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Earlier work demonstrated that the transcription factor C/EBPα can convert immature and mature murine B lineage cells into functional macrophages. Testing >20 human lymphoma and leukemia B cell lines, we found that most can be transdifferentiated at least partially into macrophage-like cells, provided that C/EBPα is expressed at sufficiently high levels. A tamoxifen-inducible subclone of the Seraphina Burkitt lymphoma line, expressing C/EBPαER, could be efficiently converted into phagocytic and quiescent cells with a transcriptome resembling normal macrophages. The converted cells retained their phenotype even when C/EBPα was inactivated, a hallmark of cell reprogramming. Interestingly, C/EBPα induction also impaired the cells' tumorigenicity. Likewise, C/EBPα efficiently converted a lymphoblastic leukemia B cell line into macrophage-like cells, again dramatically impairing their tumorigenicity. Our experiments show that human cancer cells can be induced by C/EBPα to transdifferentiate into seemingly normal cells at high frequencies and provide a proof of principle for a potential new therapeutic strategy for treating B cell malignancies.	How can B-cells transdifferentiate into macrophages?	Earlier work demonstrated that the transcription factor C/EBPα can convert immature and mature murine B lineage cells into functional macrophages.
X inactivation, the transcriptional silencing of one of the two X chromosomes in female mammals, achieves dosage compensation of X-linked genes relative to XY males. In eutherian mammals X inactivation is regulated by the X-inactive specific transcript (Xist), a cis-acting non-coding RNA that triggers silencing of the chromosome from which it is transcribed. Marsupial mammals also undergo X inactivation but the mechanism is relatively poorly understood. We set out to analyse the X chromosome in Monodelphis domestica and Didelphis virginiana, focusing on characterizing the interval defined by the Chic1 and Slc16a2 genes that in eutherians flank the Xist locus. The synteny of this region is retained on chicken chromosome 4 where other loci belonging to the evolutionarily ancient stratum of the human X chromosome, the so-called X conserved region (XCR), are also located. We show that in both M. domestica and D. virginiana an evolutionary breakpoint has separated the Chic1 and Slc16a2 loci. Detailed analysis of opossum genomic sequences revealed linkage of Chic1 with the Lnx3 gene, recently proposed to be the evolutionary precursor of Xist, and Fip1, the evolutionary precursor of Tsx, a gene located immediately downstream of Xist in eutherians. We discuss these findings in relation to the evolution of Xist and X inactivation in mammals.	The X-inactive specific transcript (Xist) gene is responsible for mediating the X-chromosome inactivation in females, where one X-chromosome is silenced and transcriptionally inactivated. What does Xist encode?	In eutherian mammals X inactivation is regulated by the X-inactive specific transcript (Xist), a cis-acting non-coding RNA that triggers silencing of the chromosome from which it is transcribed.
Purpose The aim of this study was to determine the occurrence and distribution of the 'central vein' sign in white matter lesions on susceptibility-weighted magnetic resonance images in patients with multiple sclerosis (MS) and cerebral small vessel disease (CSVD). Materials and methods T2-weighted and fluid-attenuated inversion recovery magnetic resonance images of 19 MS patients and 19 patients affected by CSVD were analysed for the presence and localisation of focal hyperintense white matter lesions. Lesions were subdivided into periventricular or non-periventricular (juxtacortical, subcortical, deep white matter and cerebellar) distributed. The number and localisation of lesions presenting with the central vein sign were recorded and compared between MS and CSVD lesions. Results A total of 313 MS patients and 75 CSVD lesions were identified on T2-weighted and fluid-attenuated inversion recovery magnetic resonance images. The central vein sign was found in 128 MS lesions (40.9%), and the majority of them (71/128, 55.5%) had a periventricular distribution. The central vein sign was found in 22 out of 75 (29.3%) CSVD lesions, and periventricular distribution was seen in six out of 22 (27.2%) CSVD lesions. The difference in the proportion of white matter hyperintense lesions that presented with the central vein sign on susceptibility-weighted images in patients with MS and CSVD was statistically different, and a significantly higher number of MS patients presented with lesions with the central vein sign compared to CSVD patients. Conclusion The presence of the central vein sign on susceptibility-weighted images for MS lesions improves the understanding of the periventricular distribution of MS lesions and could contribute as adjunctive diagnostic criteria for MS disease.	Central Vein Sign is characteristic to which disease?	Conclusion The presence of the central vein sign on susceptibility-weighted images for MS lesions improves the understanding of the periventricular distribution of MS lesions and could contribute as adjunctive diagnostic criteria for MS disease.
A novel method is developed to model and predict the transmembrane regions of beta-barrel membrane proteins. It is based on a Hidden Markov model (HMM) with architecture obeying those proteins' construction principles. The HMM is trained and tested on a non-redundant set of 11 beta-barrel membrane proteins known to date at atomic resolution with a jack-knife procedure. As a result, the method correctly locates 97% of 172 transmembrane beta-strands. Out of the 11 proteins, the barrel size for ten proteins and the overall topology for seven proteins are correctly predicted. Additionally, it successfully assigns the entire topology for two new beta-barrel membrane proteins that have no significant sequence homology to the 11 proteins. Predicted topology for two candidates for beta-barrel structure of the outer mitochondrial membrane is also presented in the paper.	What are the computational methods for the prediction of beta-barrel transmembrane proteins?	A novel method is developed to model and predict the transmembrane regions of beta-barrel membrane proteins. It is based on a Hidden Markov model (HMM) with architecture obeying those proteins' construction principles.
Necroptosis is a programmed cell death pathway triggered by activation of receptor interacting protein kinase 3 (RIPK3), which phosphorylates and activates the mixed lineage kinase-like domain pseudokinase, MLKL, to rupture or permeabilize the plasma membrane. Necroptosis is an inflammatory pathway associated with multiple pathologies including autoimmunity, infectious and cardiovascular diseases, stroke, neurodegeneration, and cancer. Here, we describe protocols that can be used to characterize MLKL as the executioner of plasma membrane rupture in necroptosis. We visualize the process of necroptosis in cells using live-cell imaging with conventional and confocal fluorescence microscopy, and in fixed cells using electron microscopy, which together revealed the redistribution of MLKL from the cytosol to the plasma membrane prior to induction of large holes in the plasma membrane. We present in vitro nuclear magnetic resonance (NMR) analysis using lipids to identify putative modulators of MLKL-mediated necroptosis. Based on this method, we identified quantitative lipid-binding preferences and phosphatidyl-inositol phosphates (PIPs) as critical binders of MLKL that are required for plasma membrane targeting and permeabilization in necroptosis.	Do cells undergoing necroptosis show disruption of their cell membranes?	Necroptosis is a programmed cell death pathway triggered by activation of receptor interacting protein kinase 3 (RIPK3), which phosphorylates and activates the mixed lineage kinase-like domain pseudokinase, MLKL, to rupture or permeabilize the plasma membrane.
