TP53 is not a prognostic markerâ clinical consequences of a generally disregarded fact

Technological progress within the last 15â 20 years has significantly increased our knowledge about the molecular basis of cancer development, tumor progression, and treatment response. As a consequence, a vast number of biomarkers have been proposed, but only a small fraction of them have found their way into clinical use. The aim of this paper is to describe the specific demands a clinically relevant biomarker should meet and how biomarkers can be tested stepwise. We name this procedure the â tripleâ R principleâ : robustness, reproducibility, and relevance. The usefulness of this principle is illustrated with the marker TP53. Since it is mutated in a broad spectrum of cancer entities, TP53 can be considered a very promising marker. Thus, TP53 has been studied in detail but there is still no explicit consensus about its clinical value. By considering our own experience and reviewing the literature, we demonstrate that a major problem of current biomarker research is disregard of whether the biomarker is prognostic or predictive. As an example, it is demonstrated that TP53 is not a prognostic marker, but rather a purely predictive marker, and that disregard of this fact has made this otherwise strong biomarker appear as not being clinically useful so far.Many biomarkers have been proposed for cancer, but only a small fraction of them are clinically useful. This paper describes the specific demands a clinically relevant biomarker should meet and how biomarkers can be tested stepwise. This is illustrated with the marker TP53, which has been studied in detail but for which there is still no explicit consensus about its clinical value.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/146810/1/nyas13947.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/146810/2/nyas13947_am.pd

Neural plasticity and adult neurogenesis: the deep biology perspective

The recognition that neurogenesis does not stop with adolescence has spun off research towards the reduction of brain disorders by enhancing brain regeneration. Adult neurogenesis is one of the tougher problems of developmental biology as it requires the generation of complex intracellular and pericellular anatomies, amidst the danger of neuroinflammation. We here review how a multitude of regulatory pathways optimized for early neurogenesis has to be revamped into a new choreography of time dependencies. Distinct pathways need to be regulated, ranging from neural growth factor induced differentiation to mitochondrial bioenergetics, reactive oxygen metabolism, and apoptosis. Requiring much Gibbs energy consumption, brain depends on aerobic energy metabolism, hence on mitochondrial activity. Mitochondrial fission and fusion, movement and perhaps even mitoptosis, thereby come into play. All these network processes are interlinked and involve a plethora of molecules. We recommend a deep thinking approach to adult neurobiology

Feasibility Study of a Simple and Low-Cost Device for Monitoring Trihalomethanes Presence in Water Supply Systems Based on Statistical Models

This paper describes a new method for predicting trihalomethanes (THMs) presence in networks of water supply systems, using a low-cost device that permits a fast monitoring of concentrations without need of complex analysis made in laboratories. This method, based on statistical models, allows the estimation of THM concentration by monitoring parameters whose determination is direct and easy, and therefore, THM presence can be carried out in real-time. These parameters values are introduced in a multiple regression model resulting in the concentration of THMs levels. This model has taken into account parameters compulsory in water quality analysis and it has been shown that six parameters are enough to determine accurately THM concentration. In addition, the feasibility of a low-cost device that directly gives THM concentration is demonstrated. This device can be easily designed to be transported to different points of the water supply network where it is intended to make control campaigns.We gratefully acknowledge financial support for this work from AGBAR Group (Aguas de Barcelona, Water Works Holding

Characterization of Chronic Gastritis in Lynch Syndrome Patients With Gastric Adenocarcinoma

