T3 levels in relation to prognostic factors in breast cancer: a population-based prospective cohort study

Background: The issue of a potential association between thyroid conditions/hormones and breast cancer has been studied extensively during the last decades but the results have been inconclusive and almost no studies have investigated breast cancer aggressiveness. We have previously found a positive association between prospectively measured levels of triiodothyronine (T3) and breast cancer incidence as well as breast cancer mortality. We now investigated prediagnostic T3 levels in relation to specific prognostic factors in breast cancer. Methods: The Malmo Preventive Project is a population-based prospective cohort including 2185 women in whom T3 levels were measured at baseline. That is, total T3 levels were measured before a potential diagnosis of breast cancer. Mean follow-up was 23.3 years and 149 women in the study population were diagnosed with invasive breast cancer. Tumours were classified according to selected prognostic factors of breast cancer; i.e. grade, tumour size, lymph node metastasis, and hormonal receptor status. T3 was handled both as tertiles and as a continuous variable. A Cox's proportional hazards analysis yielded hazard ratios with 95% confidence intervals. All analyses were also restricted to postmenopausal women. Results: Overall there was a statistically significant association between T3 and "all" breast cancers. The adjusted Hazard Ratio (HR) in the third tertile, as compared to the first, was (1.61:1.07-2.43). There was a statistically significant positive association between the third T3 tertile and large tumours, i.e. > 20 mm, (3.17:1.20-8.36) and the occurrence of lymph node metastases, (4.53:1.60-12.83). Other prognostic factors positively associated with T3 were negative oestrogen receptor (ER) status, (3.52:1.32-9.41) and negative progesterone receptor (PGR) status, (3.52:1.42-8.75). The analyses of T3 as a continuous variable and analysis restricted to postmenopausal women, confirmed the results but also showed an association with smaller tumours and in postmenopausal women a contemporary association with negative lymph nodes. Conclusions: This prospective study of serum T3 levels in relation to breast cancer aggressiveness is the first of its kind. We found statistically significant positive associations between higher prediagnostic T3 levels and larger tumours, occurrence of lymph node metastases, and negative ER and PGR status

The Future of Nondelegation: Resurrecting the Doctrine Though a Novel Balancing Test

In Gundy v. United States, the Supreme Court of the United States was split 4 - 4 on the question of nondelegation. With a vacancy on the Bench, half of the Court took no issue with Congress delegating nearly unlimited discretion to the United States Attorney General over the enforcement and applicability of the Sex Offender Registration and Notification Act to offenders whose crimes preceded the Act’s enactment. The other half of the Court saw this grant of vast power as a violation of the nondelegation doctrine; the idea that Congress may not delegate its Article I lawmaking powers to any other branch of government. The Court has not struck down a law on nondelegation grounds since before the New Deal Era. This could soon change with the new majority on the Court. By adopting a novel balancing test, known as the major rules doctrine, this new Court could resurrect the spirit of the nondelegation doctrine and begin to return federal administrative law to a more interstitial role under a more traditional understanding of separation of powers. By flipping the analysis from first considering the power delegating statute to now beginning with the promulgated administrative rule, the Court will be able to rein in actions taken by executive agencies which have far-reaching economic, political, or otherwise contentious effects. The implications of this reversal of nearly a century’s worth of judicial deference to Congress and the various administrative agencies include (1) more deliberate law-making by Congress, (2) asymmetric effects across administrative agencies, and (3) increased accountability for regulation at the federal level

Evaluating Mine Cooling Systems and Mine Ventilation Strategies to be Applied in Deep and Hot US Mines