Analysis of serum and plasma proteomes is a common approach for biomarker discovery, and the removal of high-abundant proteins, such as albumin and immunoglobins, is usually the first step in the analysis. However, albumin binds peptides and proteins, which raises concerns as to how the removal of albumin could impact the outcome of the biomarker study while ignoring the possibility that this could be a biomarker subproteome itself. The first goal of this study was to test a new commercially available affinity capture reagent from Protea Biosciences and to compare the efficiency and reproducibility to four other commercially available albumin depletion methods. The second goal of this study was to determine if there is a highly efficient albumin depletion/isolation system that minimizes sample handling and would be suitable for large numbers of samples. Two of the methods tested (Sigma and ProteaPrep) showed an albumin depletion efficiency of 97% or greater for both serum and cerebrospinal fluid (CSF). Isolated serum and CSF albuminomes from ProteaPrep spin columns were analyzed directly by LC-MS/MS, identifying 128 serum (45 not previously reported) and 94 CSF albuminome proteins (17 unique to the CSF albuminome). Serum albuminome was also isolated using Vivapure anti-HSA columns for comparison, identifying 105 proteins, 81 of which overlapped with the ProteaPrep method.	Albumin depletion is a common first step for proteomic analysis of CSF fluid. What is the advantage and disadvantage of this procedure?	However, albumin binds peptides and proteins, which raises concerns as to how the removal of albumin could impact the outcome of the biomarker study while ignoring the possibility that this could be a biomarker subproteome itself.
During mammalian oocyte maturation, protein synthesis is mainly controlled through cytoplasmic polyadenylation of stored maternal mRNAs. In this study, the role of polyadenylation modification of maternal transcripts in pig oocytes was investigated by adding cordycepin (3'-dA), a potent polyadenylation inhibitor, to the culture medium of porcine oocytes maturing in vitro. 3'-dA significantly prevented cumulus expansion regardless of the concentration used, and inhibited pig oocyte maturation in a dose-dependent manner. Further, 3'-dA 1 microg/ml-treated MII oocytes experienced significantly lower rates of cleavage (29%) and blastocyst formation (15.35%) compared to control MII oocytes (58.6% and 35.3%, respectively). Western blotting revealed that the activity of mitogen-activated protein kinase (MAPK) and p34(cdc2) was significantly decreased in oocytes and cumulus cells treated with 3'-dA at a concentration of 1 microg/ml or greater. To further explore the underlying molecular mechanisms, expression patterns and polyadenylation states of four important genes, C-mos, cyclin B, GDF9 and BMP15, were studied as representative maternal transcripts by real-time PCR and the PAT assay. 3'-dA at concentrations above 1 microg/ml significantly prevented polyadenylation and caused aberrant expression of C-mos and GDF9 during oocyte maturation. These results suggest that polyadenylation inhibitor blocked pig oocyte maturation in vitro by one or more of the following actions: (1) inactivation of MAPK and MPF in oocytes, especially at the late stages (MI and MII); (2) prevention of cumulus cell expansion through inactivation of cellular MAPK; and (3) inhibition of the maternal mRNA polyadenylation process, which in reverse, disrupted the maternal mRNA patterns in pig oocytes' maturation in vitro.	Is polyadenylation a process that stabilizes a protein by adding a string of Adenosine residues to the end of the molecule?	During mammalian oocyte maturation, protein synthesis is mainly controlled through cytoplasmic polyadenylation of stored maternal mRNAs.
Förster resonance energy transfer (FRET) is a powerful tool in biological research and has been widely used in the study of biomolecular interactions. SUMOylation is an important post-translational modification that is involved in many key biological processes. As a multi-step cascade reaction, SUMOylation involves multiple enzymes and protein-protein interactions. Here, we report the development of an in vitro FRET-based high-throughput screening (HTS) assay in SUMOylation. This assay is based on steady state and high efficiency of the fluorescent energy transfer between CyPet and YPet fused to SUMO1 and Ubc9, respectively. We optimized the assay and performed a small-scale pilot study to validate the screening platform. Carried out in 384-well plate format, our FRET-based HTS provides a powerful tool for large-scale and high-throughput applications.	Is SUMOylation a post-translational modification in eukaryotes?	SUMOylation is an important post-translational modification that is involved in many key biological processes
Septins are important components of the cytoskeleton that are highly conserved in eukaryotes and play major roles in cytokinesis, patterning, and many developmental processes. Septins form heteropolymers which assemble into higher-order structures including rings, filaments, and gauzes. In contrast to actin filaments and microtubules, the molecular mechanism by which septins assemble is not well-understood. Here, we report that in the filamentous fungus Aspergillus nidulans, four core septins form heteropolymeric complexes. AspE, a fifth septin lacking in unicellular yeasts, interacts with only one of the core septins, and only during multicellular growth. AspE is required for proper localization of three of the core septins, and requires this same subset of core septins for its own unique cortical localization. The ΔaspE mutant lacks developmentally-specific septin higher-order structures and shows reduced spore production and slow growth with low temperatures and osmotic stress. Our results show that at least two distinct septin heteropolymer populations co-exist in A. nidulans, and that while AspE is not a subunit of either heteropolymer, it is required for assembly of septin higher-order structures found in multicellular development.	What are Septins?	Septins are important components of the cytoskeleton that are highly conserved in eukaryotes and play major roles in cytokinesis, patterning, and many developmental processes.
The objective of this open single-centre study was to evaluate the efficacy and tolerability of botulinum toxin type-A (BTX-A) as add-on in the prophylactic treatment of cluster headache (CH). Twelve male patients with episodic (n=3) or chronic (n=9) CH, unresponsive to common prophylactic medications, were treated with a cumulative dose of 50 International Units (IU) BTX-A according to a standardised injection scheme into the ipsilateral pericranial muscles. One patient with chronic CH experienced a total cessation of attacks and in 2 patients attack intensity and frequency improved. In another patient with chronic CH typical attacks were not influenced, but an ipsilateral continuous occipital headache significantly improved. Patients with episodic CH did not benefit from BTX-A treatment. Tolerability was excellent. These findings provide evidence that BTX-A may be beneficial as an add-on prophylactic therapy for a limited number of patients with chronic CH.	What pharmacological and non-pharmacological interventions can be considered as prophylactic therapies in Cluster Headache patients?	The objective of this open single-centre study was to evaluate the efficacy and tolerability of botulinum toxin type-A (BTX-A) as add-on in the prophylactic treatment of cluster headache (CH).
