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Warfarin use is complicated by an erratic dose response. Warfarin is metabolized by two distinct subfamilies of the cytochrome P450 (CYP) complex. We describe two siblings with extreme sensitivity to warfarin who share an unusual CYP genotype. These individuals illustrate both the importance of genetics in influencing the metabolism of warfarin as well as the potential utility of genetic testing as a guide to prescribing this medication., (Copyright 2001 Wiley-Liss, Inc.)

Background: Deformable Image Registration (DIR) is an essential technique required in many applications of radiation oncology. However, conventional DIR approaches typically take several minutes to register one pair of 3D CT images and the resulting deformable vector fields (DVFs) are only specific to the pair of images used, making it less appealing for clinical application. Purpose: A deep‐learning‐based DIR method using CT images is proposed for lung cancer patients to address the common drawbacks of the conventional DIR approaches and in turn can accelerate the speed of related applications, such as contour propagation, dose deformation, adaptive radiotherapy (ART), etc. Methods: A deep neural network based on VoxelMorph was developed to generate DVFs using CT images collected from 114 lung cancer patients. Two models were trained with the weighted mean absolute error (wMAE) loss and structural similarity index matrix (SSIM) loss (optional) (i.e., the MAE model and the M+S model). In total, 192 pairs of initial CT (iCT) and verification CT (vCT) were included as a training dataset and the other independent 10 pairs of CTs were included as a testing dataset. The vCTs usually were taken 2 weeks after the iCTs. The synthetic CTs (sCTs) were generated by warping the vCTs according to the DVFs generated by the pre‐trained model. The image quality of the synthetic CTs was evaluated by measuring the similarity between the iCTs and the sCTs generated by the proposed methods and the conventional DIR approaches, respectively. Per‐voxel absolute CT‐number‐difference volume histogram (CDVH) and MAE were used as the evaluation metrics. The time to generate the sCTs was also recorded and compared quantitatively. Contours were propagated using the derived DVFs and evaluated with SSIM. Forward dose calculations were done on the sCTs and the corresponding iCTs. Dose volume histograms (DVHs) were generated based on dose distributions on both iCTs and sCTs generated by two models, respectively. The clinically relevant DVH indices were derived for comparison. The resulted dose distributions were also compared using 3D Gamma analysis with thresholds of 3 mm/3%/10% and 2 mm/2%/10%, respectively. Results: The two models (wMAE and M+S) achieved a speed of 263.7±163 / 265.8±190 ms and a MAE of 13.15±3.8 / 17.52±5.8 HU for the testing dataset, respectively. The average SSIM scores of 0.987±0.006 and 0.988±0.004 were achieved by the two proposed models, respectively. For both models, CDVH of a typical patient showed that less than 5% of the voxels had a per‐voxel absolute CT‐number‐difference larger than 55 HU. The dose distribution calculated based on a typical sCT showed differences of ≤2cGy[RBE] for clinical target volume (CTV) D95 and D5, within ±0.06% for total lung V5, ≤1.5cGy[RBE] for heart and esophagus Dmean, and ≤6cGy[RBE] for cord Dmax compared to the dose distribution calculated based on the iCT. The good average 3D Gamma passing rates (> 96% for 3 mm/3%/10% and > 94% for 2 mm/2%/10%, respectively) were also observed. Conclusion: A deep neural network‐based DIR approach was proposed and has been shown to be reasonably accurate and efficient to register the initial CTs and verification CTs in lung cancer. [ABSTRACT FROM AUTHOR]

Key Clinical Message: We present a patient with cri‐du‐chat syndrome secondary to a rare cytogenetic mechanism. Our patient was the product of a dichorionic diamniotic twin pregnancy initially flagged with soft markers on ultrasound and uninformative single‐nucleotide polymorphism (SNP)‐based noninvasive prenatal testing (NIPT) for chromosome 18. Subsequent NIPT using proprietary‐targeted amplification methodology returned low risk for chromosomal aneuploidies 13, 18, and 21. Due to postnatal clinical findings, a clinical microarray and chromosomal karyotype confirmed cri‐du‐chat syndrome due to a de novo psu dic(5;18) (p15.2, p11.32). In this report we focus on these cytogenetic changes and discuss some of the current guidelines for prenatal microarray indications. [ABSTRACT FROM AUTHOR]

