Presented at the American Society for Clinical Oncology Gastroenterology in January 2017 in San Francisco by Eric Raymond
Background: Sunitinib was approved by the FDA in 2011 for treatment of progressive, well-differentiated, advanced pancreatic neuroendocrine tumors (pNETs) based on a pivotal phase III study (NCT00428597) that showed a significant increase in progression-free survival (PFS) over placebo following early study termination. Subsequently, the FDA requested a post-approval study to support these findings.
Methods: In this open-label, phase IV clinical trial (NCT01525550), patients with progressive, well-differentiated, unresectable advanced/metastatic pNETs received continuous sunitinib 37.5 mg once daily. Eligibility criteria were similar to the phase III study. Primary endpoint was investigator-assessed PFS per RECIST 1.0. This study is ongoing.
Results: Sixty one treatment-naïve and 45 previously treated patients with progressive pNETs were treated with sunitinib: mean age, 54.6 years; males, 59.4%; white, 63.2%; ECOG PS 0, 65.1% or PS 1, 34.0%; and prior somatostatin analog, 48.1% (treatment-naïve, 39.3%; previously treated, 60.0%). At the data cutoff date, 82 (77%) patients discontinued treatment, mainly due to disease progression (46%). Median duration of treatment was ~11.9 months. Investigator-assessed median PFS (mPFS) was 13.2 months (95% CI, 10.9–16.7) in the overall population, with comparable mPFS in treatment-naïve and previously treated patients (13.2 vs 13.0 months). mPFS per independent radiologic review was 11.1 months (95% CI, 7.4–16.6). Objective response rate (ORR) per RECIST was 24.5%: 21.3% in treatment-naïve and 28.9% in previously treated patients. Median overall survival, although not yet mature, was 37.8 months. Treatment-emergent, all-causality adverse events (AEs) reported by ≥20% of all patients included neutropenia, diarrhea, leukopenia, fatigue, hand–foot syndrome, hypertension, abdominal pain, dysgeusia, and nausea. Most common grade 3/4 AEs were neutropenia (22%) and diarrhea (9%).
Conclusions: The mPFS of 13.2 months and ORR of 24.5% observed in this study support the outcomes of the pivotal phase III study of sunitinib in pNETs and confirm its activity in this setting. AEs were consistent with known safety profile of sunitinib.
Presented at the American Society for Clinical Oncology Gastroenterology in January 2017 in San Francisco by Eric Raymond
Background: Sunitinib was approved by the FDA in 2011 for treatment of progressive, well-differentiated, advanced pancreatic neuroendocrine tumors (pNETs) based on a pivotal phase III study (NCT00428597) that showed a significant increase in progression-free survival (PFS) over placebo following early study termination. Subsequently, the FDA requested a post-approval study to support these findings.
Methods: In this open-label, phase IV clinical trial (NCT01525550), patients with progressive, well-differentiated, unresectable advanced/metastatic pNETs received continuous sunitinib 37.5 mg once daily. Eligibility criteria were similar to the phase III study. Primary endpoint was investigator-assessed PFS per RECIST 1.0. This study is ongoing.
Results: Sixty one treatment-naïve and 45 previously treated patients with progressive pNETs were treated with sunitinib: mean age, 54.6 years; males, 59.4%; white, 63.2%; ECOG PS 0, 65.1% or PS 1, 34.0%; and prior somatostatin analog, 48.1% (treatment-naïve, 39.3%; previously treated, 60.0%). At the data cutoff date, 82 (77%) patients discontinued treatment, mainly due to disease progression (46%). Median duration of treatment was ~11.9 months. Investigator-assessed median PFS (mPFS) was 13.2 months (95% CI, 10.9–16.7) in the overall population, with comparable mPFS in treatment-naïve and previously treated patients (13.2 vs 13.0 months). mPFS per independent radiologic review was 11.1 months (95% CI, 7.4–16.6). Objective response rate (ORR) per RECIST was 24.5%: 21.3% in treatment-naïve and 28.9% in previously treated patients. Median overall survival, although not yet mature, was 37.8 months. Treatment-emergent, all-causality adverse events (AEs) reported by ≥20% of all patients included neutropenia, diarrhea, leukopenia, fatigue, hand–foot syndrome, hypertension, abdominal pain, dysgeusia, and nausea. Most common grade 3/4 AEs were neutropenia (22%) and diarrhea (9%).
Conclusions: The mPFS of 13.2 months and ORR of 24.5% observed in this study support the outcomes of the pivotal phase III study of sunitinib in pNETs and confirm its activity in this setting. AEs were consistent with known safety profile of sunitinib.
Austin Journal of Clinical Cardiology is an open access, peer reviewed, scholarly journal dedicated to publish articles in all areas of cardiology and angiology. The aim of the journal is to provide a forum for cardiologists, researchers, physicians, and other health professionals to find most recent advances in the areas of cardiology and cardiovascular diseases.
Austin Journal of Clinical Cardiology accepts original research articles, review articles, case reports, clinical images and rapid communication on all the aspects of cardiology and circulatory system.
Austin Journal of Clinical Cardiology strongly supports the scientific upgradation and fortification in related scientific research community by enhancing access to peer reviewed scientific literary works. Austin Publishing Group also brings universally peer reviewed journals under one roof thereby promoting knowledge sharing, mutual promotion of multidisciplinary science.
Austin Journal of Clinical Cardiology is an open access, peer reviewed, scholarly journal dedicated to publish articles in all areas of cardiology and angiology
Proteomics Exploration of Chronic Lymphocytic Leukemia_Crimson PublishersCrimsonpublishersCancer
Chronic Lymphocytic Leukemia (CLL) is an adult heme malignancy characterized by the presence of mature-appearing CD5+ B cells in the blood, bone marrow, and secondary lymphoid organs [1]. In the United States, there will be an estimate of 20,720 new cases and 3,930 deaths according to the American Cancer Society statistics. Symptoms include swollen lymph nodes, frequent infections, and fatigue which negatively impacts the quality of life of people affected [1]. CLL is heterogeneous in its progression and clinical outcomes. Factors that contribute to the heterogeneity include the immunoglobulin heavy chain (IGHV) status and chromosomal aberrations [2,3]. There are two subtypes of CLL: Unmutated(U-CLL) and Mutated CLL(M-CLL). 40% and 60% of patients are diagnosed with unmutated and mutated CLL. U-CLL is characterized by the presence of CLL cells that have less than two percent of their IGHV mutated, whereas M-CLL cells have more than two percent mutated [4]. U-CLL is the more aggressive phenotype [2]. These cells have increased responsiveness to antigens that bind the B cell receptor (BCR) versus M-CLL cells [5]. M-CLL is the more indolent phenotype. Increased BCR signaling results in increased cell survival and proliferation [5].
OverviewThe US is currently undergoing an energy boom largel.docxjacksnathalie
Overview
The US is currently undergoing an energy boom largely because of the development of the greatly expanded use of a well technique developed over 40 years ago - hydraulic fracking. It can be used for both oil and natural gas wells.. The technique allows previously unrecoverable oil and gas in old, played out wells to be accessed and increases the efficiency of recovery in new wells significantly. The current level of both recovery and new well drilling is dramatically higher than it has been for decades. The dramatic increase in well activity, some of which has been near towns and places no one thought drilling would ever occur. It has brought a great deal of attention to the technique and associated effects on everything from ground water and air pollution, to biodiversity disruption and earthquakes.
One important fact to weave into your opinion about fracking pro or con is that all of the sub-surface mineral rights in the US are owned by someone (a private individual, a business, or the state or federal government) but surface and mineral rights can be separated, i.e. sold. Originally, mineral rights were sold along with the land and then companies or individuals could decide if they wanted to keep or sell the mineral rights. Before mineral rights were so valuable, many people opted to sell their mineral rights to oil & gas companies. It never occurred to many people that someone would actually be drilling on their property or their neighbors. Oil and gas companies have a legal right to exercise their ownership options and if you are going to say "no" to them, then you owe them for what you are not letting them have, i.e. the money that would be produced if they were allowed to drill. This is not a trivial issue.
Instructions
This week’s discussion focuses on the pros and cons of hydraulic fracking and asks for your SCIENCE informed opinion on whether the economics and political fossil fuel issues justify the negative tradeoffs.
Address each of the following in your discussion:
How is fracking done and why are companies doing this action versus traditional drilling?
Are the environmental issues with fracking worse than conventional drilling? Why or why not?
Why are people along the Front Range and in other states where fracking is widespread, so upset about it now even though fracking has been occurring for a long time?
*In your initial post, please provide 3-4 references in APA format with in-text citations.
.
OverviewThe United Nations (UN) has hired you as a consultan.docxjacksnathalie
Overview
The United Nations (UN) has hired you as a consultant, and your task is to assess the impact that global warming is expected to have on population growth and the ability of societies in the developing world to ensure the adequate security of their food supplies.
Case Assessment
As the world’s population nears 10 billion by 2050, the effects of global warming are stripping some natural resources from the environment. As they diminish in number, developing countries will face mounting obstacles to improving the livelihoods of their citizens and stabilizing their access to enough food. The reason these governments are struggling even now is that our climate influences their economic health and the consequent diminishing living standards of their peoples. Climate changes are responsible for the current loss of biodiversity as well as the physical access to some critical farming regions. As such, these changes in global weather patterns diminish agricultural output and the distribution of food to local and international markets. These difficulties will become even more significant for these countries as the Earth’s climate changes for the worse. Temperatures are already increasing incrementally, and polar ice caps are melting, so the salient question is: what does this suggest for developing societies?
The issue before the developing world is not its lack of food, but rather how to gain access to food. Simply put, changes in our climate are affecting the global food chain, and hence, the living standards of entire populations. Added to this is the fact that food is not getting to where it is needed in time to prevent hunger or starvation. In many developing countries, shortages are due to governments’ control over distribution networks rather than an insufficient supply of food itself. In effect, these governments are weaponizing food by favoring certain ethnic or religious groups over others. When added to dramatic climate changes that we are experiencing even now, the future for billions of poor people looks increasingly dim.
Instructions
You are to write a minimum of a 5 page persuasive paper for the UN that addresses the following questions about the relationship between atmospheric weather patterns and food security in the developing world:
Climate change and global warming are often used interchangeably, but they are not the same phenomenon. What are the differences between the two concepts and what leads to the confusion between them?
In 1900, the average global temperature was about 13.7° Celsius (56.7° Fahrenheit) (Osborn, 2021), but as of 2020, the temperature has risen another 1.2°C to 14.9°C (58.9°F). According to the Earth and climate science community, if the Earth’s surface temperature rises another 2°C (3.6°F), we will suffer catastrophic weather patterns that, among other things, will raise sea levels, cause widespread droughts and wildfires, result in plant, insect, and animal extinctions, and reduce agricultura.
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Austin Journal of Clinical Cardiology is an open access, peer reviewed, scholarly journal dedicated to publish articles in all areas of cardiology and angiology. The aim of the journal is to provide a forum for cardiologists, researchers, physicians, and other health professionals to find most recent advances in the areas of cardiology and cardiovascular diseases.
Austin Journal of Clinical Cardiology accepts original research articles, review articles, case reports, clinical images and rapid communication on all the aspects of cardiology and circulatory system.
Austin Journal of Clinical Cardiology strongly supports the scientific upgradation and fortification in related scientific research community by enhancing access to peer reviewed scientific literary works. Austin Publishing Group also brings universally peer reviewed journals under one roof thereby promoting knowledge sharing, mutual promotion of multidisciplinary science.
Austin Journal of Clinical Cardiology is an open access, peer reviewed, scholarly journal dedicated to publish articles in all areas of cardiology and angiology
Proteomics Exploration of Chronic Lymphocytic Leukemia_Crimson PublishersCrimsonpublishersCancer
Chronic Lymphocytic Leukemia (CLL) is an adult heme malignancy characterized by the presence of mature-appearing CD5+ B cells in the blood, bone marrow, and secondary lymphoid organs [1]. In the United States, there will be an estimate of 20,720 new cases and 3,930 deaths according to the American Cancer Society statistics. Symptoms include swollen lymph nodes, frequent infections, and fatigue which negatively impacts the quality of life of people affected [1]. CLL is heterogeneous in its progression and clinical outcomes. Factors that contribute to the heterogeneity include the immunoglobulin heavy chain (IGHV) status and chromosomal aberrations [2,3]. There are two subtypes of CLL: Unmutated(U-CLL) and Mutated CLL(M-CLL). 40% and 60% of patients are diagnosed with unmutated and mutated CLL. U-CLL is characterized by the presence of CLL cells that have less than two percent of their IGHV mutated, whereas M-CLL cells have more than two percent mutated [4]. U-CLL is the more aggressive phenotype [2]. These cells have increased responsiveness to antigens that bind the B cell receptor (BCR) versus M-CLL cells [5]. M-CLL is the more indolent phenotype. Increased BCR signaling results in increased cell survival and proliferation [5].
OverviewThe US is currently undergoing an energy boom largel.docxjacksnathalie
Overview
The US is currently undergoing an energy boom largely because of the development of the greatly expanded use of a well technique developed over 40 years ago - hydraulic fracking. It can be used for both oil and natural gas wells.. The technique allows previously unrecoverable oil and gas in old, played out wells to be accessed and increases the efficiency of recovery in new wells significantly. The current level of both recovery and new well drilling is dramatically higher than it has been for decades. The dramatic increase in well activity, some of which has been near towns and places no one thought drilling would ever occur. It has brought a great deal of attention to the technique and associated effects on everything from ground water and air pollution, to biodiversity disruption and earthquakes.
One important fact to weave into your opinion about fracking pro or con is that all of the sub-surface mineral rights in the US are owned by someone (a private individual, a business, or the state or federal government) but surface and mineral rights can be separated, i.e. sold. Originally, mineral rights were sold along with the land and then companies or individuals could decide if they wanted to keep or sell the mineral rights. Before mineral rights were so valuable, many people opted to sell their mineral rights to oil & gas companies. It never occurred to many people that someone would actually be drilling on their property or their neighbors. Oil and gas companies have a legal right to exercise their ownership options and if you are going to say "no" to them, then you owe them for what you are not letting them have, i.e. the money that would be produced if they were allowed to drill. This is not a trivial issue.
