The literature describing the use of low-intensity ultrasound in four major areas of cancer therapy—sonodynamic therapy, ultrasound-mediated chemotherapy, ultrasound-mediated gene delivery and ...anti-vascular ultrasound therapy—was reviewed. Each technique consistently resulted in the death of cancer cells, and the bio-effects of ultrasound were attributed primarily to thermal actions and inertial cavitation. In each therapeutic modality, theranostic contrast agents composed of microbubbles played a role in both therapy and vascular imaging. The development of these agents is important as it establishes a therapeutic–diagnostic platform that can monitor the success of anti-cancer therapy. Little attention, however, has been given either to the direct assessment of the mechanisms underlying the observed bio-effects or to the viability of these therapies in naturally occurring cancers in larger mammals; if such investigations provided encouraging data, there could be prompt application of a therapy technique in the treatment of cancer patients.
Many current metrics of drought are derived solely from analyses of climate variables such as precipitation and temperature. Drought is clearly a consequence of climate anomalies, as well as of human ...water use practices, but many impacts to society are more directly related to hydrologic conditions resulting from these two factors. Modern hydrology models can provide a valuable counterpart to existing climate‐based drought indices by simulating hydrologic variables such as land surface runoff. We contrast the behavior of a standardized runoff index (SRI) with that of the well‐known standardized precipitation index (SPI) during drought events in a snowmelt region. Although the SRI and SPI are similar when based on long accumulation periods, the SRI incorporates hydrologic processes that determine seasonal lags in the influence of climate on streamflow. As a result, on monthly to seasonal time scales, the SRI is a useful complement to the SPI for depicting hydrologic aspects of drought.
Abstract
More than one in three adults worldwide is either overweight or obese. Epidemiological studies indicate that the location and distribution of excess fat, rather than general adiposity, are ...more informative for predicting risk of obesity sequelae, including cardiometabolic disease and cancer. We performed a genome-wide association study meta-analysis of body fat distribution, measured by waist-to-hip ratio (WHR) adjusted for body mass index (WHRadjBMI), and identified 463 signals in 346 loci. Heritability and variant effects were generally stronger in women than men, and we found approximately one-third of all signals to be sexually dimorphic. The 5% of individuals carrying the most WHRadjBMI-increasing alleles were 1.62 times more likely than the bottom 5% to have a WHR above the thresholds used for metabolic syndrome. These data, made publicly available, will inform the biology of body fat distribution and its relationship with disease.
GCMs are used by many national weather services to produce seasonal outlooks of atmospheric and oceanic conditions and fluxes. Postprocessing is often a necessary step before GCM forecasts can be ...applied in practice. Quantile mapping (QM) is rapidly becoming the method of choice by operational agencies to postprocess raw GCM outputs. The authors investigate whether QM is appropriate for this task. Ensemble forecast postprocessing methods should aim to 1) correct bias, 2) ensure forecasts are reliable in ensemble spread, and 3) guarantee forecasts are at least as skillful as climatology, a property called “coherence.” This study evaluates the effectiveness of QM in achieving these aims by applying it to precipitation forecasts from the POAMA model. It is shown that while QM is highly effective in correcting bias, it cannot ensure reliability in forecast ensemble spread or guarantee coherence. This is because QM ignores the correlation between raw ensemble forecasts and observations. When raw forecasts are not significantly positively correlated with observations, QM tends to produce negatively skillful forecasts. Even when there is significant positive correlation, QM cannot ensure reliability and coherence for postprocessed forecasts. Therefore, QM is not a fully satisfactory method for postprocessing forecasts where the issues of bias, reliability, and coherence pre-exist. Alternative postprocessing methods based on ensemble model output statistics (EMOS) are available that achieve not only unbiased but also reliable and coherent forecasts. This is shown with one such alternative, the Bayesian joint probability modeling approach.
Celotno besedilo
Dostopno za:
BFBNIB, DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Genetic studies have established anaplastic lymphoma kinase (ALK), a cell surface receptor tyrosine kinase, as a tractable molecular target in neuroblastoma. We describe comprehensive genomic, ...biochemical, and computational analyses of ALK mutations across 1,596 diagnostic neuroblastoma samples. ALK tyrosine kinase domain mutations occurred in 8% of samples—at three hot spots and 13 minor sites—and correlated significantly with poorer survival in high- and intermediate-risk neuroblastoma. Biochemical and computational studies distinguished oncogenic (constitutively activating) from nononcogenic mutations and allowed robust computational prediction of their effects. The mutated variants also showed differential in vitro crizotinib sensitivities. Our studies identify ALK genomic status as a clinically important therapeutic stratification tool in neuroblastoma and will allow tailoring of ALK-targeted therapy to specific mutations.
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•ALK mutations occur in 8% of neuroblastoma patients across all stages of disease•The presence of an ALK tyrosine kinase domain mutation correlates with poor prognoses•A biochemically informed computational approach identifies oncogenic mutations•Oncogenic ALK mutations differ significantly in tumor cell sensitivity to crizotinib
Bresler et al. carry out comprehensive genomic, biochemical, and computational analyses of ALK mutations across a large cohort of diagnostic neuroblastoma samples and develop computational approaches for identifying disease-significant ALK mutations, which will also allow tailoring of ALK-targeted therapies.
Score Matching for Compositional Distributions Scealy, Janice L.; Wood, Andrew T. A.