Purpose: To develop a 3D‐Unet dose prediction model to predict the three‐dimensional dose distribution of volumetric modulated arc therapy (VMAT) for cervical cancer and test the dose prediction performance of the model in endometrial cancer to explore the feasibility of model generalization. Methods: One hundred and seventeen cases of cervical cancer and 20 cases of endometrial cancer treated with VMAT were used for the model training, validation, and test. The prescribed dose was 50.4 Gy in 28 fractions. Eight independent channels of contoured structures were input to the model, and the dose distribution was used as the output of the model. The 3D‐Unet prediction model was trained and validated on the training set (n = 86) and validation set (n = 11), respectively. Then the model was tested on the test set (n = 20) of cervical cancer and endometrial cancer, respectively. The results between clinical dose distribution and predicted dose distribution were compared in the following aspects: (a) the mean absolute error (MAE) within the body, (b) the Dice similarity coefficients (DSCs) under different isodose volumes, (c) the dosimetric indexes including the mean dose (Dmean), the received dose of 2 cm3 (D2cc), the percentage volume of receiving 40 Gy dose of organs‐at‐risk (V40), planning target volume (PTV) D98%, and homogeneity index (HI), (d) dose–volume histograms (DVHs). Results: The model can accurately predict the dose distribution of the VMAT plan for cervical cancer and endometrial cancer. The overall average MAE and maximum MAE for cervical cancer were 2.43 ± 3.17% and 3.16 ± 4.01% of the prescribed dose, respectively, and for endometrial cancer were 2.70 ± 3.54% and 3.85 ± 3.11%. The average DSCs under different isodose volumes is above 0.9. The predicted dosimetric indexes and DVHs are equivalent to the clinical dose for both cervical cancer and endometrial cancer, and there is no statistically significant difference. Conclusion: A 3D‐Unet dose prediction model was developed for VMAT of cervical cancer, which can predict the dose distribution accurately for cervical cancer. The model can also be generalized for endometrial cancer with good performance. [ABSTRACT FROM AUTHOR]

Objectives: This study attempts to explore a novel peripheral lung stereotactic body radiotherapy (SBRT) planning technique that can balance the pros and cons of three-dimensional conformal radiotherapy (CRT) and intensitymodulated radiation therapy (IMRT) / volumetric modulated arc therapy (VMAT). Methods: Treatment plans were retrospectively designed based on CRT, IMRT, VMAT, and the proposed CRT-IMRT-combined (Co-CRIM) techniques using Pinnacle treatment planning system (TPS) for 20 peripheral lung cancer patients. Co-CRIM used an inverse optimization algorithm available in Pinnacle TPS.To develop a Co-CRIM plan, the number of segments in each field was limited to one, the minimum segment area was set to the internal target volume (ITV), and the minimum monitor units (MU) of the segment was the quotient of fractional dose divided by twice the number of total fields. The performance of Co-CRIM was then compared with other techniques. Results: For conformity index (CI), Co-CRIM performed comparably to IMRT/VMAT but better than CRT. For gradient index (GI), Co-CRIM was similar to IMRT/VMAT or CRT. For heterogeneity index (HI), Co-CRIM was comparable to IMRT/VMAT, higher than CRT. The dosimetric results of spinal cord and lung with Co-CRIM were better than CRT, comparable to IMRT, but inferior to VMAT. The MU resulted from Co-CRIM was lower than IMRT/VMAT but higher than CRT.For plan verification γ passing rate,Co-CRIM was higher than IMRT/VMAT, comparable to CRT.For planning time,Co-CRIM was shorter than CRT or VMAT but similar to IMRT. Conclusions: The proposed Co-CRIM technique on Pinnacle TPS is an effective planning technique for peripheral lung SBRT. [ABSTRACT FROM AUTHOR]

Cells with blocked microtubule polymerization are delayed in mitosis, but eventually manage to proliferate despite substantial chromosome missegregation. While several studies have analyzed the first cell division after microtubule depolymerization, we have asked how cells cope long‐term with microtubule impairment. We allowed 24 clonal populations of yeast cells with beta‐tubulin mutations preventing proper microtubule polymerization, to evolve for ˜150 generations. At the end of the laboratory evolution experiment, cells had regained the ability to form microtubules and were less sensitive to microtubule‐depolymerizing drugs. Whole‐genome sequencing identified recurrently mutated genes, in particular for tubulins and kinesins, as well as pervasive duplication of chromosome VIII. Recreating these mutations and chromosome VIII disomy prior to evolution confirmed that they allow cells to compensate for the original mutation in beta‐tubulin. Most of the identified mutations did not abolish function, but rather restored microtubule functionality. Analysis of the temporal order of resistance development in independent populations repeatedly revealed the same series of events: disomy of chromosome VIII followed by a single additional adaptive mutation in either tubulins or kinesins. Since tubulins are highly conserved among eukaryotes, our results have implications for understanding resistance to microtubule‐targeting drugs widely used in cancer therapy. SYNOPSIS: Cells with blocked microtubule polymerization undergo massive, death‐inducing chromosome missegregation, but may eventually restore microtubule functionality. Here, yeast laboratory evolution shows that this recurrently involves chromosome VIII disomy followed by mutually exclusive mutations in either tubulins or kinesin. After ˜150 generations, budding yeast cells impaired in microtubule formation recover the ability to polymerize tubulin.Genetically‐identical cell populations evolved in parallel exhibit similar evolutionary paths.Evolved cells first become disomic for chromosome VIII, and then acquire mutations in either tubulins or the kinesin KIP3.Disomy of chromosome VIII is present in the large majority of evolved populations, while mutations are mutually exclusive. [ABSTRACT FROM AUTHOR]