Instructions
This week’s discussion focuses on the pros and cons of hydraulic fracking and asks for your SCIENCE informed opinion on whether the economics and political fossil fuel issues justify the negative tradeoffs.
Address each of the following in your discussion:
How is fracking done and why are companies doing this action versus traditional drilling?
Are the environmental issues with fracking worse than conventional drilling? Why or why not?
Why are people along the Front Range and in other states where fracking is widespread, so upset about it now even though fracking has been occurring for a long time?
*In your initial post, please provide 3-4 references in APA format with in-text citations.
.
OverviewThe United Nations (UN) has hired you as a consultan.docxjacksnathalie
Overview
The United Nations (UN) has hired you as a consultant, and your task is to assess the impact that global warming is expected to have on population growth and the ability of societies in the developing world to ensure the adequate security of their food supplies.
Case Assessment
As the world’s population nears 10 billion by 2050, the effects of global warming are stripping some natural resources from the environment. As they diminish in number, developing countries will face mounting obstacles to improving the livelihoods of their citizens and stabilizing their access to enough food. The reason these governments are struggling even now is that our climate influences their economic health and the consequent diminishing living standards of their peoples. Climate changes are responsible for the current loss of biodiversity as well as the physical access to some critical farming regions. As such, these changes in global weather patterns diminish agricultural output and the distribution of food to local and international markets. These difficulties will become even more significant for these countries as the Earth’s climate changes for the worse. Temperatures are already increasing incrementally, and polar ice caps are melting, so the salient question is: what does this suggest for developing societies?
The issue before the developing world is not its lack of food, but rather how to gain access to food. Simply put, changes in our climate are affecting the global food chain, and hence, the living standards of entire populations. Added to this is the fact that food is not getting to where it is needed in time to prevent hunger or starvation. In many developing countries, shortages are due to governments’ control over distribution networks rather than an insufficient supply of food itself. In effect, these governments are weaponizing food by favoring certain ethnic or religious groups over others. When added to dramatic climate changes that we are experiencing even now, the future for billions of poor people looks increasingly dim.
Instructions
You are to write a minimum of a 5 page persuasive paper for the UN that addresses the following questions about the relationship between atmospheric weather patterns and food security in the developing world:
Climate change and global warming are often used interchangeably, but they are not the same phenomenon. What are the differences between the two concepts and what leads to the confusion between them?
In 1900, the average global temperature was about 13.7° Celsius (56.7° Fahrenheit) (Osborn, 2021), but as of 2020, the temperature has risen another 1.2°C to 14.9°C (58.9°F). According to the Earth and climate science community, if the Earth’s surface temperature rises another 2°C (3.6°F), we will suffer catastrophic weather patterns that, among other things, will raise sea levels, cause widespread droughts and wildfires, result in plant, insect, and animal extinctions, and reduce agricultura.
OverviewThis project will allow you to write a program to get mo.docxjacksnathalie
Overview
This project will allow you to write a program to get more practice with object-oriented ideas that we explored in the previous project, as well as some practice with more advanced ideas such as inheritance and the use of interfaces.
Ipods and other MP3 players organize a user's music selection into groups known as playlists. These are data structures that provide a collection of songs and an ordering for how those songs will be played. For this assignment you will be writing a set of PlayList classes that could be used for a program that organizes music for a user. These classes will be written to implement a particular PlayList interface so that they can be easily exchange in and out as the program requires. In addition, you will also be using the SimpleTrack class you wrote for the closed lab on Interfaces - if you did not finish this class before the end of lab, you will need to finish it before starting on this project.
Objectives
Practice with programming fundamentals
Review of various Java fundamentals (branching, loops, variables, methods, etc.)
Review of Java File I/O concepts
Practice with Java ArrayList concepts
Practice with object-oriented programming and design
Practice with Java interfaces
Project Description
The SimplePlaylist Class
Once you have coded and tested your SimpleTrack class, you will need to write a SimplePlaylist class that implements the Playist interface given in the project folder.
The SimplePlayList class stores music tracks in order - the first track added to the play list should be the first one removed from the play list. You should recognize this data structure as a
queue
(or a
first-in, first-out queue
). You do not need to implement the equals, hashCode and toString methods for this class but if you choose to do so make sure you document your implementations properly!
The PlayList Management Program
Once you have written and tested a SimpleTrack class and a SimplePlaylist class, it is time to use them to write a program to manage playlists. This program will simulate the playing of songs from a play list. For the SimplePlaylist, the songs are removed from the playlist as they are played, so you know that you're at the end of the list when your list is empty. This program should be implemented in the file MusicPlayerSimulator.java. Note that we are not defining ANY of the methods you are using for this program - the design is all up to you. You must, however, practice good programming style - make sure you are breaking the program up into smaller methods and aren't just trying to solve everything with one monolithic main method. If you have fewer than 5 methods for this program you are probably trying to fit too much into a single method.
Here is a sample transcript of the output of this program:
Enter database filename:
input.txt
Currently playing: 'Elvis Presley / Blue Suede Shoes / Elvis Presley: Legacy Edition' Next track to play: 'The Beatles / Wit.
OverviewThis week, we begin our examination of contemporary resp.docxjacksnathalie
Overview
This week, we begin our examination of contemporary responses to youths’ illegal behaviors. The goal for this week is to assess pre-adjudication responses to youths’ illegal behavior. Primarily, our focus will be on nonformal responses or diversion. As a prelude to this discussion, we will consider the “school to prison pipeline” as it provides a good way to understand the need for diversion in juvenile justice.
Objectives
Upon completion of this week’s lesson, you should be able to:
Define what is meant by the “school to prison pipeline.”
Explain how the political economy contributes to the school to prison pipeline.
Explain how trends in education, policing, and juvenile justice contribute to the school to prison pipeline
Describe juvenile arrest trends and trends in the willingness of police to refer youths to juvenile court.
Define radical nonintervention or true diversion and assess the role in can play in juvenile justice.
Explain the rationale for diversion and its value in juvenile justice.
Describe diversion programs that appear to be effective and programs that are not effective
Assess arguments that are made in support of diversion.
Assess the potential problems that should be addressed when developing or operating diversion programs
Tasks
View Video Lecture (Part 1 and Part 2 below) on the School to Prison Pipeline. While viewing the videos, use the pause feature to stop the slides when needed so that you can examine the content.
Part 1
Part 2
Watch the video:
Rethinking Challenging Kids-Where There's a Skill There's a Way | J. Stuart Ablon | TEDxBeaconStreet
Read the material below, Juvenile Diversion.
View Video Lecture 3
.
OverviewProgress monitoring is a type of formative assessment in.docxjacksnathalie
Overview
Progress monitoring is a type of formative assessment in which student learning is evaluated
on a regular basis to provide useful feedback about performance to both students and
teachers. Though there are a number of methods for monitoring a student’s progress, the most
widely used is general outcome measurement, sometimes referred to as curriculum-based
measurement (CBM). Progress monitoring consists of the frequent administration (e.g., once
per month, every two weeks) of brief probes or tests, which include sample items from every
skill taught across the academic year. After each probe is scored, the teacher or student plots
the score on an individual CBM graph. The teacher can then use this data to determine a
student’s:
• Rate of growth — Average growth of a student’s mathematics skills over a period of time
• Performance level — An indication of a student’s current mathematics skills, often
denoted by a score on a test or probe.
You will determine the rate of growth for the two students listed on page 3 using the data provided.
.
OverviewThe work you do throughout the modules culminates into a.docxjacksnathalie
Overview
The work you do throughout the modules culminates into a Customer Service Plan. This plan incorporates the following:
Module 2: Company Description & Evaluation
Module 3: Examine Customer Service & Quality
Module 4: Examine Customer Service Practices in the Twenty-First Century
Module 5: Company Analysis
Instructions
Part I:
Customer Perspective
In relation to what you have learned in Module 3 so far, observe and describe the following as you would view it from the customer’s perspective. Hint: What is each communicating to the customer?
Physical appearance of the business
How quickly is a customer greeted
Pace of the transaction
Parking lot
Hours of operation
Courtesy of customer service representative
Knowledge of customer service representative
Website - if there is a website, how user-friendly is it?
Part II: Quality Recognition
Discuss the following:
Identify criteria that your organization deems important in communications.
How do you know this criteria is important?
How are representatives evaluated on this?
What training is provided to employees in the five main methods of communication (Listening, writing, talking, reading, nonverbal expression)?
What are the expectations when using technology to communicate with customers?
Part III: Proactive Practices
Evaluate the practices in place to avoid challenging situations. What are the practices in place in your business to demonstrate:
Respecting the customer’s time
Keeping a positive attitude
Recognizing regular customers
Maintaining professional communication
Showing initiative
.
OverviewThis discussion is about organizational design and.docxjacksnathalie
Overview
This discussion is about
organizational design and leadership
, as well as
global leadership issues and practices
. Conduct research on current events relating to one of the unit concepts of interest to you. Then, share your findings in an initial post. Try to choose a concept that has not been, or is rarely, addressed by your classmates. Review peers' findings and then engage in an active discussion to learn more about the topic at hand.
Resources
Park LibraryLinks to an external site.
Click on the Library Sources tab.
Enter your topic in the search box.
Click on full text, and you will find one, or several, articles to analyze.
.
OverviewScholarly dissemination is essential for any doctora.docxjacksnathalie
Overview
Scholarly dissemination is essential for any doctoral level student. Posters are often a way to ease into scholarly communication. Building a poster is one of the ways scholars participate in the dissemination of knowledge.
Instructions
1. Your poster submission must have a central focus, as developed from the topic selected in Module 2, and that focus must be evident throughout the poster. Specifically, your introduction, analysis, and results must be focused on a set of research questions and/or hypotheses that are obvious in your theoretical diagram.
2. The focus must comprehensively place the problem/question in appropriate scholarly context (scholarly literature, theory, model, or genre).
.
OverviewRegardless of whether you own a business or are a s.docxjacksnathalie
Overview:
Regardless of whether you own a business or are a stakeholder in a business, understanding basic contract terms is important. Businesses enter into contracts with many areas, from shipping to suppliers to customers. As a business owner or manager knowledge of these basic terms will assist you in the day to day operations of the business, regardless of the field.
Instructions:
• Fill in the attached template.
• For each term, define the term with citation to authority, define the term in your own words and provide an example of each term.
Requirements:
• Use APA format for non-legal sources such as the textbook. Use Bluebook citation format for any legal citations.
• Submit a Word document using the template.
• Maximum two pages in length, excluding the Reference page.
.
OverviewImagine you have been hired as a consultant for th.docxjacksnathalie
Overview
Imagine you have been hired as a consultant for the United Nations. You have been asked to write an analysis on how global population growth has caused the following problem and how it affects
TURKEY
A growing global population that consumes natural resources is partially to blame for the release of greenhouse gases since human consumption patterns lead to deforestation, soil erosion, and farming (overturned dirt releases CO2). However, the critical issue is the burning of fossil fuels (hydrocarbons) such as coal oil and natural gas to produce energy that is used for things like electricity production, and vehicle, heating, and cooking fuels.
Instructions
Content
The U.N. has asked that your paper contain three sections. It has asked that each section be one page (or approximately 300 words) in length and answer specific questions, identified in the outline below. It also asks that you use examples from Turkey when answering the questions.
Introduction
Provide an introduction of half a page minimum that addresses points
points
1–5 below:
Explain the problem the U.N. has asked you to address in your own words.
Identify the three sections your paper will cover.
Identify the developing country (TURKEY) you will consider.
Telly
the U.N. which causes of greenhouse gases you will explore.
Provide a one-sentence statement of your solutions at the end of your introduction paragraph.
Section I. Background
What are greenhouse gases?
How do greenhouse gases contribute to global warming?
Section II. How Emissions Causes Problems for the Developing World
Which countries produce the most greenhouse gases?
What are the economic challenges of these emissions in Turkey?
What are the security challenges of these emissions in Turkey?
What are the political challenges of these emissions in Turkey?
Section III. Causes and
Solution
s of Greenhouse Gases
Name two causes of greenhouse gases.
What are potential solutions to address each of the causes you identified?
What is the relationship between population control and greenhouse gases?
Conclusion
Provide a conclusion of half a page minimum that includes a summary of your findings that the United Nations can use to inform future policy decisions.
Success Tips
In answering each question, use examples from Turkey to illustrate your points.
The U.N. needs facts and objective analysis on which to base future policy decisions. Avoid
personal opinion
and make sure your answers are based on information you find through research.
Formatting Requirements
Make sure your paper consists of 4–6 pages (1,200 words minimum, not including the cover page, reference page, and quoted material if any).
Create headings for each section of your paper as follows:
Section I. Background.
Section II. How Emissions Causes Problems for the Developing World.
Section III. Causes and
.
OverviewDevelop a 4–6-page position about a specific health care.docxjacksnathalie
Overview
Develop a 4–6-page position about a specific health care issue as it relates to a target vulnerable population. Include an analysis of existing evidence and position papers to help support your position. Your analysis should also present and respond to one or more opposing viewpoints.
Note
: Each assessment in this course builds on the work you completed in the previous assessment. Therefore, you must complete the assessments in this course in the order in which they are presented.
Position papers are a method to evaluate the most current evidence and policies related to health care issues. They offer a way for researchers to explore the views of any number of organizations around a topic. This can help you to develop your own position and approach to care around a topic or issue.
This assessment will focus on analyzing position papers about an issue related to addiction, chronicity, emotional and mental health, genetics and genomics, or immunity. Many of these topics are quickly evolving as technology advances, or as we attempt to push past stigmas. For example, technology advances and DNA sequencing provide comprehensive information to allow treatment to become more targeted and effective for the individual. However as a result, nurses must be able to understand and teach patients about the impact of this information. With this great power comes concerns that patient conditions are protected in an ethical and compassionate manner.
By successfully completing this assessment, you will demonstrate your proficiency in the following course competencies and assessment criteria:
Competency 1: Design evidence-based advanced nursing care for achieving high-quality population outcomes.