Interphase chromatin is organized into topologically associating domains (TADs). Within TADs, chromatin looping interactions are formed between DNA regulatory elements, but their functional importance for the establishment of the 3D genome organization and gene regulation during development is unclear. Using high-resolution Hi-C experiments, we analyze higher order 3D chromatin organization during Drosophila embryogenesis and identify active and repressive chromatin loops that are established with different kinetics and depend on distinct factors: Zelda-dependent active loops are formed before the midblastula transition between transcribed genes over long distances. Repressive loops within polycomb domains are formed after the midblastula transition between polycomb response elements by the action of GAGA factor and polycomb proteins. Perturbation of PRE function by CRISPR/Cas9 genome engineering affects polycomb domain formation and destabilizes polycomb-mediated silencing. Preventing loop formation without removal of polycomb components also decreases silencing efficiency, suggesting that chromatin architecture can play instructive roles in gene regulation during development. VIDEO ABSTRACT.	Do polycomb group proteins (PcG) mediate the formation of chromatin loops?	Repressive loops within polycomb domains are formed after the midblastula transition between polycomb response elements by the action of GAGA factor and polycomb proteins.
Co-option of cis-regulatory modules has been suggested as a mechanism for the evolution of expression sites during development. However, the extent and mechanisms involved in mobilization of cis-regulatory modules remains elusive. To trace the history of non-coding elements, which may represent candidate ancestral cis-regulatory modules affirmed during chordate evolution, we have searched for conserved elements in tunicate and vertebrate (Olfactores) genomes. We identified, for the first time, 183 non-coding sequences that are highly conserved between the two groups. Our results show that all but one element are conserved in non-syntenic regions between vertebrate and tunicate genomes, while being syntenic among vertebrates. Nevertheless, in all the groups, they are significantly associated with transcription factors showing specific functions fundamental to animal development, such as multicellular organism development and sequence-specific DNA binding. The majority of these regions map onto ultraconserved elements and we demonstrate that they can act as functional enhancers within the organism of origin, as well as in cross-transgenesis experiments, and that they are transcribed in extant species of Olfactores. We refer to the elements as 'Olfactores conserved non-coding elements'.	Are ultraconserved elements often transcribed?	The majority of these regions map onto ultraconserved elements and we demonstrate that they can act as functional enhancers within the organism of origin, as well as in cross-transgenesis experiments, and that they are transcribed in extant species of Olfactores
Vascular endothelial cells regulate vascular smooth muscle tone through Ca2+-dependent production and release of vasoactive molecules. Phospholamban (PLB) is a 24- to 27-kDa phosphoprotein that modulates activity of the sarco(endo)plasmic reticulum Ca2+ ATPase (SERCA). Expression of PLB is reportedly limited to cardiac, slow-twitch skeletal and smooth muscle in which PLB is an important regulator of [Ca2+]i and contractility in these muscles. In the present study, we report the existence of PLB in the vascular endothelium, a nonmuscle tissue, and provide functional data on PLB regulation of vascular contractility through its actions in the endothelium. Endothelium-dependent relaxation to acetylcholine was attenuated in aorta of PLB-deficient (PLB-KO) mice compared with wild-type (WT) controls. This effect was not due to actions of nitric oxide on the smooth muscle, because sodium nitroprusside-mediated relaxation in either denuded or endothelium-intact aortas was unaffected by PLB ablation. Relative to denuded vessels, relaxation to forskolin was enhanced in WT endothelium-intact aortas. The endothelium-dependent component of this relaxation was attenuated in PLB-KO aortas. To investigate whether these changes were due to PLB, WT mouse aorta endothelial cells were isolated. Both reverse transcriptase-polymerase chain reaction and Western blot analyses revealed the presence of PLB in endothelial cells, which were shown to be >98% pure by diI-acetylated LDL uptake and nuclear counterstaining. These data indicate that PLB is present and modulates vascular function as a result of its actions in endothelial cells. The presence of PLB in endothelial cells opens new fields for investigation of Ca2+ regulatory pathways in nonmuscle cells and for modulation of endothelial-vascular interactions.	Is phospholamban a regulatory/inhibitory protein of the Ca ATPase SERCA?	Phospholamban (PLB) is a 24- to 27-kDa phosphoprotein that modulates activity of the sarco(endo)plasmic reticulum Ca2+ ATPase (SERCA). Expression of PLB is reportedly limited to cardiac, slow-twitch skeletal and smooth muscle in which PLB is an important regulator of [Ca2+]i and contractility in these muscles.
We present a study on computational identification of uber-operons in a prokaryotic genome, each of which represents a group of operons that are evolutionarily or functionally associated through operons in other (reference) genomes. Uber-operons represent a rich set of footprints of operon evolution, whose full utilization could lead to new and more powerful tools for elucidation of biological pathways and networks than what operons have provided, and a better understanding of prokaryotic genome structures and evolution. Our prediction algorithm predicts uber-operons through identifying groups of functionally or transcriptionally related operons, whose gene sets are conserved across the target and multiple reference genomes. Using this algorithm, we have predicted uber-operons for each of a group of 91 genomes, using the other 90 genomes as references. In particular, we predicted 158 uber-operons in Escherichia coli K12 covering 1830 genes, and found that many of the uber-operons correspond to parts of known regulons or biological pathways or are involved in highly related biological processes based on their Gene Ontology (GO) assignments. For some of the predicted uber-operons that are not parts of known regulons or pathways, our analyses indicate that their genes are highly likely to work together in the same biological processes, suggesting the possibility of new regulons and pathways. We believe that our uber-operon prediction provides a highly useful capability and a rich information source for elucidation of complex biological processes, such as pathways in microbes. All the prediction results are available at our Uber-Operon Database: http://csbl.bmb.uga.edu/uber, the first of its kind.	What are the uber-operons?	Uber-operons represent a rich set of footprints of operon evolution, whose full utilization could lead to new and more powerful tools for elucidation of biological pathways and networks than what operons have provided, and a better understanding of prokaryotic genome structures and evolution
We report on a male newborn with multiple congenital abnormalities consistent with the diagnosis of VACTERL association (vertebral, anal, cardiac, tracheo-esophageal fistula, renal, and limb anomalies), who had Fanconi anemia (complementation group B) recognized by the detection of a deletion in chromosome Xp22.2 using an oligonucleotide array. The diagnosis of Fanconi anemia was confirmed by increased chromosomal breakage abnormalities observed in cultured cells that were treated with cross-linking agents. This is the first report in the literature of Fanconi anemia complementation group B detected by oligonucleotide array testing postnatally.	What is considered a reliable technique for the definitive cytogenetic diagnosis of Fanconi anemia homozygosity?	The diagnosis of Fanconi anemia was confirmed by increased chromosomal breakage abnormalities observed in cultured cells that were treated with cross-linking agents.