Background: Gastric cancer is one of the Lynch syndrome (LS)-associated malignancies. Previous studies have suggested that LS patients with gastric cancer also had chronic atrophic gastritis in the background mucosa, but further histologic characterization was not attempted. This study aims to understand the histologic features of background chronic gastritis in LS patients with gastric adenocarcinoma. Methods: Eleven LS-associated gastric cancer cases were collected from five institutions. Demographics and clinical features were retrieved by review of medical charts. Pathological material was reviewed for tumor location and histologic type. In addition, non-neoplastic gastric mucosa was assessed for inflammation (chronic and active), atrophy, intestinal metaplasia (IM) in the antrum and body, as well as pyloric gland metaplasia and enterochromaffin-like (ECL) cell hyperplasia in the body. Results: Eleven LS patients with gastric cancer (four male and seven female) with a mean age of 63 years (range: 23 - 83) were included. Ten (90.9%) had personal cancer histories; however none of the patients had family history of gastric cancer. Eight (72.7%) patients underwent gastrectomy and three had endoscopic resection. Nine (81.8%) patients had tumor in the fundus and/or body and two had tumor present in the antrum. Seven (63.6%) cases were intestinal type or mixed type carcinoma, and the remaining four were signet ring cell carcinoma. Eight (of 11, 72.7%) patients had chronic gastritis, five (45.4%) had atrophy, and four (36.3%) had intestinal metaplasia. Four of five patients with both antrum and body mucosa available for evaluation (80%), demonstrated body-predominant chronic gastritis. Four patients had germline MLH1 alterations and all of these patients had chronic gastritis, including one Helicobacter pylori (H. pylori) gastritis and three H. pylori-negative gastritis. Conclusions: None of LS patients with gastric cancer in our cohort had a family history of gastric cancer. Gastric adenocarcinomas in LS patients were primarily located in the fundus and/or body. Two-thirds of these tumors were of intestinal type and had a background chronic, H. pylori-negative gastritis. These results support a chronic atrophic gastritis with intestinal metaplasia-dysplasia-carcinoma sequence in LS-related gastric tumorigenesis, particularly in MLH1-mutated LS patients

Natural history of ROHHAD syndrome: development of severe insulin resistance and fatty liver disease over time

Absract Background Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD) is a rare syndrome with unknown etiology. Metabolic abnormalities are not known to be part of the syndrome. We present one of the oldest cases reported in the literature, who developed severe metabolic abnormalities and hepatic disease suggesting that these features may be part of the syndrome. Case presentation A 27-year-old woman, diagnosed with ROHHAD syndrome at age 15, who previously developed diabetes insipidus, growth hormone deficiency, hyperprolactinemia, and hypothyroidism in her first decade of life. This was followed by insulin resistance, NAFLD, liver fibrosis, and splenomegaly before age 14 years. Her regimen included a short course of growth hormone, and cyclic estrogen and progesterone. Her metabolic deterioration continued despite treatment with metformin. Interestingly, she had a favorable response to liraglutide therapy despite having a centrally mediated cause for her obesity. At age 26, a 1.6 cm lesion was found incidentally in her liver. Liver biopsy showed hepatocellular carcinoma which was successfully treated with radiofrequency ablation. Conclusion Metabolic abnormalities, Insulin resistance and fatty liver disease are potentially part of the ROHHAD syndrome that may develop over time. GLP1 agonists were reasonably effective to treat insulin resistance and hyperphagia. Patients with ROHHAD may benefit from close follow up in regards to liver disease.https://deepblue.lib.umich.edu/bitstream/2027.42/152179/1/40842_2019_Article_82.pd

Systems Biology in ELIXIR: modelling in the spotlight

In this white paper, we describe the founding of a new ELIXIR Community - the Systems Biology Community - and its proposed future contributions to both ELIXIR and the broader community of systems biologists in Europe and worldwide. The Community believes that the infrastructure aspects of systems biology - databases, (modelling) tools and standards development, as well as training and access to cloud infrastructure - are not only appropriate components of the ELIXIR infrastructure, but will prove key components of ELIXIR\u27s future support of advanced biological applications and personalised medicine. By way of a series of meetings, the Community identified seven key areas for its future activities, reflecting both future needs and previous and current activities within ELIXIR Platforms and Communities. These are: overcoming barriers to the wider uptake of systems biology; linking new and existing data to systems biology models; interoperability of systems biology resources; further development and embedding of systems medicine; provisioning of modelling as a service; building and coordinating capacity building and training resources; and supporting industrial embedding of systems biology. A set of objectives for the Community has been identified under four main headline areas: Standardisation and Interoperability, Technology, Capacity Building and Training, and Industrial Embedding. These are grouped into short-term (3-year), mid-term (6-year) and long-term (10-year) objectives