Methylation of cytosine in CpG dinucleotides and histone lysine and arginine residues is a chromatin modification that critically contributes to the regulation of genome integrity, replication, and accessibility. A strong correlation exists between the genome‐wide distribution of DNA and histone methylation, suggesting an intimate relationship between these epigenetic marks. Indeed, accumulating literature reveals complex mechanisms underlying the molecular crosstalk between DNA and histone methylation. These in vitro and in vivo discoveries are further supported by the finding that genes encoding DNA‐ and histone‐modifying enzymes are often mutated in overlapping human diseases. Here, we summarize recent advances in understanding how DNA and histone methylation cooperate to maintain the cellular epigenomic landscape. We will also discuss the potential implication of these insights for understanding the etiology of, and developing biomarkers and therapies for, human congenital disorders and cancers that are driven by chromatin abnormalities. [ABSTRACT FROM AUTHOR]

Rax is one of the key transcription factors crucial for vertebrate eye development. In this study, we conducted comprehensive evolutionary analysis of Rax. We found that Bilateria and Cnidaria possess Rax, but Placozoa, Porifera, and Ctenophora do not, implying that the origin of the Rax gene dates back to the common ancestor of Cnidaria and Bilateria. The results of molecular phylogenetic and synteny analyses on Rax loci between jawed and jawless vertebrates indicate that segmental duplication of the Rax locus occurred in an early common ancestor of jawed vertebrates, resulting in two Rax paralogs in jawed vertebrates, Rax and Rax2. By analyzing 86 mammalian genomes from all four major groups of mammals, we found that at least five independent Rax2 gene loss events occurred in mammals. This study may provide novel insights into the evolution of the eye. [ABSTRACT FROM AUTHOR]

Isocitrate dehydrogenases (IDHs) are metabolic enzymes that are mutated in several cancers, resulting in overproduction of d‐2‐hydroxyglutarate (D‐2HG). However, the signalling pathways and factors that regulate mutant IDHs or their metabolites remain elusive. Here, we report that in synchronized cells and cells treated with anti‐mitotic agents, wild‐type and mutant IDH proteins are induced maximally in G2/M. Moreover, mutant IDH1‐expressing cells arrested in G2/M harbour high D2HG levels. Genetic or pharmacological perturbation of Forkhead box protein M1 (FOXM1) abrogates the levels of IDH1 mRNA, protein and D2HG in G2/M. Conversely, overexpression of FOXM1 or hyperactive FOXM1 activates the IDH1 promoter and increases the abundance of its protein levels. In summary, our results show that in G2/M, higher D2HG levels are dependent on FOXM1‐mediated transcription of IDH1. [ABSTRACT FROM AUTHOR]

We evaluated an EPID‐based in‐vivo dosimetry (IVD) method for the dose verification and the treatment reproducibility of lung SBRT‐VMAT treatments in clinical routine. Ten patients with lung metastases treated with Elekta VMAT technique were enrolled. All patients were irradiated in five consecutive fractions, with total doses of 50 Gy. Set‐up was carried out with the Elekta stereotactic body frame. Eight patients were simulated and treated using the Active Breath Control (ABC) system, a spirometer enabling patients to maintain a breath‐hold at a predetermined lung volume. Two patients were simulated and treated in free‐breathing using an abdominal compressor. IVD was performed using the SOFTDISO software. IVD tests were evaluated by means of (a) ratio R between daily in‐vivo isocenter dose and planned dose and (b) γ‐analysis between EPID integral portal images in terms of percentage of points with γ‐value smaller than one (γ%) and mean γ‐values (γmean) using a 3%(global)/3 mm criteria. Alert criteria of ±5% for R ratio, γ% < 90%, and γmean > 0.67 were chosen. 50 transit EPID images were acquired. For the patients treated with ABC spirometer, the results reported a high level of accuracy in dose delivery with 100% of tests within ±5%. The γ‐analysis showed a mean value of γmean equal to 0.21 (range: 0.04–0.56) and a mean γ% equal to 96.9 (range: 78–100). Relevant discrepancies were observed only for the two patients treated without ABC, mainly due to a blurring dose effect due to residual respiratory motion. Our method provided a fast and accurate procedure in clinical routine for verifying delivered dose as well as for detecting errors. [ABSTRACT FROM AUTHOR]

Microarray testing is the recommended first-tier diagnostic test for women who undergo invasive prenatal diagnostic procedures. It is well-established that microarray analysis provides information regarding copy number for changes (or copy number variants, CNVs) that may be below the resolution level of standard chromosome analysis, and that such CNVs are not related to maternal age. What may not be appreciated by ordering providers, however, are the technical differences among laboratories with respect to the established laboratory cutoff values for reporting, the definition of targeted versus nontargeted regions, and how these differences may affect the interpretation and reporting of findings which, in turn, affects counseling and possible follow-up testing of family members. Here, we provide a detailed explanation of these technical factors and clarify how they practically impact diagnostic results. [ABSTRACT FROM AUTHOR]