X chromosome inactivation (XCI) depends on a noncoding sense-antisense transcript pair, Xist and Tsix. At the onset of XCI, Xist RNA accumulates on one of two Xs, coating and silencing the chromosome in cis. The molecular basis for monoallelic Xist upregulation is not known, though evidence predominantly supports a posttranscriptional mechanism through RNA stabilization. Here, we test whether Tsix RNA destabilizes Xist RNA. Unexpectedly, we find that Xist upregulation is not based on transcript stabilization at all but is instead controlled by transcription in a sex-specific manner. Tsix directly regulates its transcription. On the future inactive X, Tsix downregulation induces a transient heterochromatic state in Xist, followed paradoxically by high-level Xist expression. A Tsix-deficient X chromosome adopts the heterochromatic state in pre-XCI cells. This state persists through XCI establishment and "reverts" to a euchromatic state during XCI maintenance. We have therefore identified chromatin marks that preempt and predict asymmetric Xist expression.	Which is the transcript responsible for X-chromosome inactivation?	chromosome inactivation (XCI) depends on a noncoding sense-antisense transcript pair, Xist
The University of California Santa Cruz (UCSC) Genome Browser Database is an up to date source for genome sequence data integrated with a large collection of related annotations. The database is optimized to support fast interactive performance with the web-based UCSC Genome Browser, a tool built on top of the database for rapid visualization and querying of the data at many levels. The annotations for a given genome are displayed in the browser as a series of tracks aligned with the genomic sequence. Sequence data and annotations may also be viewed in a text-based tabular format or downloaded as tab-delimited flat files. The Genome Browser Database, browsing tools and downloadable data files can all be found on the UCSC Genome Bioinformatics website (http://genome.ucsc.edu), which also contains links to documentation and related technical information.	Which algorithm is used by the UCSC Genome Browser?	The database is optimized to support fast interactive performance with the web-based UCSC Genome Browser, a tool built on top of the database for rapid visualization and querying of the data at many levels. The annotations for a given genome are displayed in the browser as a series of tracks aligned with the genomic sequence. Sequence data and annotations may also be viewed in a text-based tabular format or downloaded as tab-delimited flat files.
Severe hypertriglyceridaemia is associated with pancreatitis and chronic pancreatitis-induced diabetes. Familial chylomicronaemia syndrome (FCS) is a rare autosomal recessive disorder of lipid metabolism characterised by high levels of triglycerides (TGs) due to failure of chylomicron clearance. It causes repeated episodes of severe abdominal pain, fatigue and attacks of acute pancreatitis. There are few current options for its long-term management. The only universal long-term therapy is restriction of total dietary fat intake to <10-15% of daily calories (15 to 20g per day). Many patients have been treated with fibrates and statins with a variable response, but many remain susceptible to pancreatitis. Other genetic syndromes associated with hypertriglyceridaemia include familial partial lipodystrophy (FPLD). Targeting apolipoprotein C3 (apoC3) offers the ability to increase clearance of chylomicrons and other triglyceride-rich lipoproteins. Volanesorsen is an antisense oligonucleotide (ASO) inhibitor of apoC3, which reduces TG levels by 70-80% which has been shown also to reduce rates of pancreatitis and improve well-being in FCS and reduce TGs and improve insulin resistance in FPLD. It is now undergoing licensing and payer reviews. Further developments of antisense technology including small interfering RNA therapy to apoC3 as well as other approaches to modulating triglycerides are in development for this rare disorder.	What is the target of Volanesorsen?	Volanesorsen is an antisense oligonucleotide (ASO) inhibitor of apoC3, which reduces TG levels by 70-80% which has been shown also to reduce rates of pancreatitis and improve well-being in FCS and reduce TGs and improve insulin resistance in FPLD.
Indocyanine green (ICG), a US Food and Drug Administration-approved fluorescent compound, has been on the medical stage for more than 60 years. Current uses include hepatic function evaluation before surgical procedure and fundus evaluation. The large safety margin and near-infrared fluorescent optical advantage of the drug have proved useful in several clinical trials of intraoperative systems for tumor removal. Several nanoparticle-sized formulations for thermal ablation and photodynamic therapy have also been evaluated in animal experiments. Studies have attempted to manipulate ICG as a reporter fluorophore with initial success. In this article, we reviewed ICG's histological applications, chemical and physical properties, current clinical applications, ongoing clinical trials, and biomedical studies and prospects. We believe that ICG could be used with novel biotechnological techniques, such as fluorescent endoscopy and photoacoustic equipment, in a range of biomedical fields.	How is Indocyanine green (ICG) used?	Indocyanine green (ICG), a US Food and Drug Administration-approved fluorescent compound, has been on the medical stage for more than 60 years. Current uses include hepatic function evaluation before surgical procedure and fundus evaluation.
We compared the safety and efficacy of siltuximab (S), an anti-interleukin-6 chimeric monoclonal antibody, plus bortezomib (B) with placebo (plc) + B in patients with relapsed/refractory multiple myeloma in a randomized phase 2 study. Siltuximab was given by 6 mg/kg IV every 2 weeks. On progression, B was discontinued and high-dose dexamethasone could be added to S/plc. Response and progression-free survival (PFS) were analyzed pre-dexamethasone by European Group for Blood and Marrow Transplantation (EBMT) criteria. For the 281 randomized patients, median PFS for S + B and plc + B was 8.0 and 7.6 months (HR 0.869, P = 0.345), overall response rate was 55 versus 47% (P = 0.213), complete response rate was 11 versus 7%, and median overall survival (OS) was 30.8 versus 36.8 months (HR 1.353, P = 0.103). Sustained suppression of C-reactive protein, a marker reflective of inhibition of interleukin-6 activity, was seen with S + B. Siltuximab did not affect B pharmacokinetics. Siltuximab/placebo discontinuation (75 versus 66%), grade ≥3 neutropenia (49 versus 29%), thrombocytopenia (48 versus 34%), and all-grade infections (62 versus 49%) occurred more frequently with S + B. The addition of siltuximab to bortezomib did not appear to improve PFS or OS despite a numerical increase in response rate in patients with relapsed or refractory multiple myeloma.	Which interleukin is blocked by Siltuximab?	We compared the safety and efficacy of siltuximab (S), an anti-interleukin-6 chimeric monoclonal antibody, plus bortezomib (B) with placebo (plc) + B in patients with relapsed/refractory multiple myeloma in a randomized phase 2 study.
