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https://www.readbyqxmd.com/read/28097652/mdm4-is-a-rational-target-for-treating-breast-cancers-with-mutant-p53
#1
Panimaya Jeffreena Miranda, Daniel Buckley, Dinesh Raghu, Jia-Min B Pang, Elena A Takano, Reshma Vijayakumaran, Amina F A S Teunisse, Atara Posner, Tahlia Procter, Marco J Herold, Cristina Gamell, Jean-Christophe Marine, Stephen B Fox, Aart Jochemsen, Sue Haupt, Ygal Haupt
Mutation of the key tumour suppressor p53 defines a transition in the progression toward aggressive and metastatic breast cancer (BC) with the poorest outcome. Specifically, p53 mutation frequency exceeds 50% in Triple Negative BC (TNBC). Key regulators of mutant p53 that facilitate its oncogenic functions are potential therapeutic targets. We report here that the MDM4 protein is frequently abundant in the context of mutant p53 in basal-like BC samples. Importantly, we show that MDM4 plays a critical role in the proliferation of these BC cells...
January 18, 2017: Journal of Pathology
https://www.readbyqxmd.com/read/28096293/the-role-of-mdm2-and-mdm4-in-breast-cancer-development-and-prevention
#2
REVIEW
Sue Haupt, Reshma Vijayakumaran, Jeffreena Panimaya, Andrew Burgess, Elgene Lim, Ygal Haupt
The major cause of death from breast cancer is not the primary tumour, but relapsing, drug-resistant, metastatic disease. Identifying factors that contribute to aggressive cancer offers important leads for therapy. Inherent defense against carcinogens depends on the individual molecular make-up of each person. Important molecular determinants of these responses are under the control of the mouse double minute (MDM) family: comprised of the proteins MDM2 and MDM4. In normal, healthy adult cells, the MDM family functions to critically regulate measured, cellular responses to stress and subsequent recovery...
January 17, 2017: Journal of Molecular Cell Biology
https://www.readbyqxmd.com/read/28089731/investigation-of-polymorphisms-in-genes-involved-in-estrogen-metabolism-in-menstrual-migraine
#3
Heidi G Sutherland, Morgane Champion, Amelie Plays, Shani Stuart, Larisa M Haupt, Alison Frith, E Anne MacGregor, Lyn R Griffiths
Migraine is a common, disabling headache disorder, which is influenced by multiple genes and environmental triggers. After puberty, the prevalence of migraine in women is three times higher than in men and >50% of females suffering from migraine report a menstrual association, suggesting hormonal fluctuations can influence the risk of migraine attacks. It has been hypothesized that the drop in estrogen during menses is an important trigger for menstrual migraine. Catechol-O-methyltransferase (COMT) and Cytochrome P450 (CYP) enzymes are involved in estrogen synthesis and metabolism...
January 13, 2017: Gene
https://www.readbyqxmd.com/read/28074012/reduced-abundance-of-the-e3-ubiquitin-ligase-e6ap-contributes-to-decreased-expression-of-the-ink4-arf-locus-in-non-small-cell-lung-cancer
#4
Cristina Gamell, Twishi Gulati, Yaara Levav-Cohen, Richard J Young, Hongdo Do, Pat Pilling, Elena Takano, Neil Watkins, Stephen B Fox, Prudence Russell, Doron Ginsberg, Brendon J Monahan, Gavin Wright, Alex Dobrovic, Sue Haupt, Ben Solomon, Ygal Haupt
The tumor suppressor p16(INK4a), one protein encoded by the INK4/ARF locus, is frequently absent in multiple cancers, including non-small cell lung cancer (NSCLC). Whereas increased methylation of the encoding gene (CDKN2A) accounts for its loss in a third of patients, no molecular explanation exists for the remainder. We unraveled an alternative mechanism for the silencing of the INK4/ARF locus involving the E3 ubiquitin ligase and transcriptional cofactor E6AP (also known as UBE3A). We found that the expression of three tumor suppressor genes encoded in the INK4/ARF locus (p15(INK4b), p16(INK4a), and p19(ARF)) was decreased in E6AP(-/-) mouse embryo fibroblasts...
January 10, 2017: Science Signaling
https://www.readbyqxmd.com/read/28072840/locomotor-activity-and-body-temperature-patterns-over-a-temperature-gradient-in-the-highveld-mole-rat-cryptomys-hottentotus-pretoriae
#5
Meghan Haupt, Nigel C Bennett, Maria K Oosthuizen
African mole-rats are strictly subterranean mammals that live in extensive burrow systems. High humidity levels in the burrows prevent mole-rats from thermoregulating using evaporative cooling. However, the relatively stable environment of the burrows promotes moderate temperatures and small daily temperature fluctuations. Mole-rats therefore display a relatively wide range of thermoregulation abilities. Some species cannot maintain their body temperatures at a constant level, whereas others employ behavioural thermoregulation...