Evaluate the evidence and positions of others that could support a team's approach to improving the quality and outcomes of care for a specific issue in a target population.
Evaluate the evidence and positions of others that are contrary to a team's approach to improving the quality and outcomes of care for a specific issue in a target population.
Competency 2: Evaluate the efficiency and effectiveness of interprofessional interventions in achieving desired population health outcomes.
Explain the role of the interprofessional team in facilitating improvements for a specific issue in a target population.
Competency 3: Analyze population health outcomes in terms of their implications for health policy advocacy.
Explain a position with regard to health outcomes for a specific issue in a target population.
Competency 4: Communicate effectively with diverse audiences, in an appropriate form and style, consistent with organizational, professional, and scholarly standards.
Communicate an initial viewpoint regarding a specific issue in a target population and a synthesis of existing positions in a logically structured and concise manner, writing content clearly with correct use of grammar, punctuation, and spelling.
Integrate .
Overview This purpose of the week 6 discussion board is to exam.docxjacksnathalie
Overview:
This purpose of the week 6 discussion board is to examine social class and global stratification. Answer prompt 1. Then select and answer one prompt from prompts 2-4. Refer to Chapters 7 and 8 to answer the prompts.
Instructions:
Respond to prompts in paragraph form (200-400 words
Prompt 1:
Describe 3 topics from Chapters 7 and 8 that you found interesting. Three topics I found interesting from Chapter 7 and 8 were the Dependency Theory, World Systems Theory, and Modernization Theory.
Prompt 2:
Describe 3 different social classes and criteria for membership in each.
Prompt 3:
Describe the effect of social inequality upon dominant and minority groups.
Prompt 4
: Describe social mobility regarding how to rise up the social class ladder, if it is possible.
Prompt 5:
Apply a functionalist or conflict theory perspective to social inequality.
.
Overall Scenario Always Fresh Foods Inc. is a food distributor w.docxjacksnathalie
Overall Scenario
Always Fresh Foods Inc. is a food distributor with a central headquarters and main warehouse in Colorado, as well as two regional warehouses in Nevada and Virginia. The company runs Microsoft Windows 2019 on its servers and Microsoft Windows 10 on its workstations. There are 2 database servers, 4 application servers, 2 web servers, and 25 workstation computers in the headquarters offices and main warehouse. The network uses workgroups, and users are created locally on each computer. Employees from the regional warehouses connect to the Colorado network via a virtual private network (VPN) connection. Due to a recent security breach, Always Fresh wants to increase the overall security of its network and systems. They have chosen to use a solid multilayered defense to reduce the likelihood that an attacker will successfully compromise the company’s information security. Multiple layers of defense throughout the IT infrastructure makes the process of compromising any protected resource or data more difficult than any single security control. In this way, Always Fresh protects its business by protecting its information.
Scenario 1
Assume you are an entry-level security administrator working for Always Fresh. You have been asked to evaluate the option of adding Active Directory to the company’s network.
Tasks
Create a summary report to management that answers the following questions to satisfy the key points of interest regarding the addition of Active Directory to the network:
1. System administrators currently create users on each computer where users need access. In Active Directory, where will system administrators create users?
2. How will the procedures for making changes to the user accounts, such as password changes, be different in Active Directory?
3. What action should administrators take for the existing workgroup user accounts after converting to Active Directory?
4. How will the administrators resolve differences between user accounts defined on different computers? In other words, if user accounts have different settings on different computers, how will Active Directory address that issue? (Hint: Consider security identifiers [SIDs].)
.
OverviewCreate a 15-minute oral presentation (3–4 pages) that .docxjacksnathalie
Overview
Create a 15-minute oral presentation (3–4 pages) that examines the moral and ethical issues related to triaging patients in an emergency room.
By successfully completing this assessment, you will demonstrate your proficiency in the following course competencies and assessment criteria:
· Competency 1: Explain the effect of health care policies, legislation, and legal issues on health care delivery and patient outcomes.
. Explain the health care policies that can affect emergency care.
. Recommend evidence-based decision-making strategies nurses can use during triage.
· Competency 3: Apply professional nursing ethical standards and principles to the decision-making process.
. Describe the moral and ethical challenges nurses can face when following hospital policies and protocols.
. Explain how health care disparities impact treatment decisions.
· Competency 4: Communicate in a manner that is consistent with expectations of nursing professionals.
. Write content clearly and logically, with correct use of grammar, punctuation, and mechanics.
. Correctly format citations and references using APA style.
Context
Working in an emergency room gives rise to ethical dilemmas. Due to time restraints and the patient's cognitive impairment and lack of medical history, complications can and do occur. The nurse has very little time to get detailed patient information. He or she must make a quick assessment and take action based on hospital protocol. The organized chaos of the emergency room presents unique ethical challenge, which is why nurses are required to have knowledge of ethical concepts and principles.
Questions to consider
To deepen your understanding, you are encouraged to consider the questions below and discuss them with a fellow learner, a work associate, an interested friend, or a member of your professional community.
· How does a triage nurse decide which patient gets seen first?
· How does health disparity affect the triage nurse's decision making?
· What ethical and moral issues does the triage nurse take into account when making a decision?
· What are triage-level designations?
Resources
Suggested Resources
The following optional resources are provided to support you in completing the assessment or to provide a helpful context. For additional resources, refer to the Research Resources and Supplemental Resources in the left navigation menu of your courseroom.
Capella Resources
· APA Paper Template.
· APA Paper Tutorial.
Library Resources
The following e-books or articles from the Capella University Library are linked directly in this course:
· Tingle, J., & Cribb, A. (Eds.). (2014). Nursing law and ethics (4th ed.). Somerset, NJ: John Wiley & Sons.
· Cranmer, P., & Nhemachena, J. (2013). Ethics for nurses: Theory and practice. Maidenhead, UK: Open University Press.
· Aacharya, R. P., Gastmans, C., & Denier, Y. (2011). Emergency department triage: An ethical analysis. B MC Emergency Medicine, 11(1), 16–29.
· Guidet, B., H.
Overall CommentsHi Khanh,Overall you made a nice start with y.docxjacksnathalie
Overall Comments:
Hi Khanh,
Overall you made a nice start with your U06a1 assignment; however, many of the required objectives have not been addressed in the first version of your assignment. Please carefully review the scoring guide, and review my feedback below, and be sure to contact me if you have any questions about my comments. You can reach me at: [email protected] or 813-417-0860.
Sincerely,
Dr. Marni Swain
COMPETENCY: Assess approaches for recruiting, selecting, and retaining talent.
CRITERION: Explain why and when candidate background checks will be authorized.
DISTINGUISHED
PROFICIENT
BASIC
NON-PERFORMANCE
Basic
Explains why but not when candidate background checks will be authorized.
Faculty Comments:“
You made a nice start with this discussion; however, it is important to develop your content further to address the legalities involving when a background check can be conducted during the interview process, and the other steps employers have to follow to be in compliance with the law.
”
CRITERION: Identify the top three candidates to interview for the position.
DISTINGUISHED
PROFICIENT
BASIC
NON-PERFORMANCE
Non-Performance
Does not identify the top three candidates to interview for the position.
Faculty Comments:“
Please develop your content further to address this topic in your assignment.
”
CRITERION: Explain rationale for why the selected candidates should be interviewed.
DISTINGUISHED
PROFICIENT
BASIC
NON-PERFORMANCE
Non-Performance
Does not explain rationale for why the selected candidates should be interviewed.
Faculty Comments:“
Please develop your content further to address this topic in your assignment.
”
CRITERION: Identify pre-employment screening tests for the position being recruited.
DISTINGUISHED
PROFICIENT
BASIC
NON-PERFORMANCE
Basic
Identifies a pre-employment screening test for the position being recruited.
Faculty Comments:“
I would like to see your content developed further to clearly identify your rationale for the pre-employment screening tests you selected, as this is not clear based on the limited information provided.
”
CRITERION: Select assessment methods to use based on the job being recruited and the budget available.
DISTINGUISHED
PROFICIENT
BASIC
NON-PERFORMANCE
Non-Performance
Does not select assessment methods to use based on the job being recruited and the budget available.
Faculty Comments:“
I would like to see your content developed further to clearly identify the assessment methods you will use for CapraTek's Regional Sales positions based on the available budget, as this is not identified in your work.
”
CRITERION: Develop the sequence in which methods will be used to screen applicants.
DISTINGUISHED
PROFICIENT
BASIC
NON-PERFORMANCE
Non-Performance
Does not develop the sequence in which methods will be used to screen applicants.
Faculty Comments:“
Please develop your content further to address this topic in your assignment.
”
CRITERION: Design a final candidate selection process for the CapraTek.
Overall CommentsHi Khanh,Overall you made a nice start with.docxjacksnathalie
Overall Comments:
Hi Khanh,
Overall you made a nice start with your U03a1 assignment; however, your content still does not address the required objectives. For this assignment you will need to focus the content on Capra Tek's regional sales position, and for objective #1 analyze the KSAs for this position, and for objective #2 you will need to analyze wage trends related to this position as well. Objectives 3 & 4 focus on job description and the job analysis so please carefully review what is required for these two objectives.
Please see my feedback below and be sure to let me know if you have any questions about my comments.
Sincerely,
Dr. Marni Swain
COMPETENCY: Describe how hiring practices support an organization's strategy.
CRITERION: Articulate the components of a job description for a position.
DISTINGUISHED
PROFICIENT
BASIC
NON-PERFORMANCE
Non-Performance
Does not articulate the components of a job description for this position.
Faculty Comments:“
Please see feedback above.
”
COMPETENCY: Assess approaches for recruiting, selecting, and retaining talent.
CRITERION: Identify the knowledge, skills, and abilities required for this position.
DISTINGUISHED
PROFICIENT
BASIC
NON-PERFORMANCE
Non-Performance
Does not identify the knowledge, skills, and abilities required for this position.
Faculty Comments:“
Please see feedback above.
”
COMPETENCY: Explore technology tools that support recruiting and staffing management.
CRITERION: Identify wage information and employment trends for this position in a selected state.
DISTINGUISHED
PROFICIENT
BASIC
NON-PERFORMANCE
Non-Performance
Does not identify wage information and employment trends for this position in a selected state.
Faculty Comments:“
Please see feedback above.
”
COMPETENCY: Analyze the impact of legal and regulatory issues on staffing management.
CRITERION: Explain why a job analysis is a requirement for any recruiting and selecting process.
DISTINGUISHED
PROFICIENT
BASIC
NON-PERFORMANCE
Non-Performance
Does not explain why a job analysis is a requirement for any recruiting and selecting process.
Faculty Comments:“
Please see feedback above.
”
COMPETENCY: Communicate in a manner that is scholarly and professional.
CRITERION: Communicate in a professional manner that is appropriate for the intended audience.
DISTINGUISHED
PROFICIENT
BASIC
NON-PERFORMANCE
Non-Performance
Does not communicate in a professional manner that is appropriate for the intended audience.
Faculty Comments:“
Please see feedback above.
”
Dysphagia .
Dysphagia is a serious problem and contributes to weight loss, malnutrition, dehydration, aspiration pneumonia, and death. Careful assessment of risk factors, observation for signs and symptoms, and collaboration with speech-language pathologists on interventions are essential.
Dysphagia, or difficulty swallowing, is a common problem in older adults. The prevalence of swallowing disorders is 16% to 22% in adults older than 50 years of age, and up to 60% of nursing ho.
Overall feedbackYou addressed most all of the assignment req.docxjacksnathalie
Overall feedback:
You addressed most all of the assignment requirements. The assignment had several requirements including, but not limited to: an introduction, 3 questions, conclusion, and at least 2 scholarly references to support your claims. You did include an introduction. However, the introduction should briefly identify the key areas/sections to be covered in the paper. This helps the reader navigate through the organization of both your paper and thought process. You did address the question requirements. The assignment required at least 2 scholarly peer reviewed journal articles. Although you included several references, I only saw one scholarly peer reviewed journal article. Moving forward. Be sure to carefully review the instructions before and after you complete your final draft to ensure all requirements have been met. Second, always include an introduction which briefly describes what areas will be covered. Finally, make sure that you include the required number of scholarly peer reviewed journal articles to support your claims. If you have questions, please contact me.
be sure to fully address the question with terminology and concepts from the book to apply to the case. This demonstrates proficiency at the required tasks. For example, question 2 asked:
Question #2: Discuss your plans for developing formal job descriptions for the employees at the second shop
For this question, I was looking for your approach in terms of methods discussed in the text (interviews, observations, questionnaires, etc.) and application to the case study to show application of the concepts/theories.
As far as the scholarly peer reviewed journal articles, this is an essential part of supporting your claims at the graduate level of writing. The assignment required 2 scholarly peer reviewed journal articles. I only saw one? The purpose of this requirement is to ensure that you are supporting your claims with contemporary research within the management/business discipline. Second, this also gives credit to the author's ideas. While I do not point out every error or missing item on your paper, I focus on those areas/content that are required and can be improved. Moving forward, be sure to fully address each question with terminology from the text/material, as well as provide examples to demonstrate the ability to apply the concepts to the case study. I look forward to receiving your next paper. Second, be sure to include the required number of current (within past 5 years) scholarly peer reviewed journal articles to support your paper.
.
Performance Management
Third Edition
Herman Aguinis
Kelley School of Business
Indiana University
Boston Columbus Indianapolis New York San Francisco Upper Saddle River
Amsterdam Cape Town Dubai London Madrid Milan Munich Paris Montreal Toronto
Delhi Mexico City Sao Paulo Sydney Hong Kong Seoul Singapore Taipei Tokyo
Credits and acknowledgments borrowed from other sources and reproduced, with per.
Overall Comments Overall you made a nice start with your U02a1 .docxjacksnathalie
Overall Comments:
Overall you made a nice start with your U02a1 assignment. Please see my specific feedback below for each objective, and I can be reached at: [email protected] or 813-417-0860 if you have any questions about my comments.
COMPETENCY: Analyze the impact of legal and regulatory issues on staffing management.
