions, particularly at long horizons.

The E2F and MYC transcription factors are critical regulators of cell proliferation and contribute to the development of human cancers. Here, we report on the identification of a novel E2F target gene, ATAD2, the predicted protein product of which contains both a bromodomain and an ATPase domain. The pRB-E2F pathway regulates ATAD2 expression, which is limiting for the entry into the S phase of the cell cycle. We show that ATAD2 binds the MYC oncogene and stimulates its transcriptional activity. ATAD2 maps to chromosome 8q24, 4.3 Mb distal to MYC, in a region that is frequently found amplified in cancer. Consistent with this, we show that ATAD2 expression is high in several human tumors and that the expression levels correlate with clinical outcome of breast cancer patients. We suggest that ATAD2 links the E2F and MYC pathways and contributes to the development of aggressive cancer through the enhancement of MYC-dependent transcription. [Cancer Res 2009;69(21):8491–8]

Trends in tropospheric ozone, an important air pollutant and short-lived climate forcer (SLCF), are estimated using available surface and ozonesonde profile data for 1993-2019. Using a coherent methodology, observed trends are compared to modeled trends (1995-2015) from the Arctic Monitoring Assessment Programme SLCF 2021 assessment. Statistically significant increases in observed surface ozone at Arctic coastal sites, notably during winter, and concurrent decreasing trends in surface carbon monoxide, are generally captured by multi-model median (MMM) trends. Wintertime increases are also estimated in the free troposphere at most Arctic sites, but tend to be overestimated by the MMMs. Springtime surface ozone increases in northern coastal Alaska are not simulated while negative springtime trends in northern Scandinavia are not always reproduced. Possible reasons for observed changes and model behavior are discussed, including decreasing precursor emissions, changing ozone sinks, and variability in large-scale meteorology.

With the increasing use of Computer Aided Engineering, it has become vital to be able to evaluate the accuracy of numerical models. This research poses the problem of selection of the most accurate and relevant correlation solution to a set of corridor variations. Specific methods such as CORA, widely accepted in industry, are developed to objectively evaluate the correlation between monotonic functions, while the Minimum Area Discrepancy Method, or MADM, is the only method to address the correlation of non-injective mathematical variations, usually related to force/acceleration versus displacement problems. Often, it is not possible to differentiate objectively various solutions proposed by CORA, which this paper proposes to answer. This research is original, as it proposes a new innovative correlation optimisation framework, which can select the best CORA solution by including MADM as a subsequent process. The paper and the methods are rigorous, having used an industry standard driver airbag computer model, built virtual test corridors and compared the relationship between different CORA and MADM ratings from 100 Latin Hypercube samples. For the same CORA value of ‘1’ (perfect correlation), MADM was capable to objectively differentiate between 13 of them and provide the best correlation possible. The paper has recommended the MADM settings n = 1; m = 2 or n = 3; m = 2 for a congruent relationship with CORA. As MADM is performed subsequently, this new framework can be implemented in already existing industrial processes and provide automotive manufacturers and Original Equipment Manufacturers (OEM) with a new tool to generate more accurate computer models.

A risk-averse insurance company controls its reserve, modeled as a perturbed Cramer-Lundberg process, by choice of both the premium p and the deductible K offered to potential customers. The surplus is allocated to financial investment in a riskless and a basket of risky assets potentially correlating with the insurance risks and thus serving as a partial hedge against these. Assuming customers differ in riskiness, increasing p or K reduces the number of customers n ( p , K ) and increases the arrival rate of claims per customer λ ( p , K ) through adverse selection, with a combined negative effect on the aggregate arrival rate n ( p , K ) λ ( p , K ) . We derive the optimal premium rate, deductible, investment strategy, and dividend payout rate (consumption by the owner-manager) maximizing expected discounted lifetime utility of intermediate consumption under the assumption of constant absolute risk aversion. Closed-form solutions are provided under specific assumptions on the distributions of size and frequency of claims.