2017: PloS One
https://www.readbyqxmd.com/read/28034677/thermal-preference-and-performance-in-a-sub-antarctic-caterpillar-a-test-of-the-coadaptation-hypothesis-and-its-alternatives
#6
Tanya M Haupt, Brent J Sinclair, Steven L Chown
Physiological ecologists have long assumed that thermoregulatory behaviour will evolve to optimise physiological performance. The coadaptation hypothesis predicts that an animal's preferred body temperature will correspond to the temperature at which its performance is optimal. Here we use a strong inference approach to examine the relationship between thermal preference and locomotor performance in the caterpillars of a wingless sub-Antarctic moth, Pringleophaga marioni Viette (Tineidae). The coadaptation hypothesis and its alternatives (suboptimal is optimal, thermodynamic effect, trait variation) are tested...
December 27, 2016: Journal of Insect Physiology
https://www.readbyqxmd.com/read/27999330/dysregulated-microrna-expression-profiles-and-potential-cellular-circulating-and-polymorphic-biomarkers-in-non-hodgkin-lymphoma
#7
REVIEW
Gabrielle Bradshaw, Heidi G Sutherland, Larisa M Haupt, Lyn R Griffiths
A large number of studies have focused on identifying molecular biomarkers, including microRNAs (miRNAs) to aid in the diagnosis and prognosis of the most common subtypes of non-Hodgkin lymphoma (NHL), Diffuse Large B-cell Lymphoma and Follicular Lymphoma. NHL is difficult to diagnose and treat with many cases becoming resistant to chemotherapy, hence the need to identify improved biomarkers to aid in both diagnosis and treatment modalities. This review summarises more recent research on the dysregulated miRNA expression profiles found in NHL, as well as the regulatory role and biomarker potential of cellular and circulating miRNAs found in tissue and serum, respectively...
December 17, 2016: Genes
https://www.readbyqxmd.com/read/27936766/discovery-of-mycobacterium-tuberculosis-inha-inhibitors-by-binding-sites-comparison-and-ligands-prediction
#8
Tanja Štular, Samo Lešnik, Kaja Rožman, Julia Schink, Mitja Zdouc, An Ghysels, Feng Liu, Courtney C Aldrich, V Joachim Haupt, Sebastian Salentin, Simone Daminelli, Michael Schroeder, Thierry Langer, Stanislav Gobec, Dušanka Janežič, Janez Konc
Drug discovery is usually focused on a single protein target; in this process, existing compounds that bind to related proteins are often ignored. We describe ProBiS plugin, extension of our earlier ProBiS-ligands approach, which for a given protein structure allows prediction of its binding sites and, for each binding site, the ligands from similar binding sites in the Protein Data Bank. We developed a new database of precalculated binding site comparisons of about 290000 proteins to allow fast prediction of binding sites in existing proteins...
December 22, 2016: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/27902311/ubiquitin-ligase-e6ap-mediates-nonproteolytic-polyubiquitylation-of-%C3%AE-catenin-independent-of-the-e6-oncoprotein
#9
Yael Kuslansky, Sophia Sominsky, Anna Jackman, Cristina Gamell, Brendon J Monahan, Ygal Haupt, Rina Rosin-Arbesfeld, Levana Sherman
Recently, we showed that the ubiquitin ligase E6AP stabilizes β-catenin and activates its transcriptional activity. These activities were enhanced by the human papillomavirus (HPV) E6 protein. In the present study, we explored the function of E6AP, which increases β-catenin stabilization and transcriptional activation. Here, we report that E6AP interacts with β-catenin and mediates its nonproteolytic ubiquitylation, as evidenced in transiently transfected cell-based and in vitro reconstitution ubiquitylation assays...
December 2016: Journal of General Virology
https://www.readbyqxmd.com/read/27893381/a-compressed-sensing-based-decomposition-of-electrodermal-activity-signals
#10
Swayambhoo Jain, Urvashi Oswal, Kevin Xu, Brian Eriksson, Jarvis Haupt
The measurement and analysis of Electrodermal Activity (EDA) offers applications in diverse areas ranging from market research, to seizure detection, to human stress analysis. Unfortunately, the analysis of EDA signals is made difficult by the superposition of numerous components which can obscure the signal information related to a user's response to a stimulus. We show how simple pre-processing followed by a novel compressed sensing based decomposition can mitigate the effects of the undesired noise components and help reveal the underlying physiological signal...
