Integrative Oncogenomic Analysis of Microarray Data in Hematologic Malignancies

During the last decade, gene expression microarrays and array-based comparative genomic hybridization (array-CGH) have unraveled the complexity of human tumor genomes more precisely and comprehensively than ever before. More recently, the simultaneous assessment of global changes in messenger RNA (mRNA) expression and in DNA copy number through "integrative oncogenomic" analyses has allowed researchers the access to results uncovered through the analysis of one-dimensional data sets, thus accelerating cancer gene discovery. In this chapter, we discuss the major contributions of DNA microarrays to the study of hematological malignancies, focusing on the integrative oncogenomic approaches that correlate genomic and transcriptomic data. We also present the basic aspects of these methodologies and their present and future application in clinical oncology

Manipulation of drugs to achieve the required dose is intrinsic to paediatric practice but is not supported by guidelines or evidence

Background: A lack of age-appropriate formulations can make it difficult to administer medicines to children. A manipulation of the dosage form may be required to achieve the required dose. This study aimed to describe medicines that are manipulated to achieve the required dose in paediatric practice.Method: A structured, undisguised observational study and postal survey. The observational study investigated drug manipulations occurring in clinical practice across three sites. The questionnaire, administered to a sample of paediatric nurses throughout the UK, surveyed manipulations conducted and nurses' experiences and views.Results: The observational study identified 310 manipulations, of which 62% involved tablets, 21% were intravenous drugs and 10% were sachets. Of the 54 observed manipulations 40 involved tablets with 65% of the tablets being cut and 30% dispersed to obtain a smaller dose. 188 manipulations were reported by questionnaire respondents, of these 46% involved tablets, 12% were intravenous drugs, and 12% were nebuliser solutions. Manipulations were predominantly, but not exclusively, identified in specialist clinical areas with more highly dependent patients. Questionnaire respondents were concerned about the accuracy of the dose achieved following manipulations and the lack of practice guidance.Conclusion: Manipulations to achieve the required dose occur throughout paediatric in-patient settings. The impact of manipulations on the efficacy of the drugs, the accuracy of the dose and any adverse effects on patients is not known. There is a need to develop evidence-based guidance for manipulations of medicines in children

Towards the growth of Cu2ZnSn1 xGexS4 thin films by a single stage process Effect of substrate temperature and composition

Cu2ZnSn1-xGexS4 (CZTGS) thin films prepared by flash evaporation of a Zn-rich Cu2ZnSn0.5Ge0.5S4 bulk compound in powder form, and a subsequent thermal annealing in S containing Ar atmosphere are studied. The effect of the substrate temperature during evaporation and the initial composition of the precursor powder on the growth mechanism and properties of the final CZTGS thin film are investigated. The microstructure of the films and elemental depth profiles depend strongly on the growth conditions used. Incorporation of Ge into the Cu2ZnSnS4 lattice is demonstrated by the shift of the relevant X-ray diffraction peaks and Raman vibrational modes towards higher diffraction angles and frequencies respectively. A Raman mode at around 348-351 cm-1 is identified as characteristic of CZTGS alloys for x = [Ge]/([Sn]+[Ge]) = 0.14-0.30. The supply of Ge enables the reduction of the Sn loss via a saccrifical Ge loss. This fact allows increasing the substrate temperature up to 350º C during the evaporation, forming a high quality kesterite material and therefore, reducing the deposition process to one single stageRC acknowledges financial support from Spanish MINECO within the Ramón y Cajal programme (RYC-2011-08521) and VIR for the Juan de la Cierva fellowship (JCI-2011-10782). GB also acknowledges the CSIC-JAE pre-doctoral program, co-funded by the European Social Fund. This work was supported by the Marie Curie-IRSES project (PVICOKEST, GA: 269167), Marie Curie-ITN project (KESTCELL, GA: 316488), DAAD project (INTERKEST, Ref: 57050358), and MINECO projects (SUNBEAM, ENE2013-49136-C4-3-R) (TEC2012-38901-C02-01). A. Scheu is acknowledged for GDOES measurement