The enormous genetic variability reported in HIV-1 has posed problems in the treatment of infected individuals. This is evident in the form of HIV-1 resistant to antiviral agents, neutralizing antibodies and cytotoxic T lymphocytes (CTLs) involving multiple viral gene products. Based on this, it has been suggested that a comprehensive analysis of the polymorphisms in HIV proteins is of value for understanding the virus transmission and pathogenesis as well as for the efforts towards developing anti-viral therapeutics and vaccines. This study, for the first time, describes an in-depth analysis of genetic variation in Vpr using information from global HIV-1 isolates involving a total of 976 Vpr sequences. The polymorphisms at the individual amino acid level were analyzed. The residues 9, 33, 39, and 47 showed a single variant amino acid compared to other residues. There are several amino acids which are highly polymorphic. The residues that show ten or more variant amino acids are 15, 16, 28, 36, 37, 48, 55, 58, 59, 77, 84, 86, 89, and 93. Further, the variant amino acids noted at residues 60, 61, 34, 71 and 72 are identical. Interestingly, the frequency of the variant amino acids was found to be low for most residues. Vpr is known to contain multiple CTL epitopes like protease, reverse transcriptase, Env, and Gag proteins of HIV-1. Based on this, we have also extended our analysis of the amino acid polymorphisms to the experimentally defined and predicted CTL epitopes. The results suggest that amino acid polymorphisms may contribute to the immune escape of the virus. The available data on naturally occurring polymorphisms will be useful to assess their potential effect on the structural and functional constraints of Vpr and also on the fitness of HIV-1 for replication.	How is the sequence variability defined in antibodies?	This study, for the first time, describes an in-depth analysis of genetic variation in Vpr using information from global HIV-1 isolates involving a total of 976 Vpr sequences
Cystic fibrosis is the most common hereditary disease in populations of European descent, with its prevalence depending on the populations and ethnic groups studied. In contrast to Europe and North America, there is little information about this disease in Latin America. Uruguay currently has a human population of 3,000,000, with a low rate of miscegenation and no remaining isolated Amerindian groups. In the present study, we estimated the prevalence of cystic fibrosis in this country based on the detection of DeltaF508 mutation carriers in 500 unrelated individuals and on the frequency of individuals homozygous for this mutation within the affected population. The latter was calculated from the frequency of the different mutations and genotypes observed in a sample of 52 previously described patients with confirmed cystic fibrosis. A theoretical estimate of the prevalence of cystic fibrosis based on anthropological data suggested a frequency of 25 affected individuals/100,000 inhabitants. However, our data indicated that the true prevalence in the population was considerably lower (6.9 cases/100,000 inhabitants).	Which is the prevalence of cystic fibrosis in the human population?	A theoretical estimate of the prevalence of cystic fibrosis based on anthropological data suggested a frequency of 25 affected individuals/100,000 inhabitants. However, our data indicated that the true prevalence in the population was considerably lower (6.9 cases/100,000 inhabitants)
Recently, unique areas of transcriptional regulation termed super-enhancers have been identified and implicated in human disease. Defined by their magnitude of size, transcription factor density, and binding of transcriptional machinery, super-enhancers have been associated with genes driving cell differentiation. While their functions are not completely understood, it is clear that these regions driving high-level transcription are susceptible to perturbation, and trait-associated single nucleotide polymorphisms (SNPs) occur within super-enhancers of disease-relevant cell types. Here we review evidence for super-enhancer involvement in cancers, complex diseases, and developmental disorders and discuss interactions between super-enhancers and cofactors/chromatin regulators.	What are the properties of super-enhancers?	Here we review evidence for super-enhancer involvement in cancers, complex diseases, and developmental disorders and discuss interactions between super-enhancers and cofactors/chromatin regulators.
Erythropoiesis requires large amounts of iron for hemoglobin synthesis, which is mainly provided by macrophages and the intestines in a transferrin (Tf)-bound form. Bone marrow erythroblasts incorporate Tf through endocytosis, which is mediated by transferrin receptor 1 (TFR1). Recently, human TFR1, aside from its role as a Tf receptor, was also found to be a receptor for the H-subunit of ferritin (FTH). In humans, hematopoietic erythroid precursor cells express high levels of TFR1 and specifically take up the FTH homopolymer (H-ferritin). H-ferritin inhibits the formation of burst forming unit-erythroid colonies in vitro. TFR2, which is also a Tf receptor, is predominantly expressed in hepatocytes and erythroid precursor cells. In the liver, TFR2 forms a complex with HFE, a hereditary hemochromatosis-associated protein, and acts as an iron sensor. In mice, hepatocyte-specific knockout of the TFR2 gene has been shown to cause systemic iron-overload with decreased expression of hepcidin, the central regulator of iron homeostasis. In erythroid cells, TFR2 forms a complex with the erythropoietin receptor and facilitates its trafficking to the cell membrane. Moreover, hematopoietic cell-specific knockout of the TFR2 gene causes microcytic erythrocytosis in mice. This review focuses on the molecular evolution and functions of these TFRs and their ligands.	Is the TFR1 gene dispensable for erythropoiesis?	In humans, hematopoietic erythroid precursor cells express high levels of TFR1 and specifically take up the FTH homopolymer (H-ferritin).
Prostate cancer is the leading cause of cancer-related deaths in men. Androgen ablation is the mainstay of treatment for advanced prostate cancer. This therapy is very effective in androgen-dependent cancer; however, these cancers eventually become androgen independent, rendering anti-androgen therapy ineffective. The exploration of novel modalities of treatment is therefore essential to improve the prognosis of this neoplasia. Telomeres are specialized heterochromatin structures that act as protective caps at the ends of chromosomes. Telomere maintenance in the majority of tumor cells is achieved by telomerase, a reverse transcriptase enzyme that catalyzes the synthesis of further telomeric DNA. Telomerase is detected in the majority of prostate cancers, but not in normal or benign prostatic hyperplasia tissue. Moreover, the human telomerase reverse transcriptase (hTERT) gene, the catalytic subunit of telomerase, is regulated by androgens as well as by different oncogenes including Her-2, Ras, c-Myc and Bcl-2, which seem to play an important role in prostate cancer progression. Thus, telomerase may represent a very good candidate for targeted therapy in prostate tumors. To inhibit telomere maintenance by telomerase, approaches that directly target either telomerase and telomeres or the telomerase regulatory mechanisms have been used. Moreover, strategies targeting telomerase-positive cells as a means to directly kill the tumor cells have been tested. This review summarizes the most promising results achieved by anti-telomerase strategy in different solid tumors. Most of the telomerase-associated therapies described here have proved very promising for the treatment of prostate cancer. On the basis of the good results obtained and considering the multigenic defects of human tumors, including prostate cancer, the combination of anti-telomerase strategies with conventional drugs and/or molecules capable of interfering with oncogenic pathways could efficiently improve the response of this neoplasia.	What makes telomerase a good drug target?	Telomerase is detected in the majority of prostate cancers, but not in normal or benign prostatic hyperplasia tissue.