Anisotropy and chemical composition of ultra-high energy cosmic rays using arrival directions measured by the Pierre Auger Observatory

The Pierre Auger Collaboration has reported evidence for anisotropy in the distribution of arrival directions of the cosmic rays with energies $E>E_{th}=5.5\times 10^{19}$ eV. These show a correlation with the distribution of nearby extragalactic objects, including an apparent excess around the direction of Centaurus A. If the particles responsible for these excesses at $E>E_{th}$ are heavy nuclei with charge $Z$, the proton component of the sources should lead to excesses in the same regions at energies $E/Z$. We here report the lack of anisotropies in these directions at energies above $E_{th}/Z$ (for illustrative values of $Z=6,\ 13,\ 26$). If the anisotropies above $E_{th}$ are due to nuclei with charge $Z$, and under reasonable assumptions about the acceleration process, these observations imply stringent constraints on the allowed proton fraction at the lower energies

Implications of Epigenetic Drift in Colorectal Neoplasia

NIH grants U01CA182940 (G.E. Luebeck, W.D. Hazelton, W.M. Grady, S.K. Madden, K. Curtius), U01CA199336 (G.E. Luebeck, W.D. Hazelton); Barts Charity grant 472-2300, London (K. Curtius) and UK Medical Research Council Rutherford fellowship (K. Curtius); and NIH grants (P30CA15704, U01CA152756, R01CA194663, R01CA220004, U54CA143862, P01CA077852),R.A.C.E. Charities, Cottrell Family Fund, R03CA165153, Listwin Family Foundation, Seattle Translational Tumor Research program, Fred Hutchinson Cancer Research Center (S.K. Madden, M. Yu, K.T. Carter, and W.M. Grady), R01CA189184 (C. Lee, C.M. Ulrich, S.K.Madden, M. Yu, K.T. Carter, and W.M. Grady), R01CA112516, R01CA114467, R01CA120523 (C.M. Ulrich, S.K. Madden, M. Yu, K.T. Carter, and W.M. Grady), Huntsman Cancer Foundation, U01 CA206110, R01CA189184 R01CA 207371 and P30CACA042014 (C.M. Ulrich). U24CA074794 (P.A. Newcomb, S.K. Madden, M. Yu, K.T. Carter, and W.M. Grady). This material is the result of work supported in part by resources from the VA Puget Sound Health Care System and the ColoCare Study

Azimuthal anisotropy of charged jet production in root s(NN)=2.76 TeV Pb-Pb collisions

We present measurements of the azimuthal dependence of charged jet production in central and semi-central root s(NN) = 2.76 TeV Pb-Pb collisions with respect to the second harmonic event plane, quantified as nu(ch)(2) (jet). Jet finding is performed employing the anti-k(T) algorithm with a resolution parameter R = 0.2 using charged tracks from the ALICE tracking system. The contribution of the azimuthal anisotropy of the underlying event is taken into account event-by-event. The remaining (statistical) region-to-region fluctuations are removed on an ensemble basis by unfolding the jet spectra for different event plane orientations independently. Significant non-zero nu(ch)(2) (jet) is observed in semi-central collisions (30-50% centrality) for 20 <p(T)(ch) (jet) <90 GeV/c. The azimuthal dependence of the charged jet production is similar to the dependence observed for jets comprising both charged and neutral fragments, and compatible with measurements of the nu(2) of single charged particles at high p(T). Good agreement between the data and predictions from JEWEL, an event generator simulating parton shower evolution in the presence of a dense QCD medium, is found in semi-central collisions. (C) 2015 CERN for the benefit of the ALICE Collaboration. Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).Peer reviewe