Thermochronology of the modern Indus River bedload: New insight into the controls on the marine stratigraphic record

The Indus River is the only major drainage in the western Himalaya and delivers a long geological record of continental erosion to the Arabian Sea, which may be deciphered and used to reconstruct orogenic growth if the modern bedload can be related to the mountains. In this study we collected thermochronologic data from river sediment collected near the modern delta. U-Pb ages of zircons spanning 3 Gyr show that only ∼5% of the eroding crust has been generated since India-Asia collision. The Greater Himalaya are the major source of zircons, with additional contributions from the Karakoram and Lesser Himalaya. The 39Ar/40Ar dating of muscovites gives ages that cluster between 10 and 25 Ma, differing from those recorded in the Bengal Fan. Biotite ages are generally younger, ranging 0–15 Ma. Modern average exhumation rates are estimated at ∼0.6 km/m.y. or less, and have slowed progressively since the early Miocene (∼20 Ma), although fission track (FT) dating of apatites may indicate a recent moderate acceleration in rates since the Pliocene (∼1.0 km/m.y.) driven by climate change. The 39Ar/40Ar and FT techniques emphasize the dominance of high topography in controlling the erosional flux to the ocean. Localized regions of tectonically driven, very rapid exhumation (e.g., Nanga Parbat, S. Karakoram metamorphic domes) do not dominate the erosional record

Inadequate use of antibiotics in the covid-19 era: effectiveness of antibiotic therapy

Background: Since December 2019, the COVID-19 pandemic has changed the concept of medicine. This work aims to analyze the use of antibiotics in patients admitted to the hospital due to SARS-CoV-2 infection. Methods: This work analyzes the use and effectiveness of antibiotics in hospitalized patients with COVID-19 based on data from the SEMI-COVID-19 registry, an initiative to generate knowledge about this disease using data from electronic medical records. Our primary endpoint was all-cause in-hospital mortality according to antibiotic use. The secondary endpoint was the effect of macrolides on mortality. Results: Of 13, 932 patients, antibiotics were used in 12, 238. The overall death rate was 20.7% and higher among those taking antibiotics (87.8%). Higher mortality was observed with use of all antibiotics (OR 1.40, 95% CI 1.21–1.62; p <.001) except macrolides, which had a higher survival rate (OR 0.70, 95% CI 0.64–0.76; p <.001). The decision to start antibiotics was influenced by presence of increased inflammatory markers and any kind of infiltrate on an x-ray. Patients receiving antibiotics required respiratory support and were transferred to intensive care units more often. Conclusions: Bacterial co-infection was uncommon among COVID-19 patients, yet use of antibiotics was high. There is insufficient evidence to support widespread use of empiric antibiotics in these patients. Most may not require empiric treatment and if they do, there is promising evidence regarding azithromycin as a potential COVID-19 treatment. © 2021, The Author(s)

Surface Aggregation of Urinary Proteins and Aspartic Acid-Rich Peptides on the Faces of Calcium Oxalate Monohydrate Investigated by In Situ Force Microscopy

The growth of calcium oxalate monohydrate in the presence of Tamm-Horsfall protein (THP), osteopontin, and the 27-residue synthetic peptides (DDDS)6DDD and (DDDG)6DDD (D = aspartic acid, S = serine, and G = glycine) was investigated via in situ atomic force microscopy. The results show that these four growth modulators create extensive deposits on the crystal faces. Depending on the modulator and crystal face, these deposits can occur as discrete aggregates, filamentary structures, or uniform coatings. These proteinaceous films can lead to either the inhibition of or an increase in the step speeds (with respect to the impurity-free system), depending on a range of factors that include peptide or protein concentration, supersaturation, and ionic strength. While THP and the linear peptides act, respectively, to exclusively increase and inhibit growth on the \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\left( {\bar{1}01} \right)$$\end{document} face, both exhibit dual functionality on the (010) face, inhibiting growth at low supersaturation or high modulator concentration and accelerating growth at high supersaturation or low modulator concentration. Based on analyses of growth morphologies and dependencies of step speeds on supersaturation and protein or peptide concentration, we propose a picture of growth modulation that accounts for the observations in terms of the strength of binding to the surfaces and steps and the interplay of electrostatic and solvent-induced forces at the crystal surface