Metal production in the United States contributes significantly to the national and global economies due to resource demands. As mineral reserves are becoming scarce, demand has driven mining companies to operate at increasing depths underground. Along with this, production has continued to increase year after year, as lower grade ores are excavated economically. However, the increased mining depths and increased production have resulted in enlarged heat loads in the underground mine environment. Increased heat loads can result in temperatures, which are too high for mine workers to safely work. This may cause heat related illness, injuries or even death. Mine operators must pursue heat reduction strategies in order to maintain safe temperatures to protect mine workers.There are a number of heat mitigation methods and strategies which mine operators can implement. The most common means is through the use of ventilation to provide cool air volumes to reduce the heat load and dilute the contaminants generated in the production workings below their threshold limit values (TLV). This can be done by increasing the fresh air volumes through surface accesses such as shafts, raises, adits, ramps, or other mine entrances. When ventilation alone cannot provide acceptable climatic conditions in the production workings and throughout the mine, artificial cooling methods need to be used. These methods can be very effective, however, they require large capital investments, continuous maintenance, and additional operating costs. This includes central cooling, spot cooling, and micro-climate cooling systems. Though reducing the heat load is effective, another strategy is to reduce the source of the heat generation. One such source is the heat generated by diesel engine equipment fleet. This can be decreased by switching to a battery/electric engine equipment fleet. All of these strategies can be compared based off their heat reduction, temperatures, and operating costs. This study does exactly this by using an underground metal mine’s ventilation system to compare various scenarios, and identify the most effective cooling method or system that can be used in deep and hot US mines

Funktion des C-terminalen Tryptophans cytosolischer Eisen-Schwefel-Proteine bei deren Assemblierung

Eisen-Schwefel (Fe/S)-Cluster sind als essentielle Cofaktoren zahlreicher Proteine in allen Domänen des Lebens vertreten. In eukaryotischen Zellen sind ca. 50 cytosolische und nucleäre Fe/S-Proteine an lebenswichtigen Prozessen, wie der DNA-Replikation und Reparatur, Transkription, tRNA-Modifizierung, Ribosomenassemblierung und metabolischen Stoffwechselwegen, beteiligt. Die Biosynthese und die Insertion der Fe/S-Cluster in Apoproteine erfolgt durch die cytosolische Eisen-Schwefel-Protein-Assemblierungs-maschinerie (CIA). Daran sind nach aktuellem Kenntnisstand elf Faktoren beteiligt. Die zugrunde liegenden Mechanismen sind auf molekularer Ebene jedoch noch nicht aufgeklärt. So ist die Erkennung der Apoproteine durch den CIA-Targeting-Komplex bisher nahezu unerforscht. Molekulare Erkennungsfaktoren, eingebettet in der Primärsequenz der cytosolischen und nucleären Targetproteine, wurden bisher nicht beschrieben. In bioinformatischen Analysen wurde das Tripeptid L(D/E)W am C-Terminus von cytosolischen und nucleären Fe/S-Proteinen identifiziert. Vor allem der Tryptophanrest ist auffällig hoch konserviert. Auf Grund des geringen Vorkommens dieser Aminosäure im eukaryotischen Proteom ist dieses frequente Auftreten von Interesse. Zunächst wurde der Einfluss des C-terminalen Tripeptides auf den Einbau des Fe/S-Clusters in die cytosolischen Apoproteine Leu1, Nar1 und Apd1 im Modellorganismus S. cerevisiae untersucht. C-terminal gekürzte bzw. mutierte Proteinvarianten zeigen in Enzymaktivitätsmessungen, 55Fe-Einbau-Experimenten und Wachstumsuntersuchungen einen Defekt im Clustereinbau. Im Gegensatz dazu hat das Tryptophan bei der Reifung der Isopropylmalat-Isomerase (IPMI, Leu1) in E. coli bzw. bei der chemischen Rekonstitution gereinigter Proteine keine Bedeutung, sodass eine Verbindung des Peptidmotives zur CIA-Maschinerie postuliert wird. Im zweiten Teil wurden Interaktionsstudien zwischen Targetproteinen bzw. Peptiden und den Proteinen des CIA-Targeting-Kompexes Cia1, Cia2 und Met18 durchgeführt. Als in vivo Verfahren wurden das Y2H- bzw. Y3H-System sowie die BioID angewendet. Neben Coimmunpräzipitation wurden auch Peptid-basierte in vitro Methoden wie Fluoreszenzanisotropie-Messungen, ITC und chemische Quervernetzung analysiert. Durch Depletionsstudien konnte gezeigt werden, dass das C-terminale Tryptophan insbesondere bei niedriger Cia1-Konzentration essentiell ist. Im dritten Teil war es möglich, die E. coli-IPMI durch Fusion mit der C-terminalen Sequenz der Hefe-IPMI im Hefecytosol funktionell zu exprimieren. Dieser Funktionstransfer ist abhängig von der CIA-Maschinerie. Dies ist von Bedeutung für die biotechnologische Anwendung von prokaryotischen Fe/S-Proteinen im Cytosol eukaryotischer Organismen. Diese Arbeit liefert, durch die Identifizierung des C-terminalen Tryptophans als Signalsequenz cytosolischer und nucleärer Fe/S-Proteine, einen wichtigen Beitrag zum Verständnis der Erkennung der Targetproteine durch die CIA-Maschinerie