November 23, 2016: IEEE Transactions on Bio-medical Engineering
https://www.readbyqxmd.com/read/27881154/targeted-next-generation-sequencing-identifies-novel-notch3-gene-mutations-in-cadasil-diagnostics-patients
#11
Neven Maksemous, Robert A Smith, Larisa M Haupt, Lyn R Griffiths
BACKGROUND: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a monogenic, hereditary, small vessel disease of the brain causing stroke and vascular dementia in adults. CADASIL has previously been shown to be caused by varying mutations in the NOTCH3 gene. The disorder is often misdiagnosed due to its significant clinical heterogeneic manifestation with familial hemiplegic migraine and several ataxia disorders as well as the location of the currently identified causative mutations...
November 24, 2016: Human Genomics
https://www.readbyqxmd.com/read/27857289/use-of-photoacoustic-excitation-and-laser-vibrometry-to-remotely-detect-trace-explosives
#12
C M Wynn, R W Haupt, J H Doherty, R R Kunz, W Bai, G Diebold
In this paper, we examine a laser-based approach to remotely initiate, measure, and differentiate acoustic and vibrational emissions from trace quantities of explosive materials against their environment. Using a pulsed ultraviolet laser (266 nm), we induce a significant (>100  Pa) photoacoustic response from small quantities of military-grade explosives. The photoacoustic signal, with frequencies predominantly between 100 and 500 kHz, is detected remotely via a wideband laser Doppler vibrometer. This two-laser system can be used to rapidly detect and discriminate explosives from ordinary background materials, which have significantly weaker photoacoustic response...
November 10, 2016: Applied Optics
https://www.readbyqxmd.com/read/27852900/gradients-of-phosphatidylserine-contribute-to-plasma-membrane-charge-localization-and-cell-polarity-in-fission-yeast
#13
Armin Haupt, Nicolas Minc
Surface charges at the inner leaflet of the plasma membrane may contribute to regulate the surface recruitment of key signaling factors. Phosphatidylserine (PS) is an abundant charged lipid that may regulate charge distribution in different cell types. Here we characterize the subcellular distribution and function of PS in the rod-shaped, polarized fission yeast. We find that PS preferably accumulates at cell tips and defines a gradient of negative charges along the cell surface. This polarization depends on actin-mediated endocytosis and contributes to the subcellular partitioning of charged polarity-regulating Rho GTPases like Rho1 or Cdc42 in a protein charge-dependent manner...
January 1, 2017: Molecular Biology of the Cell
https://www.readbyqxmd.com/read/27851074/1438-early-determination-of-outcomes-for-sirs-vs-qsofa-in-ed-sepsis-patients
#14
Dave Milzman, Matthew Paik, Kirsten Shuster, Rand Floyd, Aidan Neustadtl, Rob Haggerty, Shawn Haupt, Doug Johnson
No abstract text is available yet for this article.
December 2016: Critical Care Medicine
https://www.readbyqxmd.com/read/27807957/-the-contribution-of-the-italian-association-of-paediatric-haematology-and-oncology-aieop
#15
Roberto Rondelli, Momcilo Jankovic, Annarosa Soresina, Maria Grazia Valsecchi, Marisa De Rosa, Marina Cuttini, Riccardo Haupt, Maurizio Aricò, Gianni Bisogno, Franco Locatelli, Corrado Magnani, Franco Merletti, Marco Zecca, Andrea Pession
Since 1972, children affected by cancer took advantage from multi-centric diagnostic and therapeutic protocols produced by the Italian Association of paediatric haematology and oncology (AIEOP). At the beginning, these protocols were used in few well-trained centres, later in almost all Italian haemato-oncological centres. The need of a careful monitoring of his own activity induced AIEOP to achieve, in 1989, an Italian hospital- based registry (database Mod.1.01) of malignant tumours diagnosed and treated in the participating centres, with the aim to quantify the number of cases diagnosed and treated in the different centres, the agreement (or not) to official diagnostic- therapeutic protocols, and the extraregional migration...
September 2016: Epidemiologia e Prevenzione
https://www.readbyqxmd.com/read/27795959/large-gliadin-peptides-detected-in-the-pancreas-of-nod-and-healthy-mice-following-oral-administration
#16
Susanne W Bruun, Knud Josefsen, Julia T Tanassi, Aleš Marek, Martin H F Pedersen, Ulrik Sidenius, Martin Haupt-Jorgensen, Julie C Antvorskov, Jesper Larsen, Niels H Heegaard, Karsten Buschard
Gluten promotes type 1 diabetes in nonobese diabetic (NOD) mice and likely also in humans. In NOD mice and in non-diabetes-prone mice, it induces inflammation in the pancreatic lymph nodes, suggesting that gluten can initiate inflammation locally. Further, gliadin fragments stimulate insulin secretion from beta cells directly. We hypothesized that gluten fragments may cross the intestinal barrier to be distributed to organs other than the gut. If present in pancreas, gliadin could interact directly with the immune system and the beta cells to initiate diabetes development...