CRITERION: Describe the important issues in the case.
DISTINGUISHED
PROFICIENT
BASIC
NON-PERFORMANCE
Non-Performance
Does not identify the important issues in the case.
Faculty Comments:“
It is important to select a legal case of disparate impact as the focus of your assignment, and it is unclear if the case you selected is this type of case based on the information provided. Please develop your content further to clearly analyze the important issues of this case, and be sure to describe why this is a case of disparate impact.
”
CRITERION: Distinguish the theory of disparate (or adverse) impact from the theory of disparate treatment.
DISTINGUISHED
PROFICIENT
BASIC
NON-PERFORMANCE
Basic
Partially distinguishes the theory of disparate (or adverse) impact from the theory of disparate treatment.
Faculty Comments:“
You made a nice start with this objective; however, I would like to see your content developed further to clearly distinguish the theory of disparate treatment from disparate or adverse impact, and this is only briefly addressed in your assignment.
”
CRITERION: Analyze the outcome of the case.
DISTINGUISHED
PROFICIENT
BASIC
NON-PERFORMANCE
Non-Performance
Does not state the outcome of the case.
Faculty Comments:“
It is important to select a legal case of disparate impact as the focus of your assignment, and it is unclear if the case you selected is this type of case based on the information provided. Please develop your content further to clearly analyze the outcome of this case, and be sure to apply disparate impact theory.
”
CRITERION: Analyze the evidence of discriminatory effects.
DISTINGUISHED
PROFICIENT
BASIC
NON-PERFORMANCE
Non-Performance
Does not describe the evidence of discriminatory effects.
Faculty Comments:“
It is important to select a legal case of disparate impact as the focus of your assignment, and it is unclear if the case you selected is this type of case based on the information provided. Please develop your content further to clearly analyze the evidence of discriminatory effects in this case, and provide specific examples of connections to the rule, policy or process.
”
CRITERION: Describe how the Uniform Guidelines on Employee Selection Procedures help employers avoid issues related to disparate or adverse impact.
DISTINGUISHED
PROFICIENT
BASIC
NON-PERFORMANCE
Non-Performance
Does not identify how the Uniform Guidelines on Employee Selection Procedures help employers avoid issues related to disparate or adverse impact.
Faculty Comments:“
Please develop your content further to address this in your work.
”
COMPETENCY: Communicate in a manner that is scholarly and professional.
CRITERION: Commun.
Overview This purpose of the week 12 discussion board is to e.docxjacksnathalie
Overview:
This purpose of the week 12 discussion board is to examine health, healthcare, and disability status. Answer prompt 1. Then select and answer one prompt from prompts 2-4. Refer to Chapter 13 to answer the prompts.
Instructions:
Respond to prompts in paragraph form (200-400 words)
Prompt 1:
Describe 3 topics from Chapter 13 that you found interesting.Three topics I found interesting in Chapter 14 was "A Functionalist Perspective: The Sick Role", "A Symbolic Interactionist Perspective:
Prompt 2:
Describe how stereotypes regarding disability status may lead to prejudice and discrimination.
Prompt 3:
Describe how access to healthcare is associated with social class location (e.g., socioeconomic status).
Prompt 4:
How is culture associated with attitudes towards health and healthcare.
Prompt 5:
Compare how the United States pays for health care with how other nations provide health services for their citizens.
.
Over the years, the style and practice of leadership within law .docxjacksnathalie
Over the years, the style and practice of leadership within law enforcement agencies has gradually changed. In the past, leadership was primarily relegated to one individual within the department. However, there has been a transformation in leadership theory resulting in a more dynamic, multifaceted nature of teamwork, inclusion, and dispersed leadership. More and more, police chiefs are being encouraged to move toward a more participatory leadership style of management, one that encourages collaboration and cooperation in the decision-making process.
Based on your readings in the text and credible Internet research, respond to the following:
What does the term
shared leadership
mean? What advantages or disadvantages do you see in this leadership approach?
What direction should law enforcement leaders take for the future, related to leadership styles?
What does the term
visionary leadership
mean?
2-3 pages
.
Operation “Blue Star” is the only event in the history of Independent India where the state went into war with its own people. Even after about 40 years it is not clear if it was culmination of states anger over people of the region, a political game of power or start of dictatorial chapter in the democratic setup.
The people of Punjab felt alienated from main stream due to denial of their just demands during a long democratic struggle since independence. As it happen all over the word, it led to militant struggle with great loss of lives of military, police and civilian personnel. Killing of Indira Gandhi and massacre of innocent Sikhs in Delhi and other India cities was also associated with this movement.
Francesca Gottschalk - How can education support child empowerment.pptxEduSkills OECD
Francesca Gottschalk from the OECD’s Centre for Educational Research and Innovation presents at the Ask an Expert Webinar: How can education support child empowerment?
The French Revolution, which began in 1789, was a period of radical social and political upheaval in France. It marked the decline of absolute monarchies, the rise of secular and democratic republics, and the eventual rise of Napoleon Bonaparte. This revolutionary period is crucial in understanding the transition from feudalism to modernity in Europe.
For more information, visit-www.vavaclasses.com
2024.06.01 Introducing a competency framework for languag learning materials ...Sandy Millin
http://sandymillin.wordpress.com/iateflwebinar2024
Published classroom materials form the basis of syllabuses, drive teacher professional development, and have a potentially huge influence on learners, teachers and education systems. All teachers also create their own materials, whether a few sentences on a blackboard, a highly-structured fully-realised online course, or anything in between. Despite this, the knowledge and skills needed to create effective language learning materials are rarely part of teacher training, and are mostly learnt by trial and error.
Knowledge and skills frameworks, generally called competency frameworks, for ELT teachers, trainers and managers have existed for a few years now. However, until I created one for my MA dissertation, there wasn’t one drawing together what we need to know and do to be able to effectively produce language learning materials.
This webinar will introduce you to my framework, highlighting the key competencies I identified from my research. It will also show how anybody involved in language teaching (any language, not just English!), teacher training, managing schools or developing language learning materials can benefit from using the framework.
Synthetic Fiber Construction in lab .pptxPavel ( NSTU)
Synthetic fiber production is a fascinating and complex field that blends chemistry, engineering, and environmental science. By understanding these aspects, students can gain a comprehensive view of synthetic fiber production, its impact on society and the environment, and the potential for future innovations. Synthetic fibers play a crucial role in modern society, impacting various aspects of daily life, industry, and the environment. ynthetic fibers are integral to modern life, offering a range of benefits from cost-effectiveness and versatility to innovative applications and performance characteristics. While they pose environmental challenges, ongoing research and development aim to create more sustainable and eco-friendly alternatives. Understanding the importance of synthetic fibers helps in appreciating their role in the economy, industry, and daily life, while also emphasizing the need for sustainable practices and innovation.
Biological screening of herbal drugs: Introduction and Need for
Phyto-Pharmacological Screening, New Strategies for evaluating
Natural Products, In vitro evaluation techniques for Antioxidants, Antimicrobial and Anticancer drugs. In vivo evaluation techniques
for Anti-inflammatory, Antiulcer, Anticancer, Wound healing, Antidiabetic, Hepatoprotective, Cardio protective, Diuretics and
Antifertility, Toxicity studies as per OECD guidelines
A Strategic Approach: GenAI in EducationPeter Windle
Artificial Intelligence (AI) technologies such as Generative AI, Image Generators and Large Language Models have had a dramatic impact on teaching, learning and assessment over the past 18 months. The most immediate threat AI posed was to Academic Integrity with Higher Education Institutes (HEIs) focusing their efforts on combating the use of GenAI in assessment. Guidelines were developed for staff and students, policies put in place too. Innovative educators have forged paths in the use of Generative AI for teaching, learning and assessments leading to pockets of transformation springing up across HEIs, often with little or no top-down guidance, support or direction.
This Gasta posits a strategic approach to integrating AI into HEIs to prepare staff, students and the curriculum for an evolving world and workplace. We will highlight the advantages of working with these technologies beyond the realm of teaching, learning and assessment by considering prompt engineering skills, industry impact, curriculum changes, and the need for staff upskilling. In contrast, not engaging strategically with Generative AI poses risks, including falling behind peers, missed opportunities and failing to ensure our graduates remain employable. The rapid evolution of AI technologies necessitates a proactive and strategic approach if we are to remain relevant.
Macroeconomics- Movie Location
This will be used as part of your Personal Professional Portfolio once graded.
Objective:
Prepare a presentation or a paper using research, basic comparative analysis, data organization and application of economic information. You will make an informed assessment of an economic climate outside of the United States to accomplish an entertainment industry objective.
Azure Interview Questions and Answers PDF By ScholarHat
original articleT h e n e w e n g l a n d j o u r n a l.docx
1. original article
T h e n e w e n g l a n d j o u r n a l o f m e d i c i n e
n engl j med 355;23 www.nejm.org december 7, 20062408
Five-Year Follow-up of Patients Receiving
Imatinib for Chronic Myeloid Leukemia
Brian J. Druker, M.D., François Guilhot, M.D., Stephen G.
O’Brien, M.D., Ph.D.,
Insa Gathmann, M.Sc., Hagop Kantarjian, M.D., Norbert
Gattermann, M.D.,
Michael W.N. Deininger, M.D., Ph.D., Richard T. Silver, M.D.,
John M. Goldman, D.M., Richard M. Stone, M.D., Francisco
Cervantes, M.D.,
Andreas Hochhaus, M.D., Bayard L. Powell, M.D., Janice L.
Gabrilove, M.D.,
Philippe Rousselot, M.D., Josy Reiffers, M.D., Jan J.
Cornelissen, M.D., Ph.D.,
Timothy Hughes, M.D., Hermine Agis, M.D., Thomas Fischer,
M.D.,
Gregor Verhoef, M.D., John Shepherd, M.D., Giuseppe Saglio,
M.D.,
Alois Gratwohl, M.D., Johan L. Nielsen, M.D., Jerald P.
Radich, M.D.,
Bengt Simonsson, M.D., Kerry Taylor, M.D., Michele
Baccarani, M.D.,
Charlene So, Pharm.D., Laurie Letvak, M.D.,
3. lecular responses; and adverse events.
Results
The median follow-up was 60 months. Kaplan–Meier estimates
of cumulative best
rates of complete cytogenetic response among patients receiving
imatinib were 69%
by 12 months and 87% by 60 months. An estimated 7% of
patients progressed to
accelerated-phase CML or blast crisis, and the estimated overall
survival of patients
who received imatinib as initial therapy was 89% at 60 months.
Patients who had a
complete cytogenetic response or in whom levels of BCR-ABL
transcripts had fallen
by at least 3 log had a significantly lower risk of disease
progression than did pa-
tients without a complete cytogenetic response (P<0.001).
Grade 3 or 4 adverse events
diminished over time, and there was no clinically significant
change in the profile
of adverse events.
Conclusions
After 5 years of follow-up, continuous treatment of chronic-
phase CML with imatinib
as initial therapy was found to induce durable responses in a
high proportion of pa-
tients. (ClinicalTrials.gov number, NCT00006343.)
The New England Journal of Medicine
Downloaded from nejm.org on May 15, 2020. For personal use
only. No other uses without permission.
5. the interferon group switched to imatinib. In ad-
dition, at the time of Food and Drug Administra-
tion approval of imatinib, many patients who were
assigned to receive interferon alfa plus cytarabine
left the study. Consequently, the trial has evolved
into a long-term study of the result of treating
newly diagnosed patients in the chronic phase of
CML with imatinib. We now report 60 months of
follow-up data and focus on patients who received
imatinib as a primary treatment.
M e t h o d s
Study Design
The design of the study has been described pre-
viously.14 The International Randomized Study
of Interferon and STI571 (IRIS) was a multicenter,
international, open-label, phase III randomized
study. Eligible patients had to be between 18 and
70 years of age, must have been diagnosed with
Ph-positive CML in chronic phase within 6 months
before study entry, and must not have received
treatment for CML, except for hydroxyurea or ana-
grelide.
Patients were recruited from June 2000 through
January 2001 and were randomly assigned to re-
ceive imatinib at a dose of 400 mg orally per day
or subcutaneous interferon alfa at a daily tar-
get dose of 5 million U per square meter of body-
surface area, plus 10-day cycles of cytarabine at
a daily dose of 20 mg per square meter every
month. Patients receiving imatinib who did not
have a complete hematologic response within
6. 3 months or whose bone marrow contained more
than 65% Ph-positive cells at 12 months could
have a stepwise increase in the dose of imatinib
to 400 mg orally twice daily as long as there were
no dose-limiting adverse events. Patients were al-
lowed to cross over to the other treatment group
if they did not achieve either a complete hema-
tologic response after 6 months of therapy or a
major cytogenetic response after 12 months or if
they had a relapse or an increase in white-cell
count or could not tolerate treatment. All cross-
over requests were made anonymously and con-
sidered weekly by the study management com-
mittee (see the Appendix).
End Points
The primary end point was event-free survival,
which was referred to in previous presentations
and articles as the time to progression, or progres-
sion-free survival. Events were defined by the first
occurrence of any of the following: death from any
cause during treatment, progression to the acceler-
ated phase or blast crisis of CML, or loss of a com-
plete hematologic or major cytogenetic response.
Secondary end points were the rate of complete he-
matologic response (defined as a leukocyte count
<10×109 per liter, a platelet count of <450×109 per
liter, <5% myelocytes plus metamyelocytes, no
blasts or promyelocytes, no extramedullary involve-
ment, and no signs of the accelerated phase or
blast crisis of CML); a cytogenetic response in mar-
row cells, categorized as complete (no Ph-positive
metaphases), partial (1 to 35% Ph-positive meta-
phases), or major (complete plus partial responses)
on the basis of G-banding in at least 20 cells in
8. vartis, designed the study. Data-management and
statistical-support staff at a contract research or-
ganization collected the data, which were ana-
lyzed and interpreted by a biostatistician from No-
vartis in close collaboration with the investigators.
The study management committee and all aca-
demic investigators had access to the raw data. The
study management committee, composed of four
academic investigators, served as the writing com-
mittee. Along with the Novartis biostatistician,
they vouch for the accuracy and completeness of
the data.