Targeted Exercise Training for Cancer Patients: Moving beyond Generic Exercise Guidelines in Clinical Oncology Ciaran M Fairman1 and Jesper F Christensen()2,3 1Department of Exercise Science, University of South Carolina, USA 2Center for Physical Activity Research, Rigshospitalet, Copenhagen, Denmark 3Department of Sports Science and Clinical Biomechanics, Faculty of Health Sciences, University of Southern Denmark, Denmark © The Authors Abstract The field of exercise oncology has rapidly evolved over the past 30 years. Initial investigations of safety and feasibility have progressed towards efficacy and effectiveness trials with a variety of health-related outcomes in mind. More recently, it has been recognized that interventions aimed at modifying physical activity behavior (i.e. behavioral interventions to increase participation in un/structured physical activity) are distinctly different from those aiming to target a clinically relevant outcome (using a specific exercise prescription). There is a strong rationale for the latter, where cancer/treatment toxicities can result in musculoskeletal, cardiopulmonary, and/or hematological declines with important prognostic implications. Treatment intolerance, unfavorable tumor response and heightened risk of mortality are all consequences of leaving these impairments unaddressed. Importantly, the control/reversal of the decline in these systems is more likely to occur through a targeted exercise prescription, specifically designed to target the impairment, rather than interventions trying to change behavior. This requires careful consideration in the study design in exercise oncology in relation to the selection of clinically relevant outcomes, decisions on methods of assessments and ensuring the exercise is targeted to the outcome. The objective of this review is to 1) conceptualize and provide a clinical rationale for targeted exercise interventions in exercise oncology, and 2) provide a framework for consideration in the design and execution in targeted exercise interventions in oncology. We hope that this framework can encourage research into targeted exercise interventions in oncology and that our framework can be used to inform the design of future trials.

The effects of childhood hematopoietic stem cell transplantation (HSCT) on key organs can impair cardiorespiratory fitness, muscle strength, and physical performance. We aimed to provide an overview of childhood HSCT survivors' status on these parameters compared with healthy controls and discuss current insights into clinical risk factors. We performed a systematic search in six scientific databases, including studies published before April 2019 and performed a meta-analysis on cardiorespiratory fitness. Muscle strength and physical performance status were presented narratively. We included ten studies embodying 517 childhood HSCT survivors (mean 17.8 years at follow-up). The meta-analysis (n = 4 studies) showed that childhood HSCT survivors have lower cardiorespiratory fitness compared with healthy controls (Standard mean difference (SMD) -1.32 [95% CI -1-58 to -1.07]; I2 2%, p < 0.00001). Collectively, the studies indicated that childhood HSCT survivors have lower muscle strength (n = 4 studies) and physical performance (n = 3 studies) compared with healthy controls. Childhood HSCT survivors have impaired cardiorespiratory fitness years after ended treatment. Muscle strength and physical performance seem to be impaired, although these measures are insufficiently investigated. Associations between HSCT-specific clinical risk factors and cardiorespiratory fitness, muscle strength, and physical performance are required.

In frame of the H2020-EXHAUSTION project, we present estimated heat indicators from WRF (Weather Research and Forecasting model) downscaling simulations for the periods of 1980-2014 and 2015-2049 at 20 km horizontal resolution over the European domain. WRF simulations are forced by the CESM2 global model simulations, using three shared socio-economic pathways (SSP) future scenarios from the Coupled Model Intercomparison Project Phase 6 (CMIP6): SSP1-2.6, SSP2-4.5 and SSP3-7.0, addressing different levels of mitigation and adaptation. For the period of 1980-2014, another WRF simulation forced by ERA5 is used as comparison in model validation. These near-past simulations have been rigorously evaluated with observations and reanalysis data including European Climate Assessment & Dataset (ECA&D), E-OBS, and ERA5-land for the surface air temperatures. The dynamical downscaling showed clear added value on spatial distribution related to the important coastal or orographic aspects widely present over Europe. Two heat wave indicators, the Warm Spell Duration Index (WSDI) and the Heat Wave magnitude Index daily (HWMId), and four extreme heat indicators, annual maximum temperature (TX­x), NOAA heat index (HIx), wet-bulb globe temperature (WBGTx), and universal thermal climate index (UTCIx), are used to study the heat extremes trends in Europe. During the past 35 years, TXx has been estimated to increase 2.5 °C in WRF_CESM2 and 1.4 °C in WRF_ERA5; the increasing trend is estimated to remain or slow down slightly in the next 35 years with estimated smaller increase of 1.5-2.5 °C in three scenarios. The trends of other extreme heat indicators showed very similar trends with TXx. However, future heat wave duration and magnitude present a contrasted pattern. Heat waves have been estimated to increase 11.2 days of duration, and 2.1 of magnitude during 1980-2014, very similar to the observed increase of 9.1-11 days and 1.8-2.1. Whereas in 2015-2049, heat waves duration and magnitude are estimated to increase 12.3-13 days and 2.5-4.6, respectively. These heat wave changes are also not uniform from a spatial point of view. Heat wave duration and magnitude in Southern Europe are both estimated to increase significantly faster than other zones, with rates at 1.4-2.9 times of which for the whole of Europe. Heat wave indicators in future scenarios also showed much larger interannual variations compared with the past, whereas there are no distinct differences among three mitigation scenarios for all heat indicators. In summary, these results suggested that even though the future increase of air temperatures and heat extreme indicators showed a slowing down sign compared with the near-past, whereas the severity of heat waves are estimated to increase even faster than the past under different levels of mitigation. Southern Europe is expected to be the region that needs the most attention in terms of severe future heat waves.

