Molecular Biomarkers for the Evaluation of Colorectal Cancer: Guideline From the American Society for Clinical Pathology, College of American Pathologists, Association for Molecular Pathology, and American Society of Clinical Oncology

OBJECTIVES: - To develop evidence-based guideline recommendations through a systematic review of the literature to establish standard molecular biomarker testing of colorectal cancer (CRC) tissues to guide epidermal growth factor receptor (EGFR) therapies and conventional chemotherapy regimens. METHODS: - The American Society for Clinical Pathology, College of American Pathologists, Association for Molecular Pathology, and American Society of Clinical Oncology convened an expert panel to develop an evidence-based guideline to establish standard molecular biomarker testing and guide therapies for patients with CRC. A comprehensive literature search that included more than 4,000 articles was conducted. RESULTS: - Twenty-one guideline statements were established. CONCLUSIONS: - Evidence supports mutational testing for EGFR signaling pathway genes, since they provide clinically actionable information as negative predictors of benefit to anti-EGFR monoclonal antibody therapies for targeted therapy of CRC. Mutations in several of the biomarkers have clear prognostic value. Laboratory approaches to operationalize CRC molecular testing are presented

Molecular Biomarkers for the Evaluation of Colorectal Cancer

Objectives: To develop evidence-based guideline recommendations through a systematic review of the literature to establish standard molecular biomarker testing of colorectal cancer (CRC) tissues to guide epidermal growth factor receptor (EGFR) therapies and conventional chemotherapy regimens

Specific Humoral Immunity versus Polyclonal B Cell Activation in Trypanosoma cruzi Infection of Susceptible and Resistant Mice

Chagas disease, caused by the protozoan parasite Trypanosoma cruzi, affects 10–12 million people in Latin America. Patent parasitemia develops during acute disease. During this phase, polyclonal B cell activation has been reported to generate high levels of serum antibody with low parasite specificity, and delayed protective humoral immunity, which is necessary to prevent the host from succumbing to infection. In this manuscript, data show that relatively resistant mice have improved parasite-specific humoral immunity and decreased polyclonal B cell activation compared to susceptible mice. Parasite-specific humoral immunity was associated with differential expansion of B cell subsets and T cells in the spleen, as well as with increased Th1 and decreased Th2 cytokine production. These data suggest that host susceptibility/genetic biases impact the development of humoral responses to infection. Th2 cytokines are generally associated with improved antibody responses. In the context of T. cruzi infection of susceptible mice, Th2 cytokines were associated with increased total antibody production concomitant with delayed pathogen-specific humoral immunity. This study highlights the need to consider the effect of host biases when investigating humoral immunity to any pathogen that has reported polyclonal B cell activation during infection

The Changing Landscape for Stroke\ua0Prevention in AF: Findings From the GLORIA-AF Registry Phase 2

Background GLORIA-AF (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation) is a prospective, global registry program describing antithrombotic treatment patterns in patients with newly diagnosed nonvalvular atrial fibrillation at risk of stroke. Phase 2 began when dabigatran, the first non\u2013vitamin K antagonist oral anticoagulant (NOAC), became available. Objectives This study sought to describe phase 2 baseline data and compare these with the pre-NOAC era collected during phase 1. Methods During phase 2, 15,641 consenting patients were enrolled (November 2011 to December 2014); 15,092 were eligible. This pre-specified cross-sectional analysis describes eligible patients\u2019 baseline characteristics. Atrial fibrillation disease characteristics, medical outcomes, and concomitant diseases and medications were collected. Data were analyzed using descriptive statistics. Results Of the total patients, 45.5% were female; median age was 71 (interquartile range: 64, 78) years. Patients were from Europe (47.1%), North America (22.5%), Asia (20.3%), Latin America (6.0%), and the Middle East/Africa (4.0%). Most had high stroke risk (CHA2DS2-VASc [Congestive heart failure, Hypertension, Age  6575 years, Diabetes mellitus, previous Stroke, Vascular disease, Age 65 to 74 years, Sex category] score  652; 86.1%); 13.9% had moderate risk (CHA2DS2-VASc = 1). Overall, 79.9% received oral anticoagulants, of whom 47.6% received NOAC and 32.3% vitamin K antagonists (VKA); 12.1% received antiplatelet agents; 7.8% received no antithrombotic treatment. For comparison, the proportion of phase 1 patients (of N = 1,063 all eligible) prescribed VKA was 32.8%, acetylsalicylic acid 41.7%, and no therapy 20.2%. In Europe in phase 2, treatment with NOAC was more common than VKA (52.3% and 37.8%, respectively); 6.0% of patients received antiplatelet treatment; and 3.8% received no antithrombotic treatment. In North America, 52.1%, 26.2%, and 14.0% of patients received NOAC, VKA, and antiplatelet drugs, respectively; 7.5% received no antithrombotic treatment. NOAC use was less common in Asia (27.7%), where 27.5% of patients received VKA, 25.0% antiplatelet drugs, and 19.8% no antithrombotic treatment. Conclusions The baseline data from GLORIA-AF phase 2 demonstrate that in newly diagnosed nonvalvular atrial fibrillation patients, NOAC have been highly adopted into practice, becoming more frequently prescribed than VKA in Europe and North America. Worldwide, however, a large proportion of patients remain undertreated, particularly in Asia and North America. (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients With Atrial Fibrillation [GLORIA-AF]; NCT01468701