Mutations in dynamin 2 (DNM2) lead to dominant intermediate Charcot-Marie-Tooth neuropathy type B, while a different set of DNM2 mutations cause autosomal dominant centronuclear myopathy. In this study, we aimed to elucidate the disease mechanisms in dominant intermediate Charcot-Marie-Tooth neuropathy type B and to find explanations for the tissue-specific defects that are associated with different DNM2 mutations in dominant intermediate Charcot-Marie-Tooth neuropathy type B versus autosomal dominant centronuclear myopathy. We used tissue derived from Dnm2-deficient mice to establish an appropriate peripheral nerve model and found that dominant intermediate Charcot-Marie-Tooth neuropathy type B-associated dynamin 2 mutants, but not autosomal dominant centronuclear myopathy mutants, impaired myelination. In contrast to autosomal dominant centronuclear myopathy mutants, Schwann cells and neurons from the peripheral nervous system expressing dominant intermediate Charcot-Marie-Tooth neuropathy mutants showed defects in clathrin-mediated endocytosis. We demonstrate that, as a consequence, protein surface levels are altered in Schwann cells. Furthermore, we discovered that myelination is strictly dependent on Dnm2 and clathrin-mediated endocytosis function. Thus, we propose that altered endocytosis is a major contributing factor to the disease mechanisms in dominant intermediate Charcot-Marie-Tooth neuropathy type B.	Which genes are associated with autosomal dominant Charcot-Marie-Tooth?	In this study, we aimed to elucidate the disease mechanisms in dominant intermediate Charcot-Marie-Tooth neuropathy type B and to find explanations for the tissue-specific defects that are associated with different DNM2 mutations in dominant intermediate Charcot-Marie-Tooth neuropathy type B versus autosomal dominant centronuclear myopathy.
The proposed research will investigate two microbial communities that are of direct relevance to Department of Energy interests. One is the microbial community associated with the in situ bioremediation of uranium-contaminated groundwater. The second is a microbial community that harvests energy from waste organic matter in the form of electricity. These studies will address DOE needs for (1) remediation of metals and radionuclides at DOE sites and (2) the development of cleaner forms of energy and biomass conversion to energy. Our previous studies have demonstrated that the microbial communities involved in uranium bioremediation and energy harvesting are both dominated by microorganisms in the family Geobacteraceae and that the organisms in this family are responsible for uranium bioremediation and electron transfer to electrodes. The initial objectives of this study are to (1) describe the genetic potential of the Geobacteraceae that predominate in the environments of interest; (2) identify conserved patterns of gene expression within the Geobacteraceae family in response to a range of environmental conditions; (3) begin to identify mechanisms controlling the expression of key genes related to survival, growth, and activity in subsurface environments and on electrodes; and (4) use the results from subobjectives 1-3 to develop a conceptual model for predicting gene expression of Geobacteraceae in the environments of interest. This will serve as the basis for a subsequent simulation model of the growth and activity of Geobacteraceae in the subsurface and on electrodes.	List bacteria that may be useful in uranium bioremediation.	Our previous studies have demonstrated that the microbial communities involved in uranium bioremediation and energy harvesting are both dominated by microorganisms in the family Geobacteraceae and that the organisms in this family are responsible for uranium bioremediation and electron transfer to electrodes.
HOTAIR was proposed to regulate either HoxD cluster genes in trans or HoxC cluster genes in cis, a mechanism that remains unclear. We have identified a 32-nucleotide conserved noncoding element (CNE) as HOTAIR ancient sequence that likely originated at the root of vertebrate. The second round of whole-genome duplication resulted in one copy of the CNE within HOTAIR and another copy embedded in noncoding transcript of HOXD11. Paralogous CNEs underwent compensatory mutations, exhibit sequence complementarity with respect to transcripts directionality, and have high affinity in vitro. The HOTAIR CNE resembled a poised enhancer in stem cells and an active enhancer in HOTAIR-expressing cells. HOTAIR expression is positively correlated with HOXC11 in cis and negatively correlated with HOXD11 in trans. We propose a dual modality of HOTAIR regulation where transcription of HOTAIR and its embedded enhancer regulates HOXC11 in cis and sequence complementarity between paralogous CNEs suggests HOXD11 regulation in trans.	How many nucleotides long is the HOTAIR CNE?	HOTAIR was proposed to regulate either HoxD cluster genes in trans or HoxC cluster genes in cis, a mechanism that remains unclear. We have identified a 32-nucleotide conserved noncoding element (CNE) as HOTAIR ancient sequence that likely originated at the root of vertebrate. The second round of whole-genome duplication resulted in one copy of the CNE within HOTAIR and another copy embedded in noncoding transcript of HOXD11. Paralogous CNEs underwent compensatory mutations, exhibit sequence complementarity with respect to transcripts directionality, and have high affinity in vitro. The HOTAIR CNE resembled a poised enhancer in stem cells and an active enhancer in HOTAIR-expressing cells. HOTAIR expression is positively correlated with HOXC11 in cis and negatively correlated with HOXD11 in trans.
Previously, we found that treatment of cells with the Hsp90 inhibitor geldanamycin (GA) leads to a substantial reduction in the number of processing bodies (P-bodies), and also alters the size and subcellular localization of stress granules. These findings imply that the chaperone activity of Hsp90 is involved in the formation of P-bodies and stress granules. To verify these observations, we examined whether another Hsp90 inhibitor radicicol (RA) affected P-bodies and stress granules. Treatment with RA reduced the level of the Hsp90 client protein Argonaute 2 and the number of P-bodies. Although stress granules still assembled in RA-treated cells upon heat shock, they were smaller and more dispersed in the cytoplasm than those in untreated cells. Furthermore eIF4E and eIF4E-transporter were dissociated selectively from stress granules in RA-treated cells. These observations were comparable to those obtained upon treatment with GA in our previous work. Thus, we conclude that abrogation of the chaperone activity of Hsp90 affects P-body formation and the integrity of stress granules.	Which protein is required for Argonaute 2 recruitment to stress granules and P-bodies?	Treatment with RA reduced the level of the Hsp90 client protein Argonaute 2 and the number of P-bodies.
Ribosomal protein S19 (RPS19) is frequently mutated in Diamond-Blackfan anemia (DBA), a rare congenital hypoplastic anemia. Recent studies have shown that RPS19 expression decreases during terminal erythroid differentiation. Currently no information is available on the subcellular localization of normal RPS19 and the potential effects of various RPS19 mutations on cellular localization. In the present study, using wild-type and mutant RPS19 cDNA, we explored the subcellular distribution of normal and mutant proteins in a fibroblast cell line (Cos-7 cells). RPS19 was detected primarily in the nucleus, and more specifically in the nucleoli, where RPS19 colocalized with the nucleolar protein nucleolin. Using various N-terminal and C-terminal deletion constructs, we identified 2 nucleolar localization signals (NoSs) in RPS19: the first comprising amino acids Met1 to Arg16 in the NH2-terminus and the second comprising Gly120 to Asn142 in the COOH-terminus. Importantly, 2 mutations identified in DBA patients, Val15Phe and Gly127Gln, each of which localized to 1 of the 2 NoS, failed to localize RPS19 to the nucleolus. In addition to their mislocalization, there was a dramatic decrease in the expression of the 2 mutant proteins compared to the wild type. This decrease in protein expression was specific for the mutant RPS19, since expression of other proteins was normal. The present findings enable us to document the nucleolar localization signals in RPS19 and help define the phenotypic consequences of some mutations in RPS19 in DBA.	Which class of genes are mutated in Diamond Blackfan Anemia patients?	Ribosomal protein S19 (RPS19) is frequently mutated in Diamond-Blackfan anemia (DBA), a rare congenital hypoplastic anemia.
