A phase I dose-escalation study of TAK-733, an investigational oral MEK inhibitor, in patients with advanced solid tumors.

Purpose TAK-733, an investigational, selective, allosteric MEK1/2 inhibitor, has demonstrated antitumor effects against multiple cancer cell lines and xenograft models. This first-in-human study investigated TAK-733 in patients with solid tumors. Methods Patients received oral TAK-733 once daily on days 1-21 in 28-day treatment cycles. Adverse events (AEs) were graded using the Common Terminology Criteria for AEs version 3.0. Response was assessed using RECIST v1.1. Blood samples for TAK-733 pharmacokinetics and pharmacodynamics (inhibition of ERK phosphorylation) were collected during cycle 1. Results Fifty-one patients received TAK-733 0.2-22 mg. Primary diagnoses included uveal melanoma (24 %), colon cancer (22 %), and cutaneous melanoma (10 %). Four patients had dose-limiting toxicities of dermatitis acneiform, plus fatigue and pustular rash in one patient, and stomatitis in one patient. The maximum tolerated dose was 16 mg. Common drug-related AEs included dermatitis acneiform (51 %), diarrhea (29 %), and increased blood creatine phosphokinase (20 %); grade ≥ 3 AEs were reported in 27 (53 %) patients. Median Tmax was 3 h; systemic exposure increased less than dose-proportionally over the dose range 0.2-22 mg. On day 21 maximum inhibition of ERK phosphorylation in peripheral blood mononuclear cells of 46-97 % was seen in patients receiving TAK-733 ≥ 8.4 mg. Among 41 response-evaluable patients, 2 (5 %) patients with cutaneous melanoma (one with BRAF L597R mutant melanoma) had partial responses. Conclusions TAK-733 had a generally manageable toxicity profile up to the maximum tolerated dose, and showed the anticipated pharmacodynamic effect of sustained inhibition of ERK phosphorylation. Limited antitumor activity was demonstrated. Further investigation is not currently planned

ATTITUDES AND MANAGING ALCOHOL PROBLEMS IN GENERAL PRACTICE: AN INTERACTION ANALYSIS BASED ON FINDINGS FROM A WHO COLLABORATIVE STUDY

Aims: To determine if GPs' attitudes towards working with drinkers moderated the impact that training and support had on screening and brief intervention activity in routine practice. Methods: Subjects were 340 GPs from four countries who were part of a World Health Organization randomized controlled trial to evaluate the effectiveness of training and support in increasing screening and brief alcohol intervention. GPs' self-reported attitudes towards working with drinkers were measured with the Shortened Alcohol and Alcohol Problems Perception Questionnaire. Results: Whereas training and support increased GPs' screening and brief intervention rates, it did so only for practitioners who already felt secure and committed in working with drinkers. Training and support did not improve attitudes towards working with drinkers and, moreover, worsened the attitudes of those who were already insecure and uncommitted. Conclusions: To enhance the involvement of GPs in the management of alcohol problems, interventions that increase both actual experience and address practitioners' attitudes is required. Such support could take the form of on-site support agents and facilitator

PET imaging to non-invasively study immune activation leading to antitumor responses with a 4-1BB agonistic antibody

BACKGROUND: Molecular imaging with positron emission tomography (PET) may allow the non-invasive study of the pharmacodynamic effects of agonistic monoclonal antibodies (mAb) to 4-1BB (CD137). 4-1BB is a member of the tumor necrosis factor family expressed on activated T cells and other immune cells, and activating 4-1BB antibodies are being tested for the treatment of patients with advanced cancers. METHODS: We studied the antitumor activity of 4-1BB mAb therapy using [(18) F]-labeled fluoro-2-deoxy-2-D-glucose ([(18) F]FDG) microPET scanning in a mouse model of colon cancer. Results of microPET imaging were correlated with morphological changes in tumors, draining lymph nodes as well as cell subset uptake of the metabolic PET tracer in vitro. RESULTS: The administration of 4-1BB mAb to Balb/c mice induced reproducible CT26 tumor regressions and improved survival; complete tumor shrinkage was achieved in the majority of mice. There was markedly increased [(18) F]FDG signal at the tumor site and draining lymph nodes. In a metabolic probe in vitro uptake assay, there was an 8-fold increase in uptake of [(3)H]DDG in leukocytes extracted from tumors and draining lymph nodes of mice treated with 4-1BB mAb compared to untreated mice, supporting the in vivo PET data. CONCLUSION: Increased uptake of [(18) F]FDG by PET scans visualizes 4-1BB agonistic antibody-induced antitumor immune responses and can be used as a pharmacodynamic readout to guide the development of this class of antibodies in the clinic

Agnoprotein Is an Essential Egress Factor during BK Polyomavirus Infection.