Purpose: To compare dosimetric performance of volumetric‐modulated arc therapy (VMAT) and small‐spot intensity‐modulated proton therapy for stage III non‐small‐cell lung cancer (NSCLC). Methods and Materials: A total of 24 NSCLC patients were retrospectively reviewed; 12 patients received intensity‐modulated proton therapy (IMPT) and the remaining 12 received VMAT. Both plans were generated by delivering prescription doses to clinical target volumes (CTV) on averaged 4D‐CTs. The dose‐volume‐histograms (DVH) band method was used to quantify plan robustness. Software was developed to evaluate interplay effects with randomized starting phases of each field per fraction. DVH indices were compared using Wilcoxon rank sum test. Results: Compared with VMAT, IMPT delivered significantly lower cord Dmax, heart Dmean, and lung V5 Gy[RBE] with comparable CTV dose homogeneity, and protection of other OARs. In terms of plan robustness, the IMPT plans were statistically better than VMAT plans in heart Dmean, but were statistically worse in CTV dose coverage, cord Dmax, lung Dmean, and V5 Gy[RBE]. Other DVH indices were comparable. The IMPT plans still met the standard clinical requirements with interplay effects considered. Conclusions: Small‐spot IMPT improves cord, heart, and lung sparing compared to VMAT and achieves clinically acceptable plan robustness at least for the patients included in this study with motion amplitude less than 11 mm. Our study supports the usage of IMPT to treat some lung cancer patients. [ABSTRACT FROM AUTHOR]

Abstract: Purpose: The purpose of this study was to study the influence of the minimum segment width (MSW) on volumetric modulated arc therapy (VMAT) plan quality, delivery accuracy, and efficiency for cervical cancer treatment. Methods: Nineteen patients with cervical cancer were randomly selected to design VMAT plans. Three VMAT plans were generated for each patient incorporating MSWs of 0.5, 1.0, and 1.5 cm while other planning parameters remained constant using the Monaco treatment planning system (TPS) with 6 MV X rays delivered from an Elekta Synergy linear accelerator. Plan quality and delivery efficiency were evaluated based on dose‐volume histograms (DVHs), control points, monitor units (MUs), dosimetric measurement verification results, and plan delivery time. Results: Except for the small difference in target dose coverage and maximum dose, there were no statistically significant differences between the other dosimetric parameters in the planning target volumes. The 1.0 and 1.5 cm MSW plans showed lower maximum doses to the spinal cord than the 0.5 cm plan; doses to other organs at risks were similar regardless of MSWs. The mean reductions of total MUs when compared with the 0.5 cm plan were 14.5 ± 6.1% and 20.9 ± 7.9% for MSWs of 1.0 and 1.5 cm, respectively. The calculated gamma indices using the 3% and 3 mm criteria were 96.2 ± 0.6%, 97.0 ± 0.6%, and 97.6 ± 0.6% for the 0.5, 1.0 and 1.5 cm MSW plans, respectively. The plan delivery times decreased with increasing MSWs (p < 0.05). Conclusion: Increasing the MSW allows for improved plan delivery accuracy and efficiency without significantly affecting the VMAT plan quality. MSWs of 1.0 and 1.5 cm improved the plan quality, delivery accuracy, and efficiency for cervical VMAT radiation therapy. [ABSTRACT FROM AUTHOR]

Metabolic changes accompany tumor progression and metastatic dissemination of cancer cells. Yet, until recently, metabolism has received little attention in the study of cancer metastasis. Cancer cells undergo significant metabolic rewiring as they acquire metastatic traits and adapt to survive in multiple environments with varying nutrient availability, oxygen concentrations, and extracellular signals. Therefore, to effectively treat metastatic cancer, it is important to understand the metabolic strategies adopted by cancer cells during the metastatic process. Here, we focus on the metabolic pathways known to play a role in cancer metastasis, including glycolysis, the pentose phosphate pathway, tricarboxylic acid cycle, oxidative phosphorylation, amino acid metabolism, and fatty acid metabolism. Recent studies have uncovered roles for these pathways in cellular events that promote metastasis, including reactive oxygen species‐mediated signaling, epigenetic regulation, and interaction with the extracellular matrix. We also discuss the metabolic interplay between immune cells and cancer cells supporting metastasis. Finally, we highlight the current limitations of our knowledge on this topic, and present future directions for the field. WIREs Syst Biol Med 2018, 10:e1406. doi: 10.1002/wsbm.1406 This article is categorized under: Biological Mechanisms > Metabolism [ABSTRACT FROM AUTHOR]