Statistical Analysis
The study is ongoing, but January 31, 2006, was
the cutoff date for this analysis. This date marked
5 to 5.5 years after patients started to receive ima-
tinib treatment. We followed all 553 patients who
were assigned to receive imatinib for an analysis
of safety and efficacy until they stopped taking
imatinib, and we have continued to follow all pa-
tients until death, loss to follow-up, or withdraw-
al of consent. Survival data were also collected on
patients who underwent bone marrow transplan-
tation after imatinib treatment. We performed
analyses of survival and event-free survival, using
the Kaplan–Meier method according to the inten-
tion-to-treat principle and using all data available,
regardless of whether crossover occurred. Differ-
ences between subgroups of patients receiving
imatinib were calculated by the log-rank test. Cu-
mulative rates of complete hematologic and cyto-
genetic responses were estimated according to the
Kaplan–Meier method, in which data from patients
receiving imatinib who did not have an adequate
9. response, who had switched to interferon alfa plus
cytarabine, or who had discontinued treatment for
reasons other than progression of CML were cen-
sored at the last follow-up visit. For the estimation
of cumulative response rates, we censored data
from patients with progressive CML at maximum
follow-up. We used the life-table method to deter-
mine yearly event probabilities. The safety of ima-
tinib was analyzed for 551 patients who received
at least one dose of the study drug during the trial.
For the 553 patients assigned to receive interfer-
on alfa plus cytarabine, disposition and overall sur-
vival were summarized.
Table 1. Enrollment, Outcomes, and Reasons for Crossover
and Discon tinuation.*
Variable
Imatinib
(N = 553)
Interferon Alfa
plus Cytarabine
(N = 553)
no. of patients (%)
Assignment of patients
Continued first-line treatment 382 (69) 16 (3)
Discontinued first-line treatment 157 (28) 178 (32)
Crossed over to other treatment 14 (3) 359 (65)
10. Discontinued second-line treatment 14 (3) 108 (20)
Reason for crossover
Other than progression
Intolerance of treatment† 4 (<1) 144 (26)
No complete hematologic
response at 6 mo
0 41 (7)
No major cytogenetic response
at 12 mo
1 (<1) 49 (9)
Other 0 48 (9)
Progression only
Increase in white-cell count† 2 (<1) 25 (5)
Loss of complete hematologic
response
5 (<1) 29 (5)
Loss of major cytogenetic
response
2 (<1) 23 (4)
Reason for discontinuation‡
12. Im atinib a s Pr im a r y Ther a py for Chronic M y el oid Leuk
emi a
n engl j med 355;23 www.nejm.org december 7, 2006 2411
R e s u l t s
Patients
Five years after the last of 1106 patients had started
treatment, and with a median of 60 months of
follow-up, 382 of 553 patients (69%) in the ima-
tinib group and 16 of 553 patients (3%) in the
group given interferon alfa plus cytarabine con-
tinued with their initially assigned treatment (Ta-
ble 1). Of the patients given interferon plus cyta-
rabine, 359 (65%) had crossed over to imatinib,
whereas 14 patients (3%) in the imatinib group
had switched to the alternative treatment. The most
common reason for crossover among patients
given interferon plus cytarabine was intolerance
of treatment (26%). Of these patients, 90 (16%)
switched because they did not achieve a complete
hematologic or major cytogenetic response by the
designated target dates, as did 77 patients (14%)
with disease progression. An additional 178 pa-
tients (32%) given interferon alfa plus cytarabine
discontinued therapy. The reasons most common-
ly reported were withdrawal of consent (14%) and
adverse events (6%). In the imatinib group, 23 pa-
tients (4%) discontinued therapy owing to an ad-
verse event, and 25 patients (5%) withdrew con-
sent (Table 1).
Since few patients were still receiving inter-
13. feron alfa plus cytarabine at 60 months, the re-
mainder of this report focuses on the long-term
follow-up of patients who received imatinib as
the initial therapy for CML. They had been treated
with imatinib for a mean (±SD) of 50±19 months
(median, 60 months). Among the 382 patients
who continued receiving imatinib, the mean daily
dose during this reporting period was 382±50 mg.
In 82% of these patients, the last reported daily
dose was 400 mg; 6% were receiving 600 mg, 4%
were receiving 800 mg, and 8% were receiving
less than 400 mg.
Table 2. Proportion of Patients Receiving First-Line Imatinib
Therapy with Grade 3 or Grade 4 Adverse Events.
Hematologic or Hepatic Condition Grade 3 or Grade 4 Adverse
Events
Total Events
(N = 551)
Years 1 and 2
(N = 551)
Years 3 and 4
(N = 456)
After Year 4
(N = 409)
percent
Neutropenia 17 14 3* 1*
14. Thrombocytopenia 9 8 1* <1*
Anemia 4 3 1† <1‡
Elevated liver enzymes 5 5 <1* 0*
Other drug-related adverse event 17 14 4* 2*
* P<0.001 for the comparison of events in years 3 and 4 and
after 4 years with those in years 1 and 2.
† The difference between events in years 3 and 4 and those in
years 1 and 2 did not reach statistical significance.
‡ P<0.01 for the comparison of events after 4 years with those
in years 1 and 2.
22p3
R
at
es
o
f
R
es
p
o
n
se
(
18. reserved.
T h e n e w e n g l a n d j o u r n a l o f m e d i c i n e
n engl j med 355;23 www.nejm.org december 7, 20062412
Adverse Events
After a median follow-up of 60 months, the ad-
verse events reported were similar to those report-
ed previously.14 The most commonly reported ad-
verse events were edema (including peripheral and
periorbital edema) (60%), muscle cramps (49%),
diarrhea (45%), nausea (50%), musculoskeletal
pain (47%), rash and other skin problems (40%),
abdominal pain (37%), fatigue (39%), joint pain
(31%), and headache (37%). Grade 3 or 4 adverse
events consisted of neutropenia (17%), throm-
bocytopenia (9%), anemia (4%), elevated liver en-
zymes (5%), and other drug-related adverse events
(17%). Congestive heart failure was reported as
being drug-related in one patient (<1%). Newly oc-
curring or worsening grade 3 or 4 hematologic or
biochemical adverse events were infrequent after
both 2 and 4 years of therapy (Table 2).
Efficacy
Figure 1 shows the estimated cumulative rates
of complete hematologic remission: 96% at 12
months and 98% at 60 months. The best observed
rate of complete hematologic response was 97%.
At 12 months, the estimated rate of major cyto-
19. genic response was 85% and that of complete cy-
togenetic response was 69%. At 60 months, the
estimated rates were 92% and 87%, respectively.
With a median follow-up of 60 months, the best
observed rate of major cytogenetic response was
89%, and the best rate of complete cytogenetic
response was 82%. Of the 382 patients who still
received imatinib at 60 months, 368 (96%) had a
complete cytogenetic response.
There were significant differences in the rates
of cytogenetic response, according to a scoring
system devised by Sokal and colleagues,16 which
divides patients with CML into low-risk, interme-
diate-risk, and high-risk groups. In patients who
were deemed to be at low risk on the Sokal scor-
ing system, the rate of complete cytogenetic re-
sponse was 89%; the rate among patients at in-
termediate risk was 82%; and for those at high
risk, the rate was 69% (P<0.001).
Among 124 patients who had a complete cy-
togenetic response and whose blood samples tak-
en at 1 and 4 years were available, BCR-ABL tran-
scripts in the blood samples were measured. After
1 year, levels of BCR-ABL transcripts had fallen by
at least 3 log in 66 of 124 patients (53%); after
4 years, levels had fallen in 99 of 124 patients
(80%) (P<0.001). The proportion of patients with
a reduction of at least 4 log in transcript levels
increased from 22 to 41% between 1 and 4 years
(P<0.001). The median log reduction of BCR-ABL
transcripts was 3.08 at 1 year and 3.78 at 4 years
(P<0.001).
Long-term Outcomes
20. At 60 months, the estimated rate of event-free sur-
vival was 83% (95% confidence interval [CI], 79
to 87), and an estimated 93% of patients (95% CI,
90 to 96) had not progressed to the accelerated
phase or blast crisis (Fig. 2). Of the 553 patients
receiving imatinib, 35 (6%) progressed to the ac-
celerated phase or blast crisis, 14 (3%) had a he-
matologic relapse, 28 (5%) had a loss of major cy-
togenetic response, and 9 (2%) died from a cause
unrelated to CML. The estimated annual rate of
treatment failure after the start of imatinib ther-
apy was 3.3% in the first year, 7.5% in the second
year, 4.8% in the third year, 1.5% in the fourth
year, and 0.9% in the fifth year. The correspond-
ing annual rates of progression to the accelerated
phase or blast crisis were 1.5%, 2.8%, 1.6%, 0.9%,
and 0.6%, respectively. In the 454 patients who had
22p3
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Progression
All events
No. of Events
Progression
All events
No. at Risk
Progression
All events
8
18
513
505
22
55
461
447
29
76
24. 431
414
33
82
409
395
35
85
280
274
Figure 2. Kaplan–Meier Estimates of the Rates of Event-free
Survival
and Progression to the Accelerated Phase or Blast Crisis of
CML for Pa-
tients Receiving Imatinib.
At 60 months, the estimated rate of event-free survival was
83%. At that
time, 93% of the patients had not progressed to the accelerated
phase or
blast crisis. The following were considered events: death from
any cause
during treatment, progression to the accelerated phase or blast
crisis, loss
of a complete hematologic response, loss of a major cytogenetic
response,
or an increasing white-cell count. The number of patients with
events and
the number of patients available for analysis are shown.
26. for the 73 patients who did not have a major cy-
togenetic response within 12 months, the esti-
mate was 81% (95% CI, 70 to 92) (overall, P<0.001;
P<0.001 for the comparison between patients with
a complete response and those without a com-
plete response, and P = 0.20 for the comparison
between patients with a complete response and
those with a partial response) (Fig. 3A).
At 60 months, the estimated risk of disease
progression was significantly higher for the high-
risk group of patients, according to the Sokal
scoring system (P = 0.002); the estimated rates for
patients in the high-risk, intermediate-risk, and
low-risk groups were 17%, 8%, and 3%, respec-
tively. However, the Sokal score was not associ-
ated with disease progression in patients who had
a complete cytogenetic response (95%, 95%, and
99% in the high-risk, intermediate-risk, and low-
risk groups, respectively) (P = 0.20 overall; P = 0.92
for the comparison between the intermediate-risk
group and the high-risk group, and P = 0.16 for the
comparison between the low-risk group and the
high-risk group).
The molecular responses at 12 and 18 months
were also associated with long-term outcomes. At
60 months, the patients who had a complete cyto-
genetic response and a reduction of at least 3 log
in levels of BCR-ABL transcripts in bone marrow
cells after 18 months of treatment had an esti-
mated rate of survival without progression of CML
of 100%. In the group with a reduction of less
22p3
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31. 40
30
10
50
20
0
0 12 24 36 48 60 72
Months
100
Complete cytogenetic response
with ≥3 log reduction
Complete cytogenetic response
with <3 log reduction
No complete cytogenetic response
A
B
Complete cytogenetic response
Partial cytogenetic response
No major cytogenetic response
Response at 12 Mo
32. Response at 18 Mo
Figure 3. Rate of Progression to the Accelerated Phase or Blast
Crisis
on the Basis of Cytogenetic Response after 12 Months or
Molecular
Response after 18 Months of Imatinib Therapy.
Panel A shows that at 60 months, of the 350 patients with a
complete cyto-
genetic response after 12 months of imatinib therapy, an
estimated 97%
had not progressed to the accelerated phase or blast crisis. The
corre-
sponding rates for 86 patients with a partial cytogenetic
response and for
73 patients who did not have a major cytogenetic response were
93% and
81%, respectively (P<0.001; P = 0.20 for the comparison
between patients
with a complete cytogenetic response and those with a partial
response).
At 12 months, 44 patients had discontinued imatinib and thus
were not
included in this analysis. Panel B shows that at 60 months, of
the 139 pa-
tients with a complete cytogenetic response and a reduction in
levels of
BCR-ABL transcripts of at least 3 log, 100% were free from
progression to
the accelerated phase or blast crisis. The corresponding rate for
54 patients
with a complete cytogenetic response and a reduction in levels
of BCR-ABL
transcripts of less than 3 log was 98%; the rate for 88 patients
without a
34. patients had switched to interferon alfa plus cy-
tarabine. The estimated overall survival rate at 60
months was 89% (95% CI, 86 to 92) (Fig. 4). Allo-
geneic hematopoietic stem-cell transplantation
was carried out in 44 patients who discontinued
imatinib: 11 had progressed to the accelerated
phase or blast crisis, 15 had had a hematologic or
cytogenetic relapse, and 18 had stopped therapy
for other reasons (including safety and withdrawal
of consent). Of the 44 patients who underwent
transplantation, 14 (32%) died. At 60 months, with
data censored at the time of transplantation, the
estimated overall survival rate was 92% (95% CI,
89 to 95). After data were censored for patients
who had died from causes unrelated to CML or
transplantation, the overall estimated survival rate
was 95% (95% CI, 93 to 98) at 60 months (Fig. 4).