Chemotherapy-induced immune-suppression is a common, but potential detrimental, adverse reaction in patients undergoing treatment for cancer and strategies with capacity to boost the immune cell populations are needed. Physical exercise training is a potent regulator of immune cell viability and function and may serve as a viable, non-pharmacological prophylactic strategy in addition to the current pharmacological management by, for example, granulocyte-colony stimulating factor (G-CSF). Here, we review the mechanistic evidence linking exercise training to haematopoietic function and subsequent possible amelioration of chemotherapy-related neutropenia. First, we briefly describe neutrophil regulation and management of neutropenia in cancer patients. Second, we summarize the effect of acute and chronic exercise training on neutrophils and their progenitors, and finally, we outline the current clinical evidence of exercise interventions in ongoing anti-cancer treatment in regard to neutropenia incidence, treatment tolerance and related outcomes. LINKED ARTICLES: This article is part of a themed issue on New avenues in cancer prevention and treatment (BJP 75th Anniversary). To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.12/issuetoc.

Surgical resection with adjuvant chemotherapy according to stage and risk profile is the main treatment option for non-metastatic colorectal cancer (CRC). However, pervasive side effects, including...

PROSER1 promotes the interaction between TET2 and the glycosyltransferase OGT to regulate TET2 O-GlcNAcylation and stability on genomic elements that depend on the activity of the MLL3/4 complexes., DNA methylation at enhancers and CpG islands usually leads to gene repression, which is counteracted by DNA demethylation through the TET protein family. However, how TET enzymes are recruited and regulated at these genomic loci is not fully understood. Here, we identify TET2, the glycosyltransferase OGT and a previously undescribed proline and serine rich protein, PROSER1 as interactors of UTX, a component of the enhancer-associated MLL3/4 complexes. We find that PROSER1 mediates the interaction between OGT and TET2, thus promoting TET2 O-GlcNAcylation and protein stability. In addition, PROSER1, UTX, TET1/2, and OGT colocalize on many genomic elements genome-wide. Loss of PROSER1 results in lower enrichment of UTX, TET1/2, and OGT at enhancers and CpG islands, with a concomitant increase in DNA methylation and transcriptional down-regulation of associated target genes and increased DNA hypermethylation encroachment at H3K4me1-predisposed CpG islands. Furthermore, we provide evidence that PROSER1 acts as a more general regulator of OGT activity by controlling O-GlcNAcylation of multiple other chromatin signaling pathways. Taken together, this study describes for the first time a regulator of TET2 O-GlcNAcylation and its implications in mediating DNA demethylation at UTX-dependent enhancers and CpG islands and supports an important role for PROSER1 in regulating the function of various chromatin-associated proteins via OGT-mediated O-GlcNAcylation.