Several lines of evidence indicate that during transformation epithelial cancer cells can acquire mesenchymal features via a process called epithelial-to-mesenchymal transition ( EMT). This process endows cancer cells with increased invasive and migratory capacity, enabling tumour dissemination and metastasis. EMT is associated with a complex metabolic reprogramming, orchestrated by EMT transcription factors, which support the energy requirements of increased motility and growth in harsh environmental conditions. The discovery that mutations in metabolic genes such as FH, SDH and IDH activate EMT provided further evidence that EMT and metabolism are intertwined. In this review, we discuss the role of EMT in cancer and the underpinning metabolic reprogramming. We also put forward the hypothesis that, by altering chromatin structure and function, metabolic pathways engaged by EMT are necessary for its full activation. [ABSTRACT FROM AUTHOR]

X chromosome dosage compensation in Drosophila requires chromosome-wide coordination of gene activation. The male-specific lethal dosage compensation complex (DCC) identifies and binds to X-chromosomal high-affinity sites (HAS) from which it boosts transcription. A sub-class of HAS, PionX sites, represent first contacts on the X. Here, we explored the chromosomal interactions of representative PionX sites by high-resolution 4C and determined the global chromosome conformation by Hi-C in sex-sorted embryos. Male and female X chromosomes display similar nuclear architecture, concordant with clustered, constitutively active genes. PionX sites, like HAS, are evenly distributed in the active compartment and engage in short- and long-range interactions beyond compartment boundaries. Long-range, inter-domain interactions between DCC binding sites are stronger in males, suggesting that the complex refines chromatin organization. By de novo induction of DCC in female cells, we monitored the extent of activation surrounding PionX sites. This revealed a remarkable range of DCC action not only in linear proximity, but also at megabase distance if close in space, suggesting that DCC profits from pre-existing chromosome folding to activate genes. [ABSTRACT FROM AUTHOR]

Biochemistry textbooks and cell culture experiments seem to be telling us two different things about the significance of external glutamine supply for mammalian cell growth and proliferation. Despite the fact that glutamine is a nonessential amino acid that can be synthesized by cells from glucose-derived carbons and amino acid-derived ammonia, most mammalian cells in tissue culture cannot proliferate or even survive in an environment that does not contain millimolar levels of glutamine. Not only are the levels of glutamine in standard tissue culture media at least ten-fold higher than other amino acids, but glutamine is also the most abundant amino acid in the human bloodstream, where it is assiduously maintained at approximately 0.5 mM through a combination of dietary uptake, de novo synthesis, and muscle protein catabolism. The complex metabolic logic of the proliferating cancer cells' appetite for glutamine-which goes far beyond satisfying their protein synthesis requirements-has only recently come into focus. In this review, we examine the diversity of biosynthetic and regulatory uses of glutamine and their role in proliferation, stress resistance, and cellular identity, as well as discuss the mechanisms that cells utilize in order to adapt to glutamine limitation. [ABSTRACT FROM AUTHOR]

DNA methylation plays a critical role in both embryonic development and tumorigenesis and is mediated through various DNA methyltransferases. Constitutional mutations in the de novo DNA methyltransferase DNMT3A cause a recently identified Tatton-Brown-Rahman overgrowth syndrome (TBRS). Somatically acquired mutations in DNMT3A are causally associated with acute myeloid leukemia (AML), and p.Arg882His represents the most prevalent hotspot. So far, no patients with TBRS have been reported to have subsequently developed AML. Here, we report a live birth and the survival of a female with the TBRS phenotype who had a heterozygous constitutional DNMT3A mutation at the AML somatic mutation hotspot p.Arg882His in her DNA from peripheral blood and buccal tissue. Her characteristic features at birth included hypotonia, narrow palpebral fissures, ventricular septal defect, umbilical hernia, sacral cyst, Chiari type I anomaly. At the age of 6 years, she exhibited overgrowth (> 3 SD) and round face and intellectual disability. This report represents the first documentation of the same variant ( DNMT3A p.Arg882His) as both the constitutional mutation associated with TBRS and the somatic mutation hotspot of AML. The observation neither confirms nor denies the notion that mutations responsible for TBRS and those for AML might share the same mode of action. Larger data sets are required to determine whether TBRS patients with constitutional DNMT3A mutations are at an increased risk for AML. © 2016 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

The sequence of the human genome together with sequence similarity analyses has advanced the discovery of missing steps in the mitochondrial one-carbon metabolism pathway. That together with the revived interest in cancer metabolism has brought the research on one-carbon metabolism back under the spotlight. Here, we present a brief review of recent advances in the field of one-carbon metabolism, with a bias towards its relevance to cell growth and proliferation in human cancers. We will address the requirements of one-carbon metabolism for biosynthesis and the major sources to satisfy that demand. We will also discuss some recent discoveries indicating a role of one-carbon metabolism beyond biosynthesis. We conclude with a concise enumeration of some fundamental questions that remain unanswered. [ABSTRACT FROM AUTHOR]