Appropriate DevR (DosR)-Mediated Signaling Determines Transcriptional Response, Hypoxic Viability and Virulence of Mycobacterium tuberculosis

Background: The DevR(DosR) regulon is implicated in hypoxic adaptation and virulence of Mycobacterium tuberculosis. The present study was designed to decipher the impact of perturbation in DevR-mediated signaling on these properties. Methodology/Principal Findings: M. tb complemented (Comp) strains expressing different levels of DevR were constructed in Mut1 * background (expressing DevR N-terminal domain in fusion with AphI (DevRN-Kan) and in Mut2DdevR background (deletion mutant). They were compared for their hypoxia adaptation and virulence properties. Diverse phenotypes were noted; basal level expression (,5.362.3 mM) when induced to levels equivalent to WT levels (,25.869.3 mM) was associated with robust DevR regulon induction and hypoxic adaptation (Comp 9 * and 10*), whereas low-level expression (detectable at transcript level) as in Comp 11 * and Comp15 was associated with an adaptation defect. Intermediate-level expression (,3.361.2 mM) partially restored hypoxic adaptation functions in Comp2, but not in Comp1 * bacteria that coexpressed DevRN-Kan. Comp * strains in Mut1 * background also exhibited diverse virulence phenotypes; high/very low-level DevR expression was associated with virulence whereas intermediate-level expression was associated with low virulence. Transcription profiling and gene expression analysis revealed up-regulation of the phosphate starvation response (PSR) in Mut1 * and Comp11 * bacteria, but not in WT/Mut2DdevR/other Comp strains, indicating a plasticity in expression pathways that is determined by the magnitude of signaling perturbation through DevRN-Kan

Unique Flexibility in Energy Metabolism Allows Mycobacteria to Combat Starvation and Hypoxia

Mycobacteria are a group of obligate aerobes that require oxygen for growth, but paradoxically have the ability to survive and metabolize under hypoxia. The mechanisms responsible for this metabolic plasticity are unknown. Here, we report on the adaptation of Mycobacterium smegmatis to slow growth rate and hypoxia using carbon-limited continuous culture. When M. smegmatis is switched from a 4.6 h to a 69 h doubling time at a constant oxygen saturation of 50%, the cells respond through the down regulation of respiratory chain components and the F1Fo-ATP synthase, consistent with the cells lower demand for energy at a reduced growth rate. This was paralleled by an up regulation of molecular machinery that allowed more efficient energy generation (i.e. Complex I) and the use of alternative electron donors (e.g. hydrogenases and primary dehydrogenases) to maintain the flow of reducing equivalents to the electron transport chain during conditions of severe energy limitation. A hydrogenase mutant showed a 40% reduction in growth yield highlighting the importance of this enzyme in adaptation to low energy supply. Slow growing cells at 50% oxygen saturation subjected to hypoxia (0.6% oxygen saturation) responded by switching on oxygen scavenging cytochrome bd, proton-translocating cytochrome bc1-aa3 supercomplex, another putative hydrogenase, and by substituting NAD+-dependent enzymes with ferredoxin-dependent enzymes thus highlighting a new pattern of mycobacterial adaptation to hypoxia. The expression of ferredoxins and a hydrogenase provides a potential conduit for disposing of and transferring electrons in the absence of exogenous electron acceptors. The use of ferredoxin-dependent enzymes would allow the cell to maintain a high carbon flux through its central carbon metabolism independent of the NAD+/NADH ratio. These data demonstrate the remarkable metabolic plasticity of the mycobacterial cell and provide a new framework for understanding their ability to survive under low energy conditions and hypoxia