Exercise training is emerging as a supportive treatment strategy in surgical oncology, but its effects remain uncertain in patients with gastrointestinal cancer. The primary objective of this systematic review and meta-analysis was to evaluate the effects of perioperative exercise training on gastrointestinal cancer-specific mortality, recurrence, and surgical outcomes (postoperative complications, hospitalization, surgical stress) in patients with gastrointestinal cancer. Randomized or quasi-randomized controlled trials evaluating the effects of perioperative exercise training versus control in patients with GI cancer were eligible. MEDLINE, EMBASE, CENTRAL, CINAHL, PEDro, and SPORTDiscus were systematically searched on June 20, 2020. Data were synthesized using random-effects meta-analyses. Risk of bias was assessed using the Cochrane risk of bias tool 2, and the certainty of evidence was assessed using GRADE. Study selection, data extraction, risk of bias, and GRADE assessments were performed independently by two authors. Ten randomized controlled trials comprising 448 participants with gastrointestinal cancer were eligible. Meta-analyses indicated no statistical effects of exercise on postoperative complications (risk ratio: 1.11, 95% CI: 0.84; 1.47), readmissions (risk ratio: 2.76; 95% CI: 0.00, 9394.76), or postoperative length of stay (difference in means: −0.47, 95% CI: −17.2; 16.2 days). None of the eligible studies assessed gastrointestinal cancer-specific mortality or recurrence. Overall risk of bias was high or of some concerns in all studies, and the certainty of evidence was very low. The effects of perioperative exercise on cancer-specific and surgical outcomes are unknown in patients with gastrointestinal cancer due to lack of studies and very low certainty of evidence.

A disproportional large number of neurodevelopmental disorders (NDDs) is caused by variants in genes encoding transcription factors and chromatin modifiers. However, the functional interactions between the corresponding proteins are only partly known. Here, we show that KDM5C, encoding a H3K4 demethylase, is at the intersection of transcriptional axes under the control of three regulatory proteins ARX, ZNF711 and PHF8. Interestingly, mutations in all four genes (KDM5C, ARX, ZNF711 and PHF8) are associated with X-linked NDDs comprising intellectual disability as a core feature. in vitro analysis of the KDM5C promoter revealed that ARX and ZNF711 function as antagonist transcription factors that activate KDM5C expression and compete for the recruitment of PHF8. Functional analysis of mutations in these genes showed a correlation between phenotype severity and the reduction in KDM5C transcriptional activity. The KDM5C decrease was associated with a lack of repression of downstream target genes Scn2a, Syn1 and Bdnf in the embryonic brain of Arx-null mice. Aiming to correct the faulty expression of KDM5C, we studied the effect of the FDA-approved histone deacetylase inhibitor suberanilohydroxamic acid (SAHA). In Arx-KO murine ES-derived neurons, SAHA was able to rescue KDM5C depletion, recover H3K4me3 signalling and improve neuronal differentiation. Indeed, in ARX/alr-1-deficient Caenorhabditis elegans animals, SAHA was shown to counteract the defective KDM5C/rbr-2-H3K4me3 signalling, recover abnormal behavioural phenotype and ameliorate neuronal maturation. Overall, our studies indicate that KDM5C is a conserved and druggable effector molecule across a number of NDDs for whom the use of SAHA may be considered a potential therapeutic strategy.

We develop a new empirical approach to term structure analysis that allows testing for time-varying risk premiums and arbitrage opportunities in models with both unobservable factors and factors identified as the innovations to observed macroeconomic variables. Factors can play double roles as both covariance-generating common shocks driving yields and determinants of market prices of risk in cross-sectional pricing. The evidence favors time-varying risk prices significantly related to the second Stock–Watson principal component of macroeconomic variables and to changes in the industrial production index. Our preferred specification includes these two observable and two unobservable factors, with the no-arbitrage condition imposed.

Two insurance companies I 1 , I 2 with reserves R 1 ( t ) , R 2 ( t ) compete for customers, such that in a suitable stochastic differential game the smaller company I 2 with R 2 ( 0 ) R 1 ( 0 ) aims at minimizing R 1 ( t ) − R 2 ( t ) by using the premium p 2 as control and the larger I 1 at maximizing by using p 1 . The dependence of reserves on premia is derived by modelling the customer’s problem explicitly, accounting for market frictions V , reflecting differences in cost of search and switching, information acquisition and processing, or preferences. Assuming V to be random across customers, the optimal simultaneous choice p 1 ∗ , p 2 ∗ of premiums is derived and shown to provide a Nash equilibrium for beta distributed V . The analysis is based on the diffusion approximation to a standard Cramer–Lundberg risk process extended to allow investment in a risk-free asset.