D i s c u s s i o n
The initial analysis of this study, performed at a
median follow-up of 19 months, showed a high
rate of response and an acceptable rate of side ef-
fects of imatinib as initial therapy for newly diag-
nosed chronic-phase CML.14 The present analysis,
with a median follow-up of 60 months, showed
an estimated relapse rate of 17% at 60 months, and
an estimated 7% of all patients progressed to the
accelerated phase or blast crisis. The 5-year esti-
mated overall survival rate for patients who re-
ceived imatinib as initial therapy (89%) is higher
than that reported in any previously published pro-
spective study of the treatment of CML.17
This trial allowed patients to cross over to the
35. alternate treatment, and most patients in the in-
terferon group either switched to imatinib or dis-
continued interferon. On the basis of an inten-
tion-to-treat analysis, there was no significant
difference in overall survival between the group
of patients who began their treatment with inter-
feron and those who began their treatment with
imatinib (data not shown). Previous randomized
studies of interferon alfa plus cytarabine, per-
formed before the availability of imatinib, showed
a 5-year overall survival of 68 to 70%.12,13 With the
use of historical comparisons, a survival advan-
tage for initial therapy with imatinib over inter-
feron alfa can be demonstrated.18
In a landmark analysis, 97% of patients with
a complete cytogenetic response within 12 months
after starting imatinib did not progress to the ac-
celerated phase or blast crisis by 60 months. No-
tably, patients who were deemed to be at high risk
on the basis of Sokal scores had a lower rate of
complete cytogenetic response (69%) than did pa-
tients who were at low risk or intermediate risk
(89% and 82%, respectively). However, the risk of
relapse in patients who had a cytogenetic response
was not associated with the Sokal score. With
interferon treatment, by contrast, the Sokal score
was important even among patients with a com-
plete cytogenetic response.19
Remarkably, no patient who had a complete
cytogenetic response and a reduction in levels of
BCR-ABL transcripts of at least 3 log at 12 or 18
months after starting imatinib had progression
22p3
37. 0
0 12 24 36 48 60 72
Months
100
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38. REG F
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2nd
3rd
Druker
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CML-related deaths
All deaths
No. of Deaths
Related to CML
All deaths
No. at Risk
Related to CML
All deaths
3
6
536
542
39. 11
22
498
518
16
41
474
492
19
52
450
475
23
57
322
333
Figure 4. Overall Survival among Patients Treated with Imatinib
Based
on an Intention-to-Treat Analysis.
The estimated overall survival rate at 60 months was 89%. After
the cen-
soring of data for patients who died from causes unrelated to
CML or trans-
plantation, the estimated overall survival was 95% at 60
months. At the
time of analysis, 57 patients had died. The number of patients
with events
41. kinase.27
Initial studies of two new inhibitors of the
BCR-ABL kinase that are more potent than ima-
tinib — dasatinib and nilotinib — showed high
response rates in patients who had had a relapse
during imatinib therapy.28,29 Despite their poten-
cy, these inhibitors cannot eradicate all CML cells
in vitro.30 As was the case in patients in our study,
it is assumed that in patients receiving these drugs
a durable response can be achieved even without
disease eradication if there is a reduction in lev-
els of BCR-ABL transcripts of at least 3 log.
Notably, the rate of disease progression in pa-
tients in our study is apparently trending down-
ward, although the trend has not reached statis-
tical significance. If it persists, such a trend would
be consistent with the findings that mutations
in the BCR-ABL gene are the major cause of relapse
in patients treated with imatinib.31 If we presume
that mutations precede imatinib therapy (as the
data suggest),32,33 the emergence of resistance to
the drug would depend on the size of the mutant
clone at the start of therapy and its doubling
time. Since most mutated and unmutated BCR-
ABL clones have similar doubling times,34 a pa-
tient with a mutant clone should be at highest risk
for relapse during the first several years of thera-
py. This prediction is in line with the apparent
downward trend in the risk of disease progres-
sion observed in our study.
Dr. Druker’s institution is the site of clinical trials sponsored
by Novartis, but neither he nor his laboratory reports receiving
42. funds from Novartis. Dr. Guilhot reports receiving consulting
and lecture fees from Novartis; Dr. O’Brien, consulting fees
from
Novartis and Bristol-Myers Squibb and lecture fees from Novar-
tis; Ms. Gathmann, being an employee of and having equity
ownership in Novartis; Dr. Kantarjian, consulting fees from No-
vartis, Bristol-Myers Squibb, and MGI Pharma; Dr. Gattermann,
consulting and lecture fees from Novartis and Pharmion; Dr.
Deininger, consulting and lecture fees from Novartis and Bris-
tol-Myers Squibb; Dr. Silver, consulting fees from Novartis; Dr.
Goldman, lecture fees from Novartis; Dr. Stone, consulting and
lecture fees and grant support from Novartis and Bristol-Myers
Squibb; Dr. Cervantes, consulting fees from Novartis and lec-
ture fees from Novartis and Bristol-Myers Squibb; Dr.
Hochhaus,
consulting and lecture fees from Novartis and Bristol-Myers
Squibb; Dr. Powell, lecture fees from Pharmion; Dr. Gabrilove,
consulting fees from Novartis; Dr. Rousselot, lecture fees from
Novartis Oncology; Dr. Cornelissen, consulting fees from
Novar-
tis Oncology; Dr. Hughes, consulting and lecture fees from No-
vartis; Dr. Fischer, consulting fees from LymphoSign and
Novar-
tis and lecture fees from Novartis; Dr. Saglio, consulting and
lecture fees from Novartis; Dr. Gratwohl, consulting fees from
Novartis, Pfizer, and Amgen and lecture fees from Novartis; Dr.
Radich, consulting fees from Novartis and Bristol-Myers Squibb
and lecture fees from Novartis; Dr. Simonsson, consulting fees
from Novartis and Bristol-Myers Squibb; Dr. Taylor, consulting
fees from Amgen, Novartis, Bristol-Myers Squibb, and Celgene
and lecture fees from Novartis; Dr. Baccarani, consulting fees
from Novartis, Bristol-Myers Squibb, Merck, and Pfizer and
lecture fees from Novartis, Bristol-Myers Squibb, Schering, and
Pfizer; Dr. So, being an employee of Novartis and having equity
ownership in Novartis and Pfizer; Dr. Letvak, being an
employee
43. of and having equity ownership in Novartis; and Dr. Larson,
consulting and lecture fees from Novartis. No other potential
conflict of interest relevant to this article was reported.
We thank the coinvestigators; the members of the medical,
nursing, and research staff at the trial centers; the clinical trial
monitors and the data managers and programmers at Novartis
for their contributions; and Tillman Krahnke and Manisha
Mone for their invaluable collaboration.
Appendix
From the Oregon Health and Science University Cancer
Institute, Portland (B.J.D.); Centre Hospitalier Universitaire,
Poitiers, France
(F.G.); University of Newcastle, Newcastle, United Kingdom
(S.G.O.); Novartis, Basel, Switzerland (I.G.); M.D. Anderson
Cancer Center,
Houston (H.K.); Heinrich Heine University, Dusseldorf,
Germany (N.G.); Universität Leipzig, Leipzig, Germany
(M.W.N.D.); Weill–Cor-
nell Medical Center, New York (R.T.S.); National Heart, Lung,
and Blood Institute, Bethesda, MD (J.M.G.); Dana–Farber
Cancer Institute,
Boston (R.M.S.); Hospital Clinic I Provincial, Barcelona (F.C.);
University of Heidelberg, Mannheim, Germany (A.H.); Wake
Forest Uni-
versity Baptist Medical Center, Winston-Salem, NC (B.L.P.);
Mount Sinai School of Medicine, New York (J.L.G.); Hôpital
Saint Louis,
Paris (P.R.); Centre Hospitalier Universitaire de Bordeaux,
Pessac, France (J.R.); Erasmus Medical Center, Rotterdam, the
Netherlands
(J.J.C.); Royal Adelaide Hospital, Adelaide, Australia (T.H.);
Universitätsklinik für Innere Medizin I, Vienna (H.A.);
Johannes Gutenberg
Universität, Mainz, Germany (T.F.); University Hospital
45. Sydney: D. Joshua. Belgium — A.Z. Sint-Jan, Brugge: A.
Louwagie; Institut Jules Bordet,
Brussels: P. Martiat; Cliniques Universitaires, Yvoir: A. Bosly.
Canada — McGill University, Montreal: C. Shustik; Princess
Margaret Hospital, Toronto:
J. Lipton; Queen Elizabeth II Health Sciences Centre, Halifax,
NS: D. Forrest; McMaster University Medical Centre, West
Hamilton, ON: I. Walker; Uni-
versité de Montréal, Montreal: D.-C. Roy; CancerCare
Manitoba, Winnipeg: M. Rubinger; Ottawa Hospital Regional
Cancer Centre, Ottawa: I. Bence-
Bruckler; University of Calgary and Tom Baker Cancer Centre,
Calgary, AB: D. Stewart; London Regional Cancer Centre,
London, ON: M. Kovacs; Cross
Cancer Center, Edmonton, AB: A.R. Turner. Denmark —
Kobenhavns Amts Sygehus i Gentofte, Hellerup: H. Birgens;
Danish University of Pharmaceuti-
cal Sciences and University of Southern Denmark, Copenhagen:
O. Bjerrum. France — Hôpital Claude Huriez, Lille: T. Facon;
Hôtel Dieu Hospital, Nantes:
J.-L. Harousseau; Henri Mondor Hospital, Creteil: M. Tulliez;
Centre Hospitalier Universitaire (CHU) Brabois, Vandoeuvre-
les-Nancy: A. Guerci; Insti-
tut Paoli-Calmettes, Marseille: D. Blaise; Hopital Civil,
Strasbourg: F. Maloisel; CHU la Milétrie, Poitiers: M.
Michallet. Germany — University of
Regensburg, Regensburg: R. Andreesen; Krankenhaus
Muenchen Schwabing, Munich: C. Nerl; Universitätsklinikum
Rostock, Rostock: M. Freund;
Heinrich Heine University, Düsseldorf: N. Gattermann; Carl-
Gustav Carus Universität, Dresden: G. Ehninger; Leipzig
University Hospital, Leipzig: M.
Deininger; Medizinische Klinik III, Frankfurt: O. Ottmann;
Clinical Center Rechts der Isar, Munich: C. Peschel; University
of Heidelberg, Heidelberg: S.
Fruehauf; Philipps-Universität Marburg, Baldingerstraße,
46. Marburg: A. Neubauer; Humboldt Universität, Berlin: P. Le
Coutre; Robert Bosch Hospital,
Stuttgart: W. Aulitzky. Italy — University Hospital, Udine: R.
Fanin; San Orsola Hospital, Bologna: G. Rosti; Università La
Sapienza, Rome: F.
Mandelli; Istituto di Ricovero e Cura a Carattere Scientifico
(IRCCS) Policlinico San Matteo, Pavia: M. Lazzarino; Niguarda
Ca’ Granda Hospital, Milan:
E. Morra; Azienda Ospedaliera e Cliniche Universitarie San
Martino, Largo R Benzi, Genoa: A. Carella; University of Pisa,
Pisa: M. Petrini; Azienda Os-
pedaliera Bianchi-Malacrino-Morelli, Reggio Calabria: F.
Nobile; University of Bari, Policlinico, Bari: V. Liso; Cardarelli
Hospital, Naples: F. Ferrara;
University of Parma, Parma: V. Rizzoli; Ospedale Civile,
Pescara: G. Fioritoni; Institute of Hematology and Medical
Oncology Seragnoli, Bologna: G.
Martinelli; Università degli Studi di Firenze, Florence: V.
Santini. the Netherlands — Vrije Universiteit Academic
Medical Center, Amsterdam: G. Os-
senkoppele. New Zealand — University of Auckland, Auckland:
P. Browett. Norway — Medisinsk Avdeling, Rikshospitalet,
Oslo: T. Gedde-Dahl;
Ullevål Sykehus, Oslo: J.-M. Tangen; Hvidovre Hospital,
Betalende: I. Dahl. Spain — Hospital Clinic, Villarroel,
Barcelona: J. Odriozola; University of
Barcelona, Barcelona: J.C. Hernández Boluda; Hospital
Universitario de la Princesa, Madrid: J.L. Steegman; Hospital
Universitario de Salamanca,
Salamanca: C. Cañizo; San Carlos Clinical Hospital, Madrid: J.
Diaz; Institut Català d’Oncología, Barcelona: A. Granena;
Hospital Lluis Alcanyis, Cta
Xativa-Silla: M.N. Fernández. Sweden — Karolinska Hospital,
Stockholm: L. Stenke; Huddinge Sjukhus, Huddinge: C. Paul;
Medicinkliniken Uni-
versitetssjukhuset, Örebro: M. Bjoreman; Regionsjukhuset,
47. Linköping: C. Malm; Sahlgrenska Hospital, Göteborg: H.
Wadenvik; Endokrinsekt/Medklin
Universitetssjukhuset, Lund: P.-G. Nilsson;
Universitetssjukhuset Malmo University Hospital, Malmo: I.
Turesson. Switzerland — Kantonsspital, St.
Gallen: U. Hess; University of Bern, Bern: M. Solenthaler.
United Kingdom — University of Nottingham and Nottingham
City Hospital, Nottingham:
N. Russell; Kings College, London: G. Mufti; St. George’s
Hospital, Medical School, London: J. Cavenagh; Royal
Liverpool University Hospital, Liverpool:
R.E. Clark; Cambridge Institute for Medical Research,
Cambridge: A.R. Green; Glasgow Royal Infirmary, Glasgow:
T.L. Holyoake; Manchester Royal
Infirmary, Manchester: G.S. Lucas; Leeds General Infirmary,
Leeds: G. Smith; Queen Elizabeth Hospital, Edgbaston,
Birmingham: D.W. Milligan; Der-
riford Hospital, Plymouth: S.J. Rule; University Hospital of
Wales, Cardiff: A.K. Burnett; United States — Walt Disney
Memorial Cancer Institute, Or-
lando, FL: R. Moroose; Roswell Park Cancer Center, Buffalo,
NY: M. Wetzler; Gibbs Cancer Center, Spartanburg, SC: J.
Bearden; Ohio State University
School of Medicine, Columbus: S. Cataland; University of New
Mexico Health Sciences Center, Albuquerque: I. Rabinowitz;
University of Maryland Cancer
Center, Baltimore: B. Meisenberg; Montgomery Cancer Center,
Montgomery, AL: K. Thompson; State University of New York
Upstate Medical Center,
Syracuse: S. Graziano; University of Alabama at Birmingham,
Birmingham: P. Emanuel; Hematology and Oncology, Inc.,
Dayton, OH: H. Gross;
Billings Oncology Associates, Billings, MT: P. Cobb; City of
Hope National Medical Center, Duarte, CA: R. Bhatia; Cancer
Center of Kansas, Wichita: S.