A phase 1b clinical trial evaluating sifalimumab, an anti-IFN-α monoclonal antibody, shows target neutralisation of a type I IFN signature in blood of dermatomyositis and polymyositis patients

Objective: To assess the pharmacodynamic effects of sifalimumab, an investigational anti-IFN-α monoclonal antibody, in the blood and muscle of adult dermatomyositis and polymyositis patients by measuring neutralisation of a type I IFN gene signature (IFNGS) following drug exposure. Methods: A phase 1b randomised, double-blinded, placebo controlled, dose-escalation, multicentre clinical trial was conducted to evaluate sifalimumab in dermatomyositis or polymyositis patients. Blood and muscle biopsies were procured before and after sifalimumab administration. Selected proteins were measured in patient serum with a multiplex assay, in the muscle using immunohistochemistry, and transcripts were profiled with microarray and quantitative reverse transcriptase PCR assays. A 13-gene IFNGS was used to measure the pharmacological effect of sifalimumab. Results: The IFNGS was suppressed by a median of 53–66% across three time points (days 28, 56 and 98) in blood (p=0.019) and 47% at day 98 in muscle specimens post-sifalimumab administration. Both IFN-inducible transcripts and proteins were prevalently suppressed following sifalimumab administration. Patients with 15% or greater improvement from baseline manual muscle testing scores showed greater neutralisation of the IFNGS than patients with less than 15% improvement in both blood and muscle. Pathway/functional analysis of transcripts suppressed by sifalimumab showed that leucocyte infiltration, antigen presentation and immunoglobulin categories were most suppressed by sifalimumab and highly correlated with IFNGS neutralisation in muscle. Conclusions: Sifalimumab suppressed the IFNGS in blood and muscle tissue in myositis patients, consistent with this molecule's mechanism of action with a positive correlative trend between target neutralisation and clinical improvement. These observations will require confirmation in a larger trial powered to evaluate efficacy

A Novel ENU-Mutation in Ankyrin-1 Disrupts Malaria Parasite Maturation in Red Blood Cells of Mice

The blood stage of the plasmodium parasite life cycle is responsible for the clinical symptoms of malaria. Epidemiological studies have identified coincidental malarial endemicity and multiple red blood cell (RBC) disorders. Many RBC disorders result from mutations in genes encoding cytoskeletal proteins and these are associated with increased protection against malarial infections. However the mechanisms underpinning these genetic, host responses remain obscure. We have performed an N-ethyl-N-nitrosourea (ENU) mutagenesis screen and have identified a novel dominant (haploinsufficient) mutation in the Ank-1 gene (Ank1MRI23420) of mice displaying hereditary spherocytosis (HS). Female mice, heterozygous for the Ank-1 mutation showed increased survival to infection by Plasmodium chabaudi adami DS with a concomitant 30% decrease in parasitemia compared to wild-type, isogenic mice (wt). A comparative in vivo red cell invasion and parasite growth assay showed a RBC-autonomous effect characterised by decreased proportion of infected heterozygous RBCs. Within approximately 6-8 hours post-invasion, TUNEL staining of intraerythrocytic parasites, showed a significant increase in dead parasites in heterozygotes. This was especially notable at the ring and trophozoite stages in the blood of infected heterozygous mutant mice compared to wt (p<0.05). We conclude that increased malaria resistance due to ankyrin-1 deficiency is caused by the intraerythrocytic death of P. chabaudi parasites