Recurrent inactivating mutations have been identified in the X-linked plant homeodomain finger protein 6 (PHF6) gene, encoding a chromatin-binding transcriptional regulator protein, in various hematological malignancies. However, the role of PHF6 in normal hematopoiesis and its tumor-suppressor function remain largely unknown. We herein generated mice carrying a floxed Phf6 allele and inactivated Phf6 in hematopoietic cells at various developmental stages. The Phf6 deletion in embryos augmented the capacity of hematopoietic stem cells (HSCs) to proliferate in cultures and reconstitute hematopoiesis in recipient mice. The Phf6 deletion in neonates and adults revealed that cycling HSCs readily acquired an advantage in competitive repopulation upon the Phf6 deletion, whereas dormant HSCs only did so after serial transplantations. Phf6-deficient HSCs maintained an enhanced repopulating capacity during serial transplantations; however, they did not induce any hematological malignancies. Mechanistically, Phf6 directly and indirectly activated downstream effectors in tumor necrosis factor α (TNFα) signaling. The Phf6 deletion repressed the expression of a set of genes associated with TNFα signaling, thereby conferring resistance against the TNFα-mediated growth inhibition on HSCs. Collectively, these results not only define Phf6 as a novel negative regulator of HSC self-renewal, implicating inactivating PHF6 mutations in the pathogenesis of hematological malignancies, but also indicate that a Phf6 deficiency alone is not sufficient to induce hematopoietic transformation.

With the development and deployment of lightweight vehicles to the market, inclusive of autonomous pods, a review of advanced crashworthy structures and the design methodology has been conducted as it is thought that super-lightweight vehicles may pose significant risk to the occupants if they are involved in a crash. It is suggested that tests should include oblique and multiple velocity impacts to cater for the effects of assisted driving systems of future vehicles. A review of current crash structures and design methodologies revealed that the most recent research do not cater to multiple crash scenarios, nor a shorter crush allowance, therefore resulting in poor crashworthiness performance. In addition, the arbitrary seat positioning shown in autonomous pods’ concepts vastly increases the risk to occupants. Greater enhancements to passive crashworthiness are imperative. To this end, functionally graded vehicle structures should be designed as it has been found that these can provide optimized solutions. Research into nonlinear optimization methods for computationally expensive problems will become central to this.

Background: During recent years, there has been an increased focus on technology within cancer survivorship and physical activity rehabilitation. Failure to acknowledge the individuals wishes and/o...

The Cranet-survey has mapped human resource management (HRM) practices for more than 25 years, and so it is timely to take a closer look at the significance of this unique multinational, longitudinal, empirical endeavor. How may we understand the inner workings and emergent practices of this ambitious research effort in order to better assess the value of the unique data-set and propose avenues for its improvement? This is of course a daunting task if the purpose is to make a general evaluation, as was the case in 2011 in the Human Resource Management Review issue on the Cranet International Network. Rather, the contribution of this article is to examine the established research practices of the Cranet Network from the point of view of incoming researchers to identify and assess fundamental challenges of design, measurement, and project management that underlie many of the more apparent and often-discussed issues relating to validity, comparability, and the multinational adaptation of standardized research tools. To accomplish this, the article analyzes the Danish Cranet project from its inception in 1991 until today, with particular emphasis on the effort to establish a longitudinally comprehensive Danish database with application in cross-country comparisons, exemplified here through comparisons with New Zealand. On this basis, the article discusses the ramifications for the Cranet Network and proposes opportunities and potentials for improving future consistency and comparability of the global research practice.