Mitochondria are metabolic hubs within mammalian cells and demonstrate significant metabolic plasticity. In oxygenated environments with ample carbohydrate, amino acid, and lipid sources, they are able to use the tricarboxylic acid cycle for the production of anabolic metabolites and ATP. However, in conditions where oxygen becomes limiting for oxidative phosphorylation, they can rapidly signal to increase cytosolic glycolytic ATP production, while awaiting hypoxia-induced changes in the proteome mediated by the activity of transcription factors such as hypoxia-inducible factor 1. Hypoxia is a well-described phenotype of most cancers, driving many aspects of malignancy. Improving our understanding of how mitochondria change their metabolism in response to this stimulus may therefore elicit the design of new selective therapies. Many of the recent advances in our understanding of mitochondrial metabolic plasticity have been acquired through investigations of cancer-associated mutations in metabolic enzymes, including succinate dehydrogenase, fumarate hydratase, and isocitrate dehydrogenase. This review will describe how metabolic perturbations induced by hypoxia and mutations in these enzymes have informed our knowledge in the control of mitochondrial metabolism, and will examine what this may mean for the biology of the cancers in which these mutations are observed. WIREs Syst Biol Med 2016, 8:272-285. doi: 10.1002/wsbm.1334 For further resources related to this article, please visit the . [ABSTRACT FROM AUTHOR]

Three recent genome-wide studies in mice and humans have produced the most definitive map to date of genomic imprinting (gene expression that depends on parental origin) by incorporating multiple tissue types and developmental stages. Here, we explore the results of these studies in light of the kinship theory of genomic imprinting, which predicts that imprinting evolves due to differential genetic relatedness between maternal and paternal relatives. The studies produce a list of imprinted genes with around 120-180 in mice and ∼100 in humans. The studies agree on broad patterns across mice and humans including the complex patterns of imprinted expression at loci like Igf2 and Grb10. We discuss how the kinship theory provides a powerful framework for hypotheses that can explain these patterns. Finally, since imprinting is rare in the genome despite predictions from the kinship theory that it might be common, we discuss evolutionary factors that could favor biallelic expression. [ABSTRACT FROM AUTHOR]

Retroviruses, as part of their replication cycle, become integrated into the genome of their host. When this occurs in the germline the integrated proviruses can become an endogenous retrovirus (ERV) which may eventually become fixed in the population. ERVs are present in the genomes of all vertebrates including humans, where more than 50 groups of human endogenous retrovirus (HERVs) have been described within the last 30 years. Despite state-of-the-art genomic tools available for retroviral discovery and the large number of retroviral sequences described to date, there are still gaps in understanding retroviral macroevolutionary patterns and host-retrovirus interactions and a lack of a coherent systematic classification particularly for HERVs. Here, we discuss the current knowledge on ERV (and HERV) classification, distribution and origins focusing on the role of cross-species transmission in retroviral diversity. [ABSTRACT FROM AUTHOR]

Even though aerobic glycolysis, or the Warburg effect, is arguably the most common trait of metabolic reprogramming in cancer, it is unobserved in certain tumor types. Systems biology advocates a global view on metabolism to dissect which traits are consistently reprogrammed in cancer, and hence likely to constitute an obligate step for the evolution of cancer cells. We refer to such traits as symmetric. Here, we review early systems biology studies that attempted to reveal symmetric traits in the metabolic reprogramming of cancer, discuss the symmetry of reprogramming of nucleotide metabolism, and outline the current limitations that, if unlocked, could elucidate whether symmetries in cancer metabolism may be claimed. [ABSTRACT FROM AUTHOR]

52I.53II.53III.54IV.55V.55VI.56VII.57VIII.58IX.59X.59XI.61XII.6262References62 Summary: A minority of angiosperms have male and female flowers separated in distinct individuals (dioecy), and most dioecious plants do not have cytologically different (heteromorphic) sex chromosomes. Plants nevertheless have several advantages for the study of sex chromosome evolution, as genetic sex determination has evolved repeatedly and is often absent in close relatives. I review sex‐determining regions in non‐model plant species, which may help us to understand when and how (and, potentially, test hypotheses about why) recombination suppression evolves within young sex chromosomes. I emphasize high‐throughput sequencing approaches that are increasingly being applied to plants to test for non‐recombining regions. These data are particularly illuminating when combined with sequence data that allow phylogenetic analyses, and estimates of when these regions evolved. Together with comparative genetic mapping, this has revealed that sex‐determining loci and sex‐linked regions evolved independently in many plant lineages, sometimes in closely related dioecious species, and often within the past few million years. In reviewing recent progress, I suggest areas for future work, such as the use of phylogenies to allow the informed choice of outgroup species suitable for inferring the directions of changes, including testing whether Y chromosome‐like regions are undergoing genetic degeneration, a predicted consequence of losing recombination. [ABSTRACT FROM AUTHOR]