2016: Journal of Diabetes Research
https://www.readbyqxmd.com/read/27744369/paradoxical-effects-of-saa-on-lipoprotein-oxidation-suggest-a-new-antioxidant-function-for-saa
#17
Shobini Jayaraman, Christian Haupt, Olga Gursky
Oxidative stress and inflammation, which involve a dramatic increase in serum amyloid A (SAA) levels, are critical in the development of atherosclerosis. Most SAA circulates on plasma HDL particles, altering their cardioprotective properties. SAA-enriched HDL has diminished anti-oxidant effects on LDL, which may contribute to atherogenesis. We determined combined effects of SAA enrichment and oxidation on biochemical changes in HDL. Normal human HDLs were incubated with SAA, oxidized by various factors (Cu(2+), myeloperoxidase, H2O2, OCl(-)), and analyzed for lipid and protein modifications and biophysical remodeling...
December 2016: Journal of Lipid Research
https://www.readbyqxmd.com/read/27723228/basal-insulin-peglispro-overview-of-a-novel-long-acting-insulin-with-reduced-peripheral-effect-resulting-in-a-hepato-preferential-action
#18
S J Jacober, M J Prince, J M Beals, M L Hartman, Y Qu, H Linnebjerg, P Garhyan, A Haupt
Basal insulin peglispro (BIL) is a novel basal insulin with a flat, prolonged activity profile. BIL has been demonstrated in a dog model, in healthy men and in patients with type 1 diabetes (T1D) to have significant hepato-preferential action resulting from reduced peripheral activity. In the IMAGINE-Phase 3 clinical trial program, more than 6000 patients were included, of whom ~3900 received BIL. Of the 7 pivotal IMAGINE trials, 3 studies were double-blinded and 3 were in T1D patients. BIL consistently demonstrated a greater HbA1c reduction, less glycaemic variability and a clinically relevant reduction in the rates of nocturnal hypoglycaemia across comparator [glargine and isophane insulin (NPH)] studies...
October 2016: Diabetes, Obesity & Metabolism
https://www.readbyqxmd.com/read/27723227/different-effects-of-basal-insulin-peglispro-and-insulin-glargine-on-liver-enzymes-and-liver-fat-content-in-patients-with-type-1-and-type-2-diabetes
#19
K Cusi, A J Sanyal, S Zhang, B J Hoogwerf, A M Chang, S J Jacober, J M Bue-Valleskey, A N Higdon, E J Bastyr, A Haupt, M L Hartman
AIMS: To compare effects of basal insulin peglispro (BIL), a hepatopreferential insulin, to insulin glargine (glargine) on aminotransferases and liver fat content (LFC) in patients with type 1 and type 2 diabetes (T1D, T2D). MATERIALS AND METHODS: Data from two Phase 2 and five Phase 3 randomized trials comparing BIL and glargine in 1709 T1D and 3662 T2D patients were integrated for analysis of liver laboratory tests. LFC, measured by magnetic resonance imaging (MRI) at baseline, 26 and 52 weeks, was analyzed in 182 T1D patients, 176 insulin-naïve T2D patients and 163 T2D patients previously treated with basal insulin...
October 2016: Diabetes, Obesity & Metabolism
https://www.readbyqxmd.com/read/27702740/neuro-cognitive-mechanisms-of-simultanagnosia-in-patients-with-posterior-cortical-atrophy
#20
Julia Neitzel, Marion Ortner, Marleen Haupt, Petra Redel, Timo Grimmer, Igor Yakushev, Alexander Drzezga, Peter Bublak, Christoph Preul, Christian Sorg, Kathrin Finke
Posterior cortical atrophy is dominated by progressive degradation of parieto-occipital grey and white matter, and represents in most cases a variant of Alzheimer's disease. Patients with posterior cortical atrophy are characterized by increasing higher visual and visuo-spatial impairments. In particular, a key symptom of posterior cortical atrophy is simultanagnosia i.e. the inability to perceive multiple visual objects at the same time. Two neuro-cognitive mechanisms have been suggested to underlie simultanagnosia, either reduced visual short-term memory capacity or decreased visual processing speed possibly resulting from white matter impairments over and above damage to cortical brain areas...
December 2016: Brain: a Journal of Neurology
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