Journal of the American Statistical Association,
07/2023, Letnik:
118, Številka:
543
Journal Article
Recenzirano
Odprti dostop
Compositional data are challenging to analyse due to the non-negativity and sum-to-one constraints on the sample space. With real data, it is often the case that many of the compositional components ...are highly right-skewed, with large numbers of zeros. Major limitations of currently available models for compositional data include one or more of the following: insufficient flexibility in terms of distributional shape; difficulty in accommodating zeros in the data in estimation; and lack of computational viability in moderate to high dimensions. In this article, we propose a new model, the polynomially tilted pairwise interaction (PPI) model, for analysing compositional data. Maximum likelihood estimation is difficult for the PPI model. Instead, we propose novel score matching estimators, which entails extending the score matching approach to Riemannian manifolds with boundary. These new estimators are available in closed form and simulation studies show that they perform well in practice. As our main application, we analyse real microbiome count data with fixed totals using a multinomial latent variable model with a PPI model for the latent variable distribution. We prove that, under certain conditions, the new score matching estimators are consistent for the parameters in the new multinomial latent variable model.
During differentiation, thousands of genes are repositioned toward or away from the nuclear envelope. These movements correlate with changes in transcription and replication timing. Using synthetic ...(TALE) transcription factors, we found that transcriptional activation of endogenous genes by a viral trans-activator is sufficient to induce gene repositioning toward the nuclear interior in embryonic stem cells. However, gene relocation was also induced by recruitment of an acidic peptide that décondenses chromatin without affecting transcription, indicating that nuclear reorganization is driven by chromatin remodeling rather than transcription. We identified an epigenetic inheritance of chromatin decondensation that maintained central nuclear positioning through mitosis even after the TALE transcription factor was lost. Our results also demonstrate that transcriptional activation, but not chromatin decondensation, is sufficient to change replication timing.
More than 100,000 genetic variants are classified as disease causing in public databases. However, the true penetrance of many of these rare alleles is uncertain and might be over-estimated by ...clinical ascertainment. Here, we use data from 379,768 UK Biobank (UKB) participants of European ancestry to assess the pathogenicity and penetrance of putatively clinically important rare variants. Although rare variants are harder to genotype accurately than common variants, we were able to classify as high quality 1,244 of 4,585 (27%) putatively clinically relevant rare (MAF < 1%) variants genotyped on the UKB microarray. We defined as “clinically relevant” variants that were classified as either pathogenic or likely pathogenic in ClinVar or are in genes known to cause two specific monogenic diseases: maturity-onset diabetes of the young (MODY) and severe developmental disorders (DDs). We assessed the penetrance and pathogenicity of these high-quality variants by testing their association with 401 clinically relevant traits. 27 of the variants were associated with a UKB trait, and we were able to refine the penetrance estimate for some of the variants. For example, the HNF4A c.340C>T (p.Arg114Trp) (GenBank: NM_175914.4) variant associated with diabetes is <10% penetrant by the time an individual is 40 years old. We also observed associations with relevant traits for heterozygous carriers of some rare recessive conditions, e.g., heterozygous carriers of the ERCC4 c.2395C>T (p.Arg799Trp) variant that causes Xeroderma pigmentosum were more susceptible to sunburn. Finally, we refute the previous disease association of RNF135 in developmental disorders. In conclusion, this study shows that very large population-based studies will help refine our understanding of the pathogenicity of rare genetic variants.
Ensemble forecasting applied to the field of hydrology is currently an established area of research embracing a broad spectrum of operational situations. This work catalogs the various pathways of ...ensemble streamflow forecasting based on an exhaustive review of more than 700 studies over the last 40 years. We focus on the advanced state of the art in the model‐based (dynamical) ensemble forecasting approaches. Ensemble streamflow prediction systems are categorized into three leading classes: statistics‐based streamflow prediction systems, climatology‐based ensemble streamflow prediction systems and numerical weather prediction‐based hydrological ensemble prediction systems. For each ensemble approach, technical information, as well as details about its strengths and weaknesses, are provided based on a critical review of the studies listed. Through this literature review, the performance and uncertainty associated with the ensemble forecasting systems are underlined from both operational and scientific viewpoints. Finally, the remaining key challenges and prospective future research directions are presented, notably through hybrid dynamical ‐ statistical learning approaches, which obviously present new challenges to be overcome in order to allow the successful employment of ensemble streamflow forecasting systems in the next decades. Targeting students, researchers and practitioners, this review provides a detailed perspective on the major features of an increasingly important area of hydrological forecasting.
Key Points
This work summarizes the 40 years of research in the generation of streamflow forecasts based on an exhaustive review of studies
Ensemble prediction systems are categorized into three classes: statistics‐based, climatology‐based and numerical weather prediction‐based hydrological ensemble prediction systems
For each ensemble forecasting system, thorough technical information is provided
Testosterone supplementation is commonly used for its effects on sexual function, bone health and body composition, yet its effects on disease outcomes are unknown. To better understand this, we ...identified genetic determinants of testosterone levels and related sex hormone traits in 425,097 UK Biobank study participants. Using 2,571 genome-wide significant associations, we demonstrate that the genetic determinants of testosterone levels are substantially different between sexes and that genetically higher testosterone is harmful for metabolic diseases in women but beneficial in men. For example, a genetically determined 1 s.d. higher testosterone increases the risks of type 2 diabetes (odds ratio (OR) = 1.37 (95% confidence interval (95% CI): 1.22-1.53)) and polycystic ovary syndrome (OR = 1.51 (95% CI: 1.33-1.72)) in women, but reduces type 2 diabetes risk in men (OR = 0.86 (95% CI: 0.76-0.98)). We also show adverse effects of higher testosterone on breast and endometrial cancers in women and prostate cancer in men. Our findings provide insights into the disease impacts of testosterone and highlight the importance of sex-specific genetic analyses.
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