Cancer cells have fundamentally altered cellular metabolism that is associated with their tumorigenicity and malignancy. In addition to the widely studied Warburg effect, several new key metabolic alterations in cancer have been established over the last decade, leading to the recognition that altered tumor metabolism is one of the hallmarks of cancer. Deciphering the full scope and functional implications of the dysregulated metabolism in cancer requires both the advancement of a variety of omics measurements and the advancement of computational approaches for the analysis and contextualization of the accumulated data. Encouragingly, while the metabolic network is highly interconnected and complex, it is at the same time probably the best characterized cellular network. Following, this review discusses the challenges that genome-scale modeling of cancer metabolism has been facing. We survey several recent studies demonstrating the first strides that have been done, testifying to the value of this approach in portraying a network-level view of the cancer metabolism and in identifying novel drug targets and biomarkers. Finally, we outline a few new steps that may further advance this field. [ABSTRACT FROM AUTHOR]

Stereotactic body radiotherapy ( SBRT) is a high precision radiotherapy technique used for the treatment of small to moderate extra-cranial tumours. Early studies utilising SBRT have shown favourable outcomes. However, major disadvantages of static field SBRT include long treatment times and toxicity complications. Volumetric modulated arc therapy ( VMAT) and intensity modulated radiotherapy ( IMRT) may potentially mitigate these disadvantages. This review aims to assess the feasibility of emerging VMAT and IMRT-based SBRT treatment techniques and qualify which offers the best outcome for patients, whilst identifying any emerging and advantageous SBRT planning trends. A review and synthesis of data from current literature up to September 2013 was conducted on EMBASE, Medline, PubMed, Science Direct, Proquest central, Google Scholar and the Cochrane Database of Systematic reviews. Only full text papers comparing VMAT and or IMRT and or Static SBRT were included. Ten papers were identified that evaluated the results of VMAT/ IMRT SBRT. Five related to medically inoperable stage 1 and 2 non-small-cell lung cancer ( NSCLC), three to spinal metastasis, one related to abdominal lymph node malignancies, with the final one looking at pancreatic adenocarcinoma. Overall treatment times with VMAT were reduced by 66-70% for lung, 46-58% for spine, 42% and 21% for lymph node and pancreatic metastasis respectively, planning constraints were met with several studies showing improved organs at risk sparing with IMRT/ VMAT to static SBRT. Both IMRT and VMAT were able to meet all planning constraints in the studies reviewed, with VMAT offering the greatest treatment efficiency. Early clinical outcomes with VMAT and IMRT SBRT have demonstrated excellent local control and favourable survival outcomes. [ABSTRACT FROM AUTHOR]

Myeloid malignancies including acute myeloid leukemia ( AML) and myelodysplastic syndromes ( MDS) are a heterogeneous group of disorders that share a common biology and are a major source of morbidity and mortality. In the last several years, studies using next-generation sequencing ( NGS) have identified a core set of recurrently mutated myeloid malignancy genes in the majority of patients with AML and MDS, including those with normal cytogenetics. DNA-level mutations in several of these genes including NPM1, FLT3, and CEBPA in AML and ASXL1, ETV6, EZH2, RUNX1, and TP53 in MDS are associated with changes in patient outcomes and are now tested for in clinical laboratories. In addition to providing prognostic information, these gene mutations can be used to monitor patient disease burden through the use of ultrasensitive detection techniques. In this review, we will focus on the clinical utility of various NGS-based methods including whole-genome sequencing, exome sequencing, and targeted panel-based sequencing in the initial diagnosis and management of AML and MDS and cover recent methodological advances for the molecular monitoring of AML and MDS. [ABSTRACT FROM AUTHOR]

Acute myeloid leukemia ( AML) is a complex disease, for which our understanding of the role of genetic and epigenetic changes has undergone significant advancements. Newer diagnostic and prognostic classifications have increasingly incorporated such information, and novel therapies have been developed to target specific genes, processes, and pathways based on this growing understanding. Given the rapid evolution of this field, it is critical for physicians and translational researchers to have a more in-depth understanding of this evolving landscape. Here, we review both genetics and epigenetics in acute myeloid leukemia from a practical standpoint. [ABSTRACT FROM AUTHOR]

In the 10 years since the discovery of lysine-specific demethylase 1 (LSD1), this epigenetic eraser has emerged as an important target of interest in oncology. More specifically, research has demonstrated that it plays an essential role in the self-renewal of leukemic stem cells in acute myeloid leukemia (AML). This review will cover clinical aspects of AML, the role of epigenetics in the disease, and discuss the research that led to the first irreversible inhibitors of LSD1 entering clinical trials for the treatment of AML in 2014. We also review recent achievements and progress in the development of potent and selective reversible inhibitors of LSD1. These compounds differ in their mode of action from tranylcypromine derivatives and could facilitate novel biochemical studies to probe the pathways mediated by LSD1. In this review, we will critically evaluate the strengths and weaknesses of published series of reversible LSD1 inhibitors. Overall, while the development of reversible inhibitors to date has been less fruitful than that of irreversible inhibitors, there is still the possibility for their use to facilitate further research into the roles and functions of LSD1 and to expand the therapeutic applications of LSD1 inhibitors in the clinic. [ABSTRACT FROM AUTHOR]