Combinatorial chemistry needs focused molecular diversity applied to the druglike chemical space (drugspace). A drugspace map can be obtained by systematically applying the same conventions when examining the chemical space, in a manner similar to the Mercator convention in geography: Rules are equivalent to dimensions (e.g., longitude and latitude), while structures are equivalent to objects (e.g., cities and countries). Selected rules include size, lipophilicity, polarizability, charge, flexibility, rigidity, and hydrogen bond capacity. For these, extreme values were set, e.g., maximum molecular weight 1500, calculated negative logarithm of the octanol/water partition between -10 and 20, and up to 30 nonterminal rotatable bonds. Only S, N, O, P, and halogens were considered as elements besides C and H. Selected objects include a set of "satellite" structures and a set of representative drugs ("core" structures). Satellites, intentionally placed outside drugspace, have extreme values in one or several of the desired properties, while containing druglike chemical fragments. ChemGPS (chemical global positioning system) is a tool that combines these predefined rules and objects to provide a global drugspace map. The ChemGPS drugspace map coordinates are t-scores extracted via principal component analysis (PCA) from 72 descriptors that evaluate the above-mentioned rules on a total set of 423 satellite and core structures. Global ChemGPS scores describe well the latent structures extracted with PCA for a set of 8599 monocarboxylates, a set of 45 heteroaromatic compounds, and for 87 alpha-amino acids. ChemGPS positions novel structures in drugspace via PCA-score prediction, providing a unique mapping device for the druglike chemical space. ChemGPS scores are comparable across a large number of chemicals and do not change as new structures are predicted, making this tool a well-suited reference system for comparing multiple libraries and for keeping track of previously explored regions of the chemical space.	Which are the components that evaluate druglikeness?	. Selected rules include size, lipophilicity, polarizability, charge, flexibility, rigidity, and hydrogen bond capacity. For these, extreme values were set, e.g., maximum molecular weight 1500, calculated negative logarithm of the octanol/water partition between -10 and 20, and up to 30 nonterminal rotatable bonds
null	Moreover, computational gene finding in newly sequenced genomes is especially a difficult task due to the absence of a training set of abundant validated genes. Here we present a new gene-finding program, SCGPred, to improve the accuracy of prediction by combining multiple sources of evidence.	null
There is compelling evidence that glial-immune interactions contribute to the progression of neurodegenerative diseases. The adaptive immune response has been implicated in disease processes of amyotrophic lateral sclerosis (ALS), but it remains unknown if innate immune signaling also contributes to ALS progression. Here we report that deficiency of the innate immune adaptor TIR domain-containing adaptor inducing interferon-β (TRIF), which is essential for certain Toll-like receptor (TLR) signaling cascades, significantly shortens survival time and accelerates disease progression of ALS mice. While myeloid differentiation factor 88 (MyD88) is also a crucial adaptor for most TLR signaling pathways, MyD88 deficiency had only a marginal impact on disease course. Moreover, TRIF deficiency reduced the number of natural killer (NK), NK-T-lymphocytes, and CD8-T cells infiltrating into the spinal cord of ALS mice, but experimental modulation of these populations did not substantially influence survival time. Instead, we found that aberrantly activated astrocytes expressing Mac2, p62, and apoptotic markers were accumulated in the lesions of TRIF-deficient ALS mice, and that the number of aberrantly activated astrocytes was negatively correlated with survival time. These findings suggest that TRIF pathway plays an important role in protecting a microenvironment surrounding motor neurons by eliminating aberrantly activated astrocytes.	What links immune response pathways to ALS?	he adaptive immune response has been implicated in disease processes of amyotrophic lateral sclerosis (ALS), but it remains unknown if innate immune signaling also contributes to ALS progression. H
Signal transduction networks allow cells to recognize and respond to changes in the extracellular environment. All eukaryotic cells have MAPK (mitogen-activated protein kinase) pathways that participate in diverse cellular functions, including differentiation, survival, transformation and movement. Five distinct groups of MAPKs have been characterized in mammals, the most extensively studied of which is the Ras/Raf/MEK [MAPK/ERK (extracellular-signal-regulated kinase) kinase]/ERK cascade. Numerous stimuli, including growth factors and phorbol esters, activate MEK/ERK signalling. How disparate extracellular signals are translated by MEK/ERK into different cellular functions remains obscure. Originally identified in yeast, scaffold proteins are now recognized to contribute to the specificity of MEK/ERK pathways in mammalian cells. These scaffolds include KSR (kinase suppressor of Ras), beta-arrestin, MEK partner-1, Sef and IQGAP1. Scaffolds organize multiprotein signalling complexes. This targets MEK/ERK to specific substrates and facilitates communication with other pathways, thereby mediating diverse functions. The adaptor proteins regulate the kinetics, amplitude and localization of MEK/ERK signalling, providing an efficient mechanism that enables an individual extracellular stimulus to promote a specific biological response.	List scaffold proteins of the ERK signaling pathway.	Originally identified in yeast, scaffold proteins are now recognized to contribute to the specificity of MEK/ERK pathways in mammalian cells. These scaffolds include KSR (kinase suppressor of Ras), beta-arrestin, MEK partner-1, Sef and IQGAP1.
A patient with human immunodeficiency virus-1 infection presented with sub-acute liver failure, temporally related to commencement of an antiretroviral therapy regimen containing dolutegravir (Triumeq). The patient was not a carrier of HLA-B5701, and abacavir hypersensitivity was unlikely. We believe this is the first report of severe dolutegravir-related hepatotoxicity resulting in sub-acute liver failure and transplantation and highlights a potential need for closer monitoring after drug initiation.	List drugs included in the TRIUMEQ pill.	A patient with human immunodeficiency virus-1 infection presented with sub-acute liver failure, temporally related to commencement of an antiretroviral therapy regimen containing dolutegravir (Triumeq).