Analysis of impacts of Law 1819 of 2016 on the Industry and Commerce Tax : Bogotá D.C. and Medellin

La Ley 1819 de 2016 fue el arquetipo de exposición de una reforma tributaria estructural, integral y progresiva, por lo que modificó varios elementos sustanciales de los impuestos colombianos. En esta medida, el objetivo de este trabajo es analizar e interpretar las implicaciones positivas y negativas de los cambios efectuados en los elementos de la obligación tributaria sustancial del Impuesto de Industria y Comercio. Como caso de estudio, se hizo un comparativo entre las ciudades de Bogotá y Medellín, el cual da cuenta de mejoras en la territorialidad, desgaste judicial, unificación, presunciones, entre otros.Law 1819 of 2016 was the archetype of exposing a structural, integral and progressive tax reform, so it modified several substantial elements of Colombian taxes. In this measure, the objective of this work is to analyze and interpret the positive and negative implications of the changes made in the elements of the substantial tax obligation of the Industry and Commerce Tax. As a case study, a comparison was made between the cities of Bogotá and Medellín, which accounts for improvements in territoriality, judicial attrition, unification, presumptions, among others.Especialista en Derecho TributarioEspecializació

Dendrites from all genotypes grow and arborize over the course of three weeks.

<p>Confocal images of MAP2 immunolabeled neurons at 7 DIV (A–D) and 14 DIV (E–H). Magnification bar = 50 µm. These and similar preparations were traced in their entirety using Neurolucida. (I–L) Examples of such tracings are shown for 21 DIV neurons. Color-coding of dendrite branches corresponds to branch order. The maps shown are not to scale, but have been sized to fit the frame.</p

LRRK2-G2019S^OE negatively regulates dendritic growth and branching.

<p>Line graph (A) plots total dendritic length per neuron over time for neurons of all four genotypes. Data are shown as mean ± SEM. Table (B) shows results of Bonferroni's post-tests, indicating the sources of significant differences identified in a two-way ANOVA (see text). *p<0.05; **p<0.01; ***p<0.001, n.s.  =  not significant. Numbers in parentheses refer to DIV. Line graph (C) is an expanded view of results from the first week of development shown in (A), and the table (D) shows the post hoc analyses from this subset. Line graph (E) plots the total number of dendritic branch points for all genotypes and the table (F) shows the results of Bonferroni's post-tests. The line graph (G) is an expanded view of the data shown in (E) and the table (H) shows the post hoc analyses from the first week of development. At least 10 neurons from at least two culture preparations each (at least 20 neurons total) were traced and measured per genotype per time point assessed.</p

LRRK2-KO neurites show increased motility and those from LRRK2-WT^OE and LRRK2-G2019S^OE show decreased motility on PLL.

<p>Line graphs plot cumulative motility of axons (A) and dendrites (B) over 7.5 hours. Data shown are mean ± SEM. A one-way ANOVA indicates significant differences in motility for both axons and dendrites (see text) and the sources for those differences were identified using Bonferroni's post-tests, and are shown in tables (C) and (D) for axons and dendrites, respectively; *p<0.05; **p<0.01; ***p<0.001. Scatter plots of mean total growth (extension minus retraction ± SEM) of axons (E) and dendrites (F) at the end of imaging. For each genotype, 10–18 neurons were tracked from at least two different culture preparations, one axon per neuron and 2–4 dendritic endpoints. (G) Bright field images of axon extension over time in a KO neuron illustrate the highly dynamic extension and retraction observed. Times (t in h) are indicated at the top. Arrowheads mark the position of the axonal growth cone at t = 0. Squares mark the site of furthest extension of the axonal growth cone, which was observed at t = 6 h.</p

LRRK2 levels or mutation do not affect axonal development or branching.

<p>(A) Image of a 3 DIV LRRK2-WT^OE transgenic neuron immunolabeled for SMI-31 (magenta) and MAP2 (green) illustrates the normal polarization of proteins achieved in neurons from all genotypes. Scatter plots of polarity indices (PI) calculated for 3 DIV neurons of each genotype for SMI-31 (B) and for MAP2 (C). Mean ± SEM indicated by horizontal line and error bars. At least 10 neurons from two culture preparations each (at least 20 neurons total) were analyzed per genotype. Bar graphs of mean axon lengths (D) and mean number of axon terminal endings (E) measured in fixed 3 DIV neurons (± SEM). At least 10 neurons from at least two culture preparations each (at least 20 neurons total) were traced and measured per genotype.</p