Background: Interleukin (IL) 37 has been described as a negative regulator of innate immunity, as it reduces the activation and cytokine production of different innate immune cells. Recently, results from the CLARA childhood asthma cohort suggested an implication of IL-37 for human asthma pathogenesis. This study aimed to investigate the effects of IL-37 on allergic airway inflammation in a mouse model of experimental asthma. Methods: Peripheral blood mononuclear cells (PBMCs) of children were cultured for 48 h (anti-CD3/anti-CD28 stimulation or unstimulated), and IL-37 concentrations in supernatants were determined. Wild-type, IL-18Rα-deficient (-/-), and SIGIRR -/- C57BL/6 mice were sensitized to ovalbumin (OVA) and challenged with OVA aerosol to induce acute experimental asthma, and IL-37 was applied intranasally prior to each OVA challenge. Airway hyper-responsiveness (AHR), airway inflammation, cytokine levels in broncho-alveolar lavage fluid, and mucus production were determined. Results: IL-37 production of human PBMCs was significantly lower in allergic asthmatics vs healthy children. In wild-type mice, intranasal administration of IL-37 ablated allergic airway inflammation as well as cytokine production and subsequently diminished the hallmarks of experimental asthma including mucus hyperproduction and AHR. In contrast, local application of IL-37 produced none of these effects in mice lacking either IL18Rα or SIGIRR/IL-1R8. Conclusions: This study demonstrates that IL-37 is able to ablate a TH2 celldirected allergic inflammatory response and the hallmarks of experimental asthma in mice, suggesting that IL-37 may be critical for asthma pathogenesis. Furthermore, these data suggest a mode of action of IL-37 that involves IL18Rα as well as the orphan receptor SIGIRR/IL-1R8. [ABSTRACT FROM AUTHOR]

Introduction Acute myeloid leukemia ( AML) is a heterogeneous clonal disorder of hemopoietic progenitor cells diagnosed in individuals of any age, but with a median age of 67 years at presentation in adults. Assessment of the mutation status of nucleophosmin protein-1 ( NPM1) and FMS-like tyrosine kinase 3 internal tandem duplication ( FLT3- ITD) is essential for the prognosis, and treatment of AML. Methods A total of 160 de novo AML cases, both cytogenetically normal and abnormal, were analyzed for the presence of NPM1 and FLT3- ITD mutations, and the results assessed in conjunction with epidemiological, clinical, and laboratory findings. Results Nucleophosmin protein-1 mutations were found in 7.5%, while FLT3- ITD was present in 12% of these cases. Both of these were lower than expected. The median age at diagnosis of AML was 41 years, and for the FLT3- ITD only cases, median age was 33 years; these ages were younger than expected. Conclusion The lower reported frequencies and younger median age at diagnosis of AML and these specific mutations may be contributed to by a number of factors including effects of race on age of presentation, inclusion of patients diagnosed with de novo AML only, and a generally younger median age of the South African population. [ABSTRACT FROM AUTHOR]

Introduction Multiparameter flow cytometry ( MFC) is commonly used to detect minimal residual disease ( MRD) during the course of chemotherapy or relapse. Only one study addressed the immunophenotypic changes in refractory disease. We studied changes in leukemia-associated aberrant immunophenotype ( LAIP) in patients with refractory and relapsed acute myeloid leukemia ( AML). Method We analyzed 47 patients (refractory = 22; relapsed = 25) by MFC, morphology, and cytogenetic studies. Results Thirty-five patients (74%) showed variably changed LAIPs. The frequently altered LAIPs were lack of lineage-specific antigen and lineage infidelity. The most frequently changed marker was CD13, followed by CD33, CD56, CD7, CD4, and CD11b. Cytogenetic clonal evolution at persistence/relapse was observed in 15 patients (32%). Morphologically, three patients (6%) showed significant changes at relapse. Patients with refractory AML had a higher association with poor cytogenetic risk and classification of AML with myelodysplasia-related changes. Positive MRD at postinduction was of prognostic significance. Allogeneic stem cell transplant improved overall survival. Conclusions LAIP alterations in refractory/relapsed AMLs are common findings. Presence of persistent disease indicates a poor prognosis, regardless of cytogenetic risk or expression of CD7 or CD56. Discordance between cytogenetic and LAIP changes suggests that gross cytogenetic clonal evolution during disease progression only partly contributes to immunophenotypic instability. [ABSTRACT FROM AUTHOR]