BK polyomavirus (BKPyV; hereafter referred to as BK) causes a lifelong chronic infection and is associated with debilitating disease in kidney transplant recipients. Despite its importance, aspects of the virus life cycle remain poorly understood. In addition to the structural proteins, the late region of the BK genome encodes for an auxiliary protein called agnoprotein. Studies on other polyomavirus agnoproteins have suggested that the protein may contribute to virion infectivity. Here, we demonstrate an essential role for agnoprotein in BK virus release. Viruses lacking agnoprotein fail to release from host cells and do not propagate to wild-type levels. Despite this, agnoprotein is not essential for virion infectivity or morphogenesis. Instead, agnoprotein expression correlates with nuclear egress of BK virions. We demonstrate that the agnoprotein binding partner α-soluble N-ethylmaleimide sensitive fusion (NSF) attachment protein (α-SNAP) is necessary for BK virion release, and siRNA knockdown of α-SNAP prevents nuclear release of wild-type BK virions. These data highlight a novel role for agnoprotein and begin to reveal the mechanism by which polyomaviruses leave an infected cell

The Grizzly, December 3, 1990

Wismer Hall to be Renovated by Next Fall • Quad Intruder Returns • Politics Honors Projects • Foreign Policy and the Press • Ursinus Offers St. Joseph\u27s Post-MBA Certificates • Dance Marathon Planned • Crazy Toys • Holiday Messages Encouraged • Exam Schedule • Mixed Up • Jane\u27s Addiction Concert Review • European Old Master Prints • At the Playhouse • Attention Skiers • Edie Brickell Reviewed • In the Spotlight • Swimmers Host Double-Header Weekend • Lady Hoopsters Shoot for Title • Are We Going to War? • Why are We Really There? • Hey! Who\u27s the New Guy? • Brain in Brief • Bonnie and SAM (not Clyde)https://digitalcommons.ursinus.edu/grizzlynews/1266/thumbnail.jp

Guidance on allergenicity assessment of genetically modified plants

This document provides supplementary guidance on specific topics for the allergenicity risk assessment of genetically modified plants. In particular, it supplements general recommendations outlined in previous EFSA GMO Panel guidelines and Implementing Regulation (EU) No 503/2013. The topics addressed are non-IgE-mediated adverse immune reactions to foods, in vitro protein digestibility tests and endogenous allergenicity. New scientific and regulatory developments regarding these three topics are described in this document. Considerations on the practical implementation of those developments in the risk assessment of genetically modified plants are discussed and recommended, where appropriate. (C) 2017 European Food Safety Authority. EFSA Journal published by John Wiley and Sons Ltd on behalf of European Food Safety Authority

City of El Campo Downtown Revitalization Plan

The Revitalization Plan for Downtown El Campo is a planning document that provides guidance for the development of Downtown El Campo. This planning document includes an overview and analysis of the existing conditions in the City of El Campo and the El Campo Downtown Revitalization Area, a design proposal with vision, goals, and objectives for enhancing Downtown El Campo and a detailed implementation chapter for successful execution of the plan.This planning document presents the revitalization plan for downtown El Campo, Texas. This document was developed by Texas Target Communities (TTC) in partnership with the City of El Campo. The City of El Campo collaborated with Texas Target Communities in fall 2016 through the summer of 2017 to create a plan for revitalization of downtown El Campo. The purpose of the collaboration was to assess current community conditions, develop goals, objectives, and implementation strategies related to future development & growth strategies, through a public participatory process, in order to help guide the future growth of the City

City of El Campo Downtown Revitalization Plan

The Revitalization Plan for Downtown El Campo is a planning document that provides guidance for the development of Downtown El Campo. This planning document includes an overview and analysis of the existing conditions in the City of El Campo and the El Campo Downtown Revitalization Area, a design proposal with vision, goals, and objectives for enhancing Downtown El Campo and a detailed implementation chapter for successful execution of the plan.This planning document presents the revitalization plan for downtown El Campo, Texas. This document was developed by Texas Target Communities (TTC) in partnership with the City of El Campo. The City of El Campo collaborated with Texas Target Communities in fall 2016 through the summer of 2017 to create a plan for revitalization of downtown El Campo. The purpose of the collaboration was to assess current community conditions, develop goals, objectives, and implementation strategies related to future development & growth strategies, through a public participatory process, in order to help guide the future growth of the City

Small area analysis methods in an area of limited mapping : exploratory geospatial analysis of firearm injuries in Port-au-Prince, Haiti

Background: The city of Port-au-Prince, Haiti, is experiencing an epidemic of firearm injuries which has resulted in high burdens of morbidity and mortality. Despite this, little scientific literature exists on the topic. Geospatial research could inform stakeholders and aid in the response to the current firearm injury epidemic. However, traditional small-area geospatial methods are difficult to implement in Port-au-Prince, as the area has limited mapping penetration. Objectives of this study were to evaluate the feasibility of geospatial analysis in Port-au-Prince, to seek to understand specific limitations to geospatial research in this context, and to explore the geospatial epidemiology of firearm injuries in patients presenting to the largest public hospital in Port-au-Prince. Results: To overcome limited mapping penetration, multiple data sources were combined. Boundaries of informally developed neighborhoods were estimated from the crowd-sourced platform OpenStreetMap using Thiessen polygons. Population counts were obtained from previously published satellite-derived estimates and aggregated to the neighborhood level. Cases of firearm injuries presenting to the largest public hospital in Port-au-Prince from November 22nd, 2019, through December 31st, 2020, were geocoded and aggregated to the neighborhood level. Cluster analysis was performed using Global Moran’s I testing, local Moran’s I testing, and the SaTScan software. Results demonstrated significant geospatial autocorrelation in the risk of firearm injury within the city. Cluster analysis identified areas of the city with the highest burden of firearm injuries. Conclusions: By utilizing novel methodology in neighborhood estimation and combining multiple data sources, geospatial research was able to be conducted in Port-au-Prince. Geospatial clusters of firearm injuries were identified, and neighborhood level relative-risk estimates were obtained. While access to neighborhoods experiencing the largest burden of firearm injuries remains restricted, these geospatial methods could continue to inform stakeholder response to the growing burden of firearm injuries in Port-au-Prince