BackgroundDespite evidence of selective outcome reporting across multiple disciplines, this has not yet been assessed in trials studying the effects of exercise in people with cancer. Therefore, the purpose of our study was to explore prospectively registered randomised controlled trials (RCTs) in exercise oncology for evidence of selective outcome reporting.MethodsEligible trials were RCTs that 1) investigated the effects of at least partially supervised exercise interventions in people with cancer; 2) were preregistered (i.e. registered before the first patient was recruited) on a clinical trials registry; and 3) reported results in a peer-reviewed published manuscript. We searched the PubMed database from the year of inception to September 2020 to identify eligible exercise oncology RCTs clinical trial registries. Eligible trial registrations and linked published manuscripts were compared to identify the proportion of sufficiently preregistered outcomes reported correctly in the manuscripts, and cases of outcome omission, switching, and silently introduction of non-novel outcomes.ResultsWe identified 31 eligible RCTs and 46 that were ineligible due to retrospective registration. Of the 405 total prespecified outcomes across the 31 eligible trials, only 6.2% were preregistered complete methodological detail. Only 16% (n=148/929) of outcomes reported in published results manuscripts were linked with sufficiently preregistered outcomes without outcome switching. We found 85 total cases of outcome switching. A high proportion (41%) of preregistered outcomes were omitted from the published results manuscripts, and many published outcomes (n=394; 42.4%) were novel outcomes that had been silently introduced (median, min-max=10, 0-50 per trial). We found no examples of preregistered efficacy outcomes that were measured, assessed, and analysed as planned.ConclusionsWe found evidence suggestive of widespread selective outcome reporting and non-reporting bias (outcome switching, omitted preregistered outcomes, and silently introduced novel outcomes). The existence of such reporting discrepancies has implications for the integrity and credibility of RCTs in exercise oncology.Preregistered protocolhttps://osf.io/dtkar/ (posted: November 19, 2019)

This work presents results from downscaling experiments using the Weather Research and Forecasting (WRF) in frame of the H2020-EXHAUSTION project for the period of 1980-2010 at 20km horizontal resolution over the European domain. Two simulations were carried out driven by ERA5 input by grid nudging (WRF_ERA5) and CESM2 output using 6 waves spectral nudging (WRF_CESM2), respectively. These near-past simulations have been rigorously evaluated with observations and reanalysis data including European Climate Assessment & Dataset (ECA&D), EOBS, and ERA5-land for the daily mean (TG), maximum (TX), and minimum (TN) surface temperatures over the whole Europe as well as five climate zones. The WRF simulations compared reasonably well with the observations. WRF_ERA5 showed a smaller root mean square error (RMSE) and higher correlations (r), while WRF_CESM2 performed better in terms of mean and normalized mean bias (MB and NMB). WRF_CESM2 is overall reliable to be used for future simulations. In terms of the 30-year trend of TG, TX, and TN, WRF_CESM2 (0.6-0.66 °C/10yrs) showed faster increasing trends than WRF_ERA5 (0.29-0.35 °C/10yrs) and observations (0.27-0.41 °C/10yrs). Evaluations in different climate zones show smaller bias in north-western Europe and southern Europe. In terms of temporal evolution, eastern Europe showed the highest correlations. The worst model performance has been calculated for northern Europe. In addition, the Warm Spell Duration Index (WSDI) and the Heat Wave Magnitude Index daily (HWMId) have been calculated to represent the duration and magnitude of heat waves, respectively, for both simulations and observations. Strong and significant increasing trends are shown in eastern Europe and northern Europe for both WSDI and HWMId in all cases, with the fastest trends shown in EOBS (4 days/10yrs for WSDI, and 2/10yrs for HWMId), slowest trends in ECA&D (2 days/10yrs for WSDI, and 1/10yrs for HWMId), and trends in two WRF simulations are in between. No significant trends were found in southern Europe and north-western Europe in ECA&D, EOBS, and WRF_ERA5 simulation, while significant increasing trends were simulated in WRF_CESM2 in these two zones. The preliminary results suggested an increasing trend in the evolution of the future heat waves over Europe with implications on both direct impacts on human health, as well as indirect impacts through changes in exposure to pollutants such as ozone and particulate matter. Various future simulations are ongoing to address the impacts of climate change on the severity of heat waves under different levels of mitigation.