Etanercept (ETN) (Enbrel®) is a soluble protein that binds to, and specifically inhibits, tumor necrosis factor (TNF), a proinflammatory cytokine. ETN is synthesized in Chinese hamster ovary cells by recombinant DNA technology as a fusion protein, with a fully human TNFRII ectodomain linked to the Fc portion of human IgG1. Successful manufacture of biologics, such as ETN, requires sophisticated process and product understanding, as well as meticulous control of operations to maintain product consistency. The objective of this evaluation was to show that the product profile of ETN drug substance (DS) has been consistent over the course of production. Multiple orthogonal biochemical analyses, which included evaluation of attributes indicative of product purity, potency, and quality, were assessed on >2,000 batches of ETN from three sites of DS manufacture, during the period 1998-2015. Based on the key quality attributes of product purity (assessed by hydrophobic interaction chromatography HPLC), binding activity (to TNF by ELISA), potency (inhibition of TNF-induced apoptosis by cell-based bioassay) and quality (N-linked oligosaccharide map), we show that the integrity of ETN DS has remained consistent over time. This consistency was maintained through three major enhancements to the initial process of manufacturing that were supported by detailed comparability assessments, and approved by the European Medicines Agency. Examination of results for all major quality attributes for ETN DS indicates a highly consistent process for over 18 years and throughout changes to the manufacturing process, without affecting safety and efficacy, as demonstrated across a wide range of clinical trials of ETN in multiple inflammatory diseases.	What is the chemical structure of Etanercept (ETN)?	ETN is synthesized in Chinese hamster ovary cells by recombinant DNA technology as a fusion protein, with a fully human TNFRII ectodomain linked to the Fc portion of human IgG1.
Amyotrophic lateral sclerosis (ALS) is a multifactorial neurodegenerative disease involving motor neuron (MN) degeneration in the spinal cord, brain stem and primary motor cortex. The existence of inflammatory processes around MN and axonal degeneration in ALS has been shown. Unfortunately, none of the successful therapies in ALS animal models has improved clinical outcomes in patients with ALS. Therefore, the detection of blood biomarkers to be used as screening tools for disease onset and progression has been an expanding research area with few advances in the development of drugs for the treatment of ALS. In this review, we will address the available data analyzing regarding the relationship of lipid metabolism and lipid derived- products with ALS. We will address the advances on the studies about the role that lipids plays at the onset, progression and lifespan extension of ALS patients.	What links lipid metabolism pathways to ALS?	eview, we will address the available data analyzing regarding the relationship of lipid metabolism and lipid derived- products with ALS. We will a
Growth factor signaling pathways are tightly regulated by phosphorylation and include many important kinase targets of interest for drug discovery. Small molecule inhibitors of the bone morphogenetic protein (BMP) receptor kinase ALK2 (ACVR1) are needed urgently to treat the progressively debilitating musculoskeletal disease fibrodysplasia ossificans progressiva (FOP). Dorsomorphin analogues, first identified in zebrafish, remain the only BMP inhibitor chemotype reported to date. By screening an assay panel of 250 recombinant human kinases we identified a highly selective 2-aminopyridine-based inhibitor K02288 with in vitro activity against ALK2 at low nanomolar concentrations similar to the current lead compound LDN-193189. K02288 specifically inhibited the BMP-induced Smad pathway without affecting TGF-β signaling and induced dorsalization of zebrafish embryos. Comparison of the crystal structures of ALK2 with K02288 and LDN-193189 revealed additional contacts in the K02288 complex affording improved shape complementarity and identified the exposed phenol group for further optimization of pharmacokinetics. The discovery of a new chemical series provides an independent pharmacological tool to investigate BMP signaling and offers multiple opportunities for pre-clinical development.	What genes are drug targets for Fibrodysplasia Ossificans Progressiva (FOP)?	By screening an assay panel of 250 recombinant human kinases we identified a highly selective 2-aminopyridine-based inhibitor K02288 with in vitro activity against ALK2 at low nanomolar concentrations similar to the current lead compound LDN-193189
Patients with severe chronic neutropenia have blood neutrophil level <0.5 × 10(9)/L, predisposing them to increased susceptibility to life-threatening bacterial infections. This chapter focuses on cyclic and congenital neutropenia, two very interesting and rare hematological conditions causing severe chronic neutropenia. Both disorders respond well to treatment with the myeloid growth factor, granulocyte colony-stimulating factor (G-CSF). This chapter describes the basic features of these diseases and addresses several current clinical issues regarding their diagnosis and management. Cyclic neutropenia is a rare, inherited autosomal dominant disorder due to mutations in the gene for neutrophil elastase (ELA-2 or ELANE). Usually these patients have regular oscillation of blood neutrophil counts with periods of severe neutropenia occurring every 21 days. During these periods, they have painful mouth ulcers, fevers, and bacterial infections. The most severe consequences are gangrene, bacteremia, and septic shock. Cyclic neutropenia patients respond well to treatment with granulocyte colony-stimulating factor (G-CSF) given by subcutaneous injections on a daily or alternate-day basis. Severe congenital neutropenia is also a rare hematological disease, but it is probably more common than cyclic neutropenia. Blood neutrophils are extremely low on a continuing basis; the levels may be <0.2 × 10(9)/L, and the risk of severe bacterial infections is even greater than in cyclic neutropenia. The majority of cases are due to autosomal dominant inheritance of mutations in the ELA-2 or ELANE gene. Less commonly, mutations in HAX-1, G6PC3, and other genes cause this disorder. Treatment with G-CSF is usually effective, but the dose of G-CSF required to normalize blood neutrophils varies greatly. Ten to thirty percent of severe congenital neutropenia patients evolve to develop acute myeloid leukemia, necessitating careful clinical monitoring.	Which treatment leads to an increase in neutrophil counts in severe congenital neutropenia?	This chapter focuses on cyclic and congenital neutropenia, two very interesting and rare hematological conditions causing severe chronic neutropenia. Both disorders respond well to treatment with the myeloid growth factor, granulocyte colony-stimulating factor (G-CSF)
Identifying genomic variants is a fundamental first step toward the understanding of the role of inherited and acquired variation in disease. The accelerating growth in the corpus of sequencing data that underpins such analysis is making the data-download bottleneck more evident, placing substantial burdens on the research community to keep pace. As a result, the search for alternative approaches to the traditional "download and analyze" paradigm on local computing resources has led to a rapidly growing demand for cloud-computing solutions for genomics analysis. Here, we introduce the Genome Variant Investigation Platform (GenomeVIP), an open-source framework for performing genomics variant discovery and annotation using cloud- or local high-performance computing infrastructure. GenomeVIP orchestrates the analysis of whole-genome and exome sequence data using a set of robust and popular task-specific tools, including VarScan, GATK, Pindel, BreakDancer, Strelka, and Genome STRiP, through a web interface. GenomeVIP has been used for genomic analysis in large-data projects such as the TCGA PanCanAtlas and in other projects, such as the ICGC Pilots, CPTAC, ICGC-TCGA DREAM Challenges, and the 1000 Genomes SV Project. Here, we demonstrate GenomeVIP's ability to provide high-confidence annotated somatic, germline, and de novo variants of potential biological significance using publicly available data sets.	What is GenomeVIP?	Here, we introduce the Genome Variant Investigation Platform (GenomeVIP), an open-source framework for performing genomics variant discovery and annotation using cloud- or local high-performance computing infrastructure.