Dakhil; Alta Bates Comprehensive Cancer Center, Berkeley,
48. CA: D. Irwin; Cancer Research Center of Hawaii, Honolulu: B.
Issell; University of Nebraska
Medical Center, Omaha: S. Pavletic; Columbus Community
Clinical Oncology Program, Columbus, OH: P. Kuebler;
Michigan State University Hematol-
ogy/Oncology, Lansing: E. Layhe; Brown University School of
Medicine, Providence, RI: P. Butera; Loyola University Medical
Center, Shreveport, LA: J.
Glass; Duke University Medical Center, Durham, NC: J. Moore;
University of Vermont, Burlington: B. Grant; University of
Tennessee, Memphis: H. Niell;
University of Louisville Hospital, Louisville, KY: R. Herzig;
Sarah Cannon Cancer Center, Nashville: H. Burris; University
of Minnesota, Minneapolis: B.
Peterson; Cleveland Clinic Foundation, Cleveland: M. Kalaycio;
Fred Hutchinson Cancer Research Center, Seattle: D. Stirewalt;
University of Utah, Salt
Lake City: W. Samlowski; Memorial Sloan-Kettering Cancer
Center, New York: E. Berman; University of North Carolina
School of Medicine, Charlotte: S.
Limentani; Atlanta Cancer Center, Atlanta: T. Seay; University
of North Carolina School of Medicine, Chapel Hill: T. Shea;
Indiana Blood and Marrow
Institute, Beech Grove: L. Akard; San Juan Regional Cancer
Center, Farmington, NM: G. Smith; University of Massachusetts
Memorial Medical Center,
Worcester: P. Becker; Washington University School of
Medicine, St. Louis: S. Devine; Veterans Affairs Medical
Center, Milwaukee: R. Hart; Louisiana
State University Medical Center, New Orleans: R. Veith;
Decatur Memorial Hospital, Decatur, IL: J. Wade; Rocky
Mountain Cancer Centers, Denver: M.
Brunvand; Oncology-Hematology Group of South Florida,
Miami: L. Kalman; Memphis Cancer Center, Memphis, TN: D.
Strickland; Henry Ford Hospi-
tal, Detroit: M. Shurafa; University of California, San Diego,
49. Medical Center, La Jolla: A. Bashey; Western Pennsylvania
Cancer Institute, Pittsburgh: R.
Shadduck; Tulane Cancer Center, New Orleans: H. Safah;
Southbay Oncology Hematology Partners, Campbell, CA: M.
Rubenstein; University of Texas
Southwest Medical Center, Dallas: R. Collins; Cancer Care
Associates, Tulsa, OK: A. Keller; Robert H. Lurie
Comprehensive Cancer Center, Chicago: M.
Tallman; Northern New Jersey Cancer Center, Hackensack: A.
Pecora; University of Pittsburgh Medical Center, Hillman
Cancer Center, Pittsburgh: M. Agha;
Texas Oncology, Dallas: H. Holmes; and New Mexico Oncology
Hematology Consultants, Albuquerque: R. Guidice. Study
Management Committee:
Oregon Health and Science University Cancer Institute
Research and Patient Care, Portland: B.J. Druker; University
Hospital, Poitier, France: F. Guilhot;
University of Chicago, Chicago: R.A. Larson; University of
Newcastle upon Tyne, Newcastle upon Tyne, UK: S.G. O’Brien.
Independent Data Monitor-
ing Board: Rambam Medical Center, Haifa, Israel: J. Rowe;
Wayne State University, Barbara Ann Karmanos Cancer
Institute, Detroit: C.A. Schiffer;
International Drug Development Institute, Brussels: M. Buyse.
Protocol Working Group: Policlinico San Orsola–Malpighi,
Bologna, Italy: M. Bacca-
rani; Hospital Clinic, Barcelona: F. Cervantes; Erasmus Medical
Center, Rotterdam, the Netherlands: J. Cornelissen; Johannes
Gutenberg Universität,
Mainz, Germany: T. Fischer; Universität Heidelberg,
Mannheim, Germany: A. Hochhaus; Hanson Institute Centre for
Cancer, Adelaide, Australia: T.
Hughes; Medical University of Vienna, Vienna: K. Lechner;
Aarhus Amtssygehus, Aarhus, Denmark: J.L. Nielsen; CHU de
Bordeaux, Pessac, France: J.
Reiffers; Hôpital Saint Louis, Paris: P. Rousselot; San Luigi
51. Klein A, Grosveld G. Structural organiza-
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4. Konopka JB, Watanabe SM, Witte ON.
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5. Shtivelman E, Lifshitz B, Gale RP, Ca-
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6. Druker BJ, Tamura S, Buchdunger E,
et al. Effects of a selective inhibitor of the
ABL tyrosine kinase on the growth of Bcr-
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7. Druker BJ, Sawyers CL, Kantarjian H,
et al. Activity of a specific inhibitor of the
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8. Druker BJ, Talpaz M, Resta DJ, et al.
Efficacy and safety of a specific inhibitor
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9. Kantarjian H, Sawyers C, Hochhaus A,
et al. Hematologic and cytogenetic re-
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10. Sawyers CL, Hochhaus A, Feldman E,
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13. Guilhot F, Chastang C, Michallet M,
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14. O’Brien SG, Guilhot F, Larson RA, et
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15. Hughes TP, Kaeda J, Branford S, et al.
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19. Bonifazi F, de Vivo A, Rosti G, et al.
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20. Rousselot P, Huguet F, Rea D, et al.
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21. Breccia M, Diverio D, Pane F, et al.
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in long lasting complete cytogenetic re-
mission (CCR) induced by interferon. Leuk
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22. Mauro MJ, Druker BJ, Maziarz RT. Di-
vergent clinical outcome in two CML pa-
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54. 23. Merante S, Orlandi E, Bernasconi P,
Calatroni S, Boni M, Lazzarino M. Out-
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24. Cortes J, O’Brien S, Kantarjian H. Dis-
continuation of imatinib therapy after
achieving a molecular response. Blood
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25. Thomas J, Wang L, Clark RE, Pirmo-
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26. Chu S, Xu H, Shah NP, et al. Detection
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29. Kantarjian H, Giles F, Wunderle L, et
al. Nilotinib in imatinib-resistant CML
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30. Copland M, Hamilton A, Elrick LJ, et
56. 6) KEEP RESPONSE WITH ANSWER EACH ANSWER NEED
TO HAVE A SCHOLARY SOURCE with a Hyperlink
Make sure the Responses includes the Following: (a) an
understanding of the weekly content as supported by a scholarly
resource, (b) the provision of a probing question. (c) stay on
topic
1. A categorical approach is an approach that classifies mental
disorders through assessment. Whether an individual may have
the disorder based on symptoms and characteristics, in which
can be described as typical type of disorder. The categorical
approach is classified in two strategies ICD and DSM. ICD
identifies symptoms, that indicate the presence of a disorder.
The DSM names the disorder and defines them in specific terms
(Potuzak et a.l, 2012).
A dimensional approach is an approach that classifies mental
disorders that measures a person’s symptoms. Many other
characteristics of interest are represented with numerical values,
that are measured on one or more scales or continuums and are
not just assigned to a mental disorder category. The dimensional
approach provides detailed information for each symptom, with
a significant number of factors that are taken in to account. I
think this approach is best to classify disorders symptoms are
actually measured. The categorical approach, I think can lead to
misdiagnoses. The reason being is just because symptoms are
displayed does not mean someone has a personality disorder,
there should be more measured research to show what the true
issues are (Comer, 2018) .
2. Both the DSM-5 and the DSM (IV-TR), were created in order
for clinicians to classify and diagnose disorders within an
individual. The DSM(IV-TR) was described as a multiaxial
approach, intended to assist with comprehensive evaluations of
a client’s overall level of functioning (Whitbourne, 2013). This
version derived disorder using five different dimensions, as the
idea was mental illness often can impact one across many
different life areas. The newer DSM-5 essentially eliminated
57. what was considered a cumbersome five axis diagnostic system;
this included rating each client according to criteria other than
their primary disorder (Whitbourne, 2013). Another positive for
DSM-5 is that it reorganized and eliminated some disorders that
no longer made sense,
Personally, I support he categorical approach as there are more
buckets and ways to look at metal illness across all areas of life.
I also think that it is the best in classifying personality
disorders is the SDM-IV-TR approach. This approach looks at
personality disorders in how an individual relates to the world,
including antisocial and histrionic personality disorders
(Whitbourne, 2013).
3. The dimensional approach of Diagnostic and Statistical
Manual of Mental Disorders (DSM) is better because it gives
the severity of personality traits rather than the presence or
absence of specific traits. People with a personality disorder are
those who display extreme degrees of problematic traits. DSM-5
overlap so much that clinicians often find it difficult to
distinguish one disorder from another, resulting in frequent
disagreements about which diagnosis is correct for a person
with a personality disorder (Comer, 2018). The categorical
model assumes each personality disorder is a separate and
distinct category. For example, separate from other personality
disorders, and distinct from "normal" personalities. The
categorical approach assumes a lot can be wrong or not wrong
with someone, which is why the dimensional approach makes it
more clear. Lets say you have a dog, that dog is a husky, which
is a type of wolf. To further explore the history of this dog, one
has to look into it's traits to see why we have categorized it as a
wolf breed. This is just like the dimensional approach to a
disorder, to see what other reasons someone is or isn't paranoid,
antisocial or has obsessive- compulsive (OCD).
4. Autism spectrum disorder (ASD) is classified as a spectrum
disorder because there is a wide variation of how the disorder
affects people (Comer, 2018) Autism spectrum disorder is a
58. very hot topic of debate for many individuals and each one has
a differ in opinion on what causes the disorder. However, it is
not really known what causes autism spectrum disorder it is said
that it could be because of genetic factors or even
environmental factors. The symptoms of autism can vary
depending on the individual. I have a nephew who has autism
spectrum disorder and the symptoms that he has are difficulties
being in large rooms of people he doesn’t know, sound
aversions, texture aversions, repetitive aversions, repetitive
behavior, and restricted interests. Trying to find solutions to
make an individual who has autism spectrum disorder life easier
can vary as well. My nephew goes to behavior therapy to help
him learn how to communicate with those around him, and new
people.
5. Autism Spectrum Disorder can present in a variety of
degrees. The most common features are extreme aloofness,
inability to share attention with others, lack of interest in other
people, low empathy levels, poor language skills or failure to
speak, and rigid behaviors, activities, and interests (Comer,
2018). Recent biological and psychological studies point to
cognitive limitations and brain abnormalities as the primary
causes (Comer, 2018). Boys are much more likely than girls to
have ADS and if one sibling has it the chances are around 20%
for other siblings to develop ASD. Cognitive-behavioral
therapy, communication training, and parent training are some
of the treatments for ASD (Comer, 2018). Unfortunately, these
treatments are mostly geared toward skill development because
ADS is generally a life-long condition.
6. Autism spectrum disorder (ASD) is when a child shows signs
of being unresponsive and has trouble communicating with
others. “These symptoms appear early in life, typically around 3
years of age (Comer, 2018).” The symptoms for this disorder
can be different for every child. Some children show symptoms
of being unresponsive in social situations. These children may
59. lack interest in certain activities and can be hard for them to
give attention to others. “Many people with the disorder have
great difficulty understanding speech or using language for
conversational purposes (Comer, 2018).”
“More recent work in the psychological and biological spheres
has persuaded clinical theorists that cognitive limitations and
brain abnormalities are the primary causes of the disorder
(Comer, 2018).” Theorists look toward these two causes for this
disorder because they explain more about the causes of this
disorder. The psychological cause for this disorder focuses more
on the brain and the way the child is thinking. Most children
develop a way of thinking and reading other people, but
children with ASD have a harder time doing this. The biological
cause focuses more on the genetic standpoint and birth
complications. If a child is born with a certain abnormality
within the brain, this can lead to this disorder.
Some treatments for this disorder would be cognitive-behavioral
therapy, communication training, parent training, and
community integration. These treatments aim to help the child
and the family understand this disorder and learn how to
function everyday. Every treatment focuses on the child and
helps them feel like everybody else and not left out.
Review article
The molecular biology of chronic myeloid leukemia
Michael W. N. Deininger, John M. Goldman, and Junia V. Melo
Chronic myeloid leukemia (CML) is probably the most
extensively
studied human malignancy. The discovery of the Philadelphia
(Ph)
chromosome in 19601 as the first consistent chromosomal
abnormal-
60. ity associated with a specific type of leukemia was a
breakthrough
in cancer biology. It took 13 years before it was appreciated
that the
Ph chromosome is the result of a t(9;22) reciprocal
chromosomal
translocation2 and another 10 years before the translocation was
shown to involve theABL proto-oncogene normally on chromo-
some 93 and a previously unknown gene on chromosome 22,
later
termedBCR for breakpoint cluster region.4 The deregulated Abl
tyrosine kinase activity was then defined as the pathogenetic
principle,5 and the first animal models were developed.6 The
end of
the millennium sees all this knowledge transferred from the
bench
to the bedside with the arrival of Abl-specific tyrosine kinase
inhibitors that selectively inhibit the growth ofBCR-ABL–
positive
cells in vitro7,8 and in vivo.9
In this review we will try to summarize what is currently known
about the molecular biology of CML. Because several aspects of
CML pathogenesis may be attributable to the altered function of
the
2 genes involved in the Ph translocation, we will also address
the
physiological roles ofBCRandABL. We concede that a review of
this nature can never be totally comprehensive without losing
clarity, and we therefore apologize to any authors whose work
we
have not cited.
The physiologic function
of the translocation partners
61. The ABL gene is the human homologue of the v-abl oncogene
carried by the Abelson murine leukemia virus (A-MuLV),10 and
it
encodes a nonreceptor tyrosine kinase.11 Human Abl is a
ubiqui-
tously expressed 145-kd protein with 2 isoforms arising from
alternative splicing of the first exon.11 Several structural
domains
can be defined within the protein (Figure 1). Three SRC
homology
domains (SH1-SH3) are located toward the NH2 terminus. The
SH1 domain carries the tyrosine kinase function, whereas the
SH2
and SH3 domains allow for interaction with other proteins.12
Proline-rich sequences in the center of the molecule can, in
turn,
interact with SH3 domains of other proteins, such as Crk.13
Toward
the 39 end, nuclear localization signals14 and the DNA-
binding15
and actin-binding motifs16 are found.