Exercise training has been hypothesized to lower the inflammatory burden for patients with cancer, but the role of exercise intensity is unknown. To this end, we compared the effects of high-intensity (HI) and low-to-moderate intensity (LMI) exercise on markers of inflammation in patients with curable breast, prostate and colorectal cancer undergoing primary adjuvant cancer treatment in a secondary analysis of the Phys-Can randomized trial (NCT02473003). Sub-group analyses focused on patients with breast cancer undergoing chemotherapy. Patients performed 6 months of combined aerobic and resistance exercise on either HI or LMI during and after primary adjuvant cancer treatment. Plasma taken at baseline, immediately post-treatment and post-intervention was analyzed for levels of interleukin 1 beta (IL1B), IL6, IL8, IL10, tumor-necrosis factor alpha (TNFA) and C-reactive protein (CRP). Intention-to-treat analyses of 394 participants revealed no significant between-group differences. Regardless of exercise intensity, significant increases of IL6, IL8, IL10 and TNFA post-treatment followed by significant declines, except for IL8, until post-intervention were observed with no difference for CRP or IL1B. Subgroup analyses of 154 patients with breast cancer undergoing chemotherapy revealed that CRP (estimated mean difference (95% CI): 0.59 (0.33; 1.06); P = 0.101) and TNFA (EMD (95% CI): 0.88 (0.77; 1); P = 0.053) increased less with HI exercise post-treatment compared to LMI. Exploratory cytokine co-regulation analysis revealed no difference between the groups. In patients with breast cancer undergoing chemotherapy, HI exercise resulted in a lesser increase of CRP and TNFA immediately post-treatment compared to LMI, potentially protecting against chemotherapy-related inflammation.

We present a novel approach to analyzing stock return predictability that accommodates (i) arbitrary predictor persistence, (ii) panels with common factors, (iii) multiple predictors, (iv) short- and long-horizon analysis, and relies on standard inference from least-squares estimation of a suitably adjusted predictive regression. We analyze US and international equity premia and find that dividend- and earnings-related price ratios have negligible predictive power over long horizons, whereas the dividend yield has considerable predictive power over short horizons, with positive coefficients, consistent with present value theory. Long-term government bond yields exhibit predictive power over all horizons from one month through five years.

Using annual data from 1978 through 2016, and monthly data from January 2005 through November 2017 from Denmark, we provide a precise estimate of the upper bound on the potential impact of the adoption of wind energy on the reduction of CO2 emissions from energy production. We separate causal impacts from endogenous effects in regressions using instrumental variables including average wind speed, and from spurious effects in dynamic systems using impulse-response analysis and cointegration techniques. A one percentage point increase in the share of wind in total energy production is found to cause a reduction in CO2 emissions of the order 0.3%, based on endogeneity-corrected regression, and 0.5% over 2 years in a fractional vector error-correction model, after allowing the cumulative effects to take place. This corresponds to an upper bound estimate of 0.69 tonnes of CO2 emissions avoided per additional MWh of wind energy produced. We find that after a structural break at the time of introduction of the EU ETS and the Kyoto Protocol in 2005, the country has been on track towards meeting its long-term goals for emission reduction and green energy production, but not before.

This paper proposes a model for discrete-time hedging based on continuous-time movements in portfolio and foreign currency exchange rate returns. In particular, the vector of optimal currency exposures is shown to be given by the negative realized regression coefficients from a one-period conditional expectation of the intra-period quadratic covariation matrix for portfolio and foreign exchange rate returns. These are labelled the realized currency betas. The model, hence, facilitates dynamic hedging strategies that depend exclusively on the dynamic evolution of the ex-post quadratic covariation matrix. These hedging strategies are suggested implemented using modern, yet simple, non-parametric techniques to accurately measure and dynamically model historical quadratic covariation matrices. The empirical results from an extensive hedging exercise for equity investments illustrate that the realized currency betas exhibit important time variation, leading to substantial economic, as well as statistically significant, volatility reductions from the proposed hedging strategies, compared to existing benchmarks, without sacrificing returns. As a result, a risk-averse investor is shown to be willing to pay several hundred basis points to switch from existing hedging methods to the proposed realized currency beta approach. Interestingly, the empirical analysis strongly suggests that the superior performance of the latter during the most recent global financial crisis of 2008 is, at least partially, funded by carry traders.

The mutant protein FOXL2C134W is expressed in at least 95% of adult-type ovarian granulosa cell tumors (AGCT) and is considered to be a driver of oncogenesis in this disease. However, the molecular mechanism by which FOXL2C134W contributes to tumorigenesis is not known. Here, we show that mutant FOXL2C134W acquires the ability to bind SMAD4, forming a FOXL2C134W/SMAD4/SMAD2/3 complex that binds a novel hybrid DNA motif AGHCAHAA, unique to the FOXL2C134W mutant. This binding induced an enhancer-like chromatin state, leading to transcription of nearby genes, many of which are characteristic of epithelial-to-mesenchymal transition. FOXL2C134W also bound hybrid loci in primary AGCT. Ablation of SMAD4 or SMAD2/3 resulted in strong reduction of FOXL2C134W binding at hybrid sites and decreased expression of associated genes. Accordingly, inhibition of TGFβ mitigated the transcriptional effect of FOXL2C134W. Our results provide mechanistic insight into AGCT pathogenesis, identifying FOXL2C134W and its interaction with SMAD4 as potential therapeutic targets to this condition. Significance: FOXL2C134W hijacks SMAD4 and leads to the expression of genes involved in EMT, stemness, and oncogenesis in AGCT, making FOXL2C134W and the TGFβ pathway therapeutic targets in this condition.

The mutant protein FOXL2(C134W) is expressed in at least 95% of adult-type ovarian granulosa cell tumors (AGCT) and is considered to be a driver of oncogenesis in this disease. However, the molecular mechanism by which FOXL2(C134W) contributes to tumorigenesis is not known. Here we show that mutant FOXL2(C134W) acquires the ability to bind SMAD4, forming a FOXL2(C134W)/SMAD4/SMAD2/3 complex that binds a novel hybrid DNA motif AGHCAHAA, unique to the FOXL2(C134W) mutant. This binding induced an enhancer-like chromatin state, leading to transcription of nearby genes, many of which are characteristic of epithelial-to-mesenchymal transition. FOXL2(C134W) also bound hybrid loci in primary AGCT. Ablation of SMAD4 or SMAD2/3 resulted in strong reduction of FOXL2(C134W) binding at hybrid sites and decreased expression of associated genes. Accordingly, inhibition of TGFβ mitigated the transcriptional effect of FOXL2(C134W). Our results provide mechanistic insight into AGCT pathogenesis, identifying FOXL2(C134W) and its interaction with SMAD4 as potential therapeutic targets to this condition.

Polycomb group proteins are important for maintaining gene expression patterns and cell identity in metazoans. The mammalian Polycomb repressive deubiquitinase (PR-DUB) complexes catalyze removal of monoubiquitination on lysine 119 of histone H2A (H2AK119ub1) through a multiprotein core comprised of BAP1, HCFC1, FOXK1/2, and OGT in combination with either of ASXL1, 2, or 3. Mutations in PR-DUB components are frequent in cancer. However, mechanistic understanding of PR-DUB function in gene regulation is limited. Here, we show that BAP1 is dependent on the ASXL proteins and FOXK1/2 in facilitating gene activation across the genome. Although PR-DUB was previously shown to cooperate with PRC2, we observed minimal overlap and functional interaction between BAP1 and PRC2 in embryonic stem cells. Collectively, these results demonstrate that PR-DUB, by counteracting accumulation of H2AK119ub1, maintains chromatin in an optimal configuration ensuring expression of genes important for general functions such as cell metabolism and homeostasis.

Random forest regression (RF) is an extremely popular tool for the analysis of high-dimensional data. Nonetheless, its benefits may be lessened in sparse settings, due to weak predictors, and a pre-estimation dimension reduction (targeting) step is required. We show that proper targeting controls the probability of placing splits along strong predictors, thus providing an important complement to RF's feature sampling. This is supported by simulations using representative finite samples. Moreover, we quantify the immediate gain from targeting in terms of increased strength of individual trees. Macroeconomic and financial applications show that the bias-variance tradeoff implied by targeting, due to increased correlation among trees in the forest, is balanced at a medium degree of targeting, selecting the best 10-30% of commonly applied predictors. Improvements in predictive accuracy of targeted RF relative to ordinary RF are considerable, up to 12-13%, occurring both in recessions and expansions, particularly at long horizons.