Several fairly diverse functions have been attributed to Abl, and
the emerging picture is complex. Thus, the normal Abl protein
is
involved in the regulation of the cell cycle,17,18 in the cellular
response to genotoxic stress,19 and in the transmission of
informa-
tion about the cellular environment through integrin
signaling.20
(For a comprehensive review of Abl function, see Van Etten21).
Overall, it appears that the Abl protein serves a complex role as
62. a
cellular module that integrates signals from various
extracellular
and intracellular sources and that influences decisions in regard
to
cell cycle and apoptosis. It must be stressed, however, that
many of
the data are based solely on in vitro studies in fibroblasts, not
hematopoietic cells, and are still controversial. Unfortunately,
the
generation ofABL knockout mice failed to resolve most of the
outstanding issues.22,23
The 160-kd Bcr protein, like Abl, is ubiquitously expressed.11
Several structural motifs can be delineated (Figure 2). The first
N-terminal exon encodes a serine–threonine kinase. The only
substrates of this kinase identified so far are Bap-1, a member
of the
14-3-3 family of proteins,24 and possibly Bcr itself.11 A
coiled–coil
domain at the N-terminus of Bcr allows dimer formation in
vivo.25
The center of the molecule contains a region withdbl-like and
pleckstrin-homology (PH) domains that stimulate the exchange
of
guanidine triphosphate (GTP) for guanidine diphosphate (GDP)
on
Rho guanidine exchange factors,26 which in turn may activate
transcription factors such as NF-kB.27 The C-terminus has
GTPase
activity for Rac,28 a small GTPase of the Ras superfamily that
regulates actin polymerization and the activity of an NADPH
oxidase in phagocytic cells.29 In addition, Bcr can be
phosphory-
63. lated on several tyrosine residues,30 especially tyrosine 177,
which
binds Grb-2, an important adapter molecule involved in the
activation of the Ras pathway.31 Interestingly, Abl has been
shown
to phosphorylate Bcr in COS1 cells, resulting in a reduction of
Bcr
kinase activity.31,32 Although these data argue for a role of Bcr
in
signal transduction, their true biologic relevance remains to be
determined. The fact thatBCR knockout mice are viable and the
fact that an increased oxidative burst in neutrophils is thus far
the
only recognized defect33 probably reflect the redundancy of
signaling pathways. If there is a role for Bcr in the pathogenesis
of
Ph-positive leukemias, it is not clearly discernible because the
incidence and biology of P190BCR-ABL-induced leukemia are
the
same inBCR2/2 mice as they are in wild-type mice.34
Molecular anatomy
of the BCR-ABL translocation
The breakpoints within theABL gene at 9q34 can occur
anywhere
over a large (greater than 300 kb) area at its 59 end, either
upstream
From the Department of Hematology/Oncology, University of
Leipzig,
Germany; and the Department of Haematology, Imperial
College School of
Medicine, Hammersmith Hospital, London, United Kingdom.
Submitted November 16, 1999; accepted July 12, 2000.
65. of the first alternative exon Ib, downstream of the second
alterna-
tive exon Ia, or, more frequently, between the two35 (Figure 3).
Regardless of the exact location of the breakpoint, splicing of
the
primary hybrid transcript yields an mRNA molecule in
whichBCR
sequences are fused toABL exon a2. In contrast toABL, break-
points within BCR localize to 1 of 3 so-called breakpoint
cluster
regions (bcr). In most patients with CML and in approximately
one
third of patients with Ph-positive acute lymphoblastic leukemia
(ALL), the break occurs within a 5.8-kb area
spanningBCRexons
12-16 (originally referred to as exons b1-b5), defined as the
major
breakpoint cluster region (M-bcr). Because of alternative
splicing,
fusion transcripts with either b2a2 or b3a2 junctions can be
formed.
A 210-kd chimeric protein (P210BCR-ABL) is derived from this
mRNA. In the remaining patients with ALL and rarely in
patients
with CML, characterized clinically by prominent
monocytosis,36,37
the breakpoints are further upstream in the 54.4-kb region
between
the alternativeBCRexons e29 and e2, termed the minor
breakpoint
cluster region (m-bcr). The resultant e1a2 mRNA is translated
into
a 190-kd protein (P190BCR-ABL). Recently, a third breakpoint
cluster
region (m-bcr) was identified downstream of exon 19, giving
66. rise to
a 230-kd fusion protein (P230BCR-ABL) associated with the
rare
Ph-positive chronic neutrophilic leukemia,38 though not in all
cases.39 If sensitive techniques such as nested reverse
transcription–
polymerase chain reaction are used, transcripts with the e1a2
fusion
are detectable in many patients with classical P210BCR-
ABLCML.40
The low level of expression of these P190-type transcripts com-
pared to P210 indicates that they are most likely the result of
alternative splicing of the primary mRNA. Occasional cases
with
other junctions, such as b2a3, b3a3, e1a3, e6a2,41 or e2a2,42
have
been reported in patients with ALL and CML. These
“experiments
of nature” provide important information as to the function of
the
various parts ofBCR and ABL in the oncogenic fusion protein.
Interestingly,ABL exon 1, even if retained in the genomic
fusion, is
never part of the chimeric mRNA. Thus, it must be spliced out
during processing of the primary mRNA; the mechanism
underly-
ing this apparent peculiarity is unknown. Based on the
observation
that the Abl part in the chimeric protein is almost invariably
constant while the Bcr portion varies greatly, one may deduce
that
Abl is likely to carry the transforming principle whereas the
different sizes of the Bcr sequence may dictate the phenotype of
the
67. disease. In support of this notion, rare cases of ALL express a
TEL-ABL fusion gene,43,44 indicating that theBCR moiety can
in
principle be replaced by other sequences and still cause
leukemia.
Interestingly, a fusion betweenTEL(ETV6) and theABL-related
geneARG has recently been described in a patient with AML.45
Although all 3 major Bcr-Abl fusion proteins induce a CML-
like
disease in mice, they differ in their ability to induce lymphoid
leukemia,46 and, in contrast to P190 and P210, transformation
to
growth factor independence by P230BCR-ABL is incomplete,47
which
is consistent with the relatively benign clinical course of P230-
positive chronic neutrophilic leukemia.38
One of the most intriguing questions relates to the events
responsible for the chromosomal translocation in the first place.
From epidemiologic studies it is well known that exposure to
ionizing radiation (IR) is a risk factor for CML.48,49 Moreover,
BCR-ABLfusion transcripts can be induced in hematopoietic
cells
by exposure to IR in vitro50; such IR-induced translocations
may
not be random events but may depend on the cellular
background
and on the particular genes involved. Two recent reports showed
that the physical distance between theBCR and theABL genes in
human lymphocytes51 and CD341 cells52 is shorter than might
be
expected by chance; such physical proximity could favor
transloca-
tion events involving the 2 genes. However, the presence of the
BCR-ABL translocation in a hematopoietic cell is not in itself
68. sufficient to cause leukemia becauseBCR-ABLfusion transcripts
of
M-bcr and m-bcr type are detectable at low frequency in the
blood
of many healthy individuals.53,54 It is unclear why Ph-positive
leukemia develops in a tiny minority of these persons. It may be
that the translocation occurs in cells committed to terminal
differentiation that are thus eliminated or that an immune
response
suppresses or eliminates Bcr-Abl–expressing cells. Indirect evi-
dence that such a mechanism may be relevant comes from the
observation that certain HLA types protect against CML.55
Another
possibility is thatBCR-ABLis not the only genetic lesion
required
to induce chronic-phase CML. Indeed, a skewed pattern of G-
6PD
Figure 1. Structure of the Abl protein. Type Ia isoform is
slightly shorter than type
Ib, which contains a myristoylation (myr) site for attachment to
the plasma mem-
brane. Note the 3 SRC-homology (SH) domains situated toward
the NH2 terminus.
Y393 is the major site of autophosphorylation within the kinase
domain, and
phenylalanine 401 (F401) is highly conserved in PTKs
containing SH3 domains. The
middle of each protein is dominated by proline-rich regions
(PxxP) capable of binding
to SH3 domains, and it harbors 1 of 3 nuclear localization
signals (NLS). The carboxy
terminus contains DNA as well as G- and F-actin–binding
domains. Phosphorylation
sites by Atm, cdc2, and PKC are shown. The arrowhead
indicates the position of the
69. breakpoint in the Bcr-Abl fusion protein.
Figure 2. Structure of the Bcr protein. Note the dimerization
domain (DD) and the 2
cyclic adenosine monophosphate kinase homologous domains at
the N terminus.
Y177 is the autophosphorylation site crucial for binding to Grb-
2. The center of the
molecule contains a region homologous to Rho guanidine
nucleotide exchange
factors (Rho-GEF) as well as dbl-like and pleckstrin homology
(PH) domains. Toward
the C-terminus a putative site for calcium-dependent lipid
binding (CaLB) and a
domain with activating function for Rac-GTPase (Rac-GAP) are
found. Arrowheads
indicate the position of the breakpoints in the BCR-ABL fusion
proteins.
Figure 3. Locations of the breakpoints in the ABL and BCR
genes and structure
of the chimeric mRNAs derived from the various breaks.
3344 DEININGER et al BLOOD, 15 NOVEMBER 2000 z
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70. isoenzymes has been detected in Ph-negative Epstein-Barr
virus-
transformed B-cell lines derived from patients with CML,
suggest-
ing that a Ph-negative pathologic state may precede the
emergence
of the Ph chromosome.56
Mechanisms of BCR-ABL –mediated
malignant transformation
Essential features of the Bcr-Abl protein
Mutational analysis identified several features in the chimeric
protein that are essential for cellular transformation (Figure 4).
In
Abl they include the SH1, SH2, and actin-binding domains
(Figure
1), and in Bcr they include a coiled–coil motif contained in
amino
acids 1-63,25 the tyrosine at position 177,57 and
phosphoserine–
threonine-rich sequences between amino acids 192-242 and 298-
41358 (Figure 2). It is, however, important to note that essential
features depend on the experimental system. For example, SH2
deletion mutants of Bcr-Abl are defective for fibroblast
transforma-
tion,59 but they retain the capacity to transform cell lines to
factor
independence and are leukemogenic in animals.60
Deregulation of the Abl tyrosine kinase
Abl tyrosine kinase activity is tightly regulated under physi-
ologic conditions. The SH3 domain appears to play a critical
71. role in this inhibitory process because its deletion14 or
positional
alteration61 activates the kinase; it is replaced by viralgag
sequences in v-abl.62 Both cis- and trans-acting mechanisms
have been proposed to mediate the repression of the kinase.
Several proteins have been identified that bind to the SH3
domain.63-65 Abi-1 and Abi-2 (Abl interactor proteins 1 and 2)
activate the inhibitory function of the SH3 domain; even more
interesting, activated Abl proteins promote the proteasome-
mediated degradation of Abi-166 and Abi-2. Another candidate
inhibitor of Abl is Pag/Msp23. On exposure of cells to oxidative
stress such as ionizing radiation, this small protein is oxidized
and dissociates from Abl, whose kinase is in turn activated.67
These results are in line with previous observations that highly
purified Abl protein is kinase-active,61 suggesting that its
constitutive inhibition derives from a trans-acting mechanism.
Alternatively, the SH3 domain may bind internally to the
proline-rich region in the center of the Abl protein, causing a
conformational change that inhibits interaction with sub-
strates.68 Furthermore, a mutation of Phe401 to Val (within the
kinase domain) leads to the transformation of rodent fibroblasts.
Because this residue is highly conserved in tyrosine kinases
with
N-terminal SH3 domains, it may bind internally to the SH3
domain.69 It is conceivable that the fusion of Bcr sequences 59
of
the Abl SH3 domain abrogates the physiologic suppression of
the kinase. This might be the consequence of homodimer
formation; indeed, the N-terminal dimerization domain is an
essential feature of the Bcr-Abl protein but can be functionally
replaced by other sequences that allow for dimer formation,
such as the N-terminus of theTEL (ETV-6) transcription factor
in the TEL-ABL fusion associated with the t(9;12).43,70 It is
possible that deregulated tyrosine kinase activity is a unifying
72. feature of chronic myeloproliferative disorders. Several other
reciprocal translocations have been cloned from patients with
chronic BCR-ABL–negative myeloproliferative disorders. Re-
markably, most of these turn out to involve tyrosine kinases
such
as fibroblast growth factor receptor 171 and platelet-derived
growth factorb receptor (PDGFbR).72
A host of substrates can be tyrosine phosphorylated byBcr-Abl
(Table 1). Most important, because of autophosphorylation,
there is
a marked increase of phosphotyrosine onBcr-Abl itself, which
creates binding sites for the SH2 domains of other proteins.
Generally, substrates ofBcr-Abl can be grouped according to
their
physiologic role into adapter molecules (such as Crkl and
p62DOK),
proteins associated with the organization of the cytoskeleton
and
the cell membrane (such as paxillin and talin), and proteins with
catalytic function (such as the nonreceptor tyrosine kinase Fes
or
the phosphatase Syp). It is important to note that the choice of
substrates depends on the cellular context. For example, Crkl is
the
major tyrosine-phosphorylated protein in CML neutrophils,73
whereas phosphorylated p62DOK is predominantly found in
early
progenitor cells.74
Tyrosine phosphatases counterbalance and regulate the effects
of tyrosine kinases under physiologic conditions, keeping
cellular
phosphotyrosine levels low. Two tyrosine phosphatases, Syp83
and
73. PTP1B,84 have been shown to form complexes with Bcr-Abl,
and
both appear to dephosphorylate Bcr-Abl. Interestingly, PTP1B
levels increase in a kinase-dependent manner, suggesting that
the
cell attempts to limit the impact of Bcr-Abl tyrosine kinase
activity.
At least in fibroblasts, transformation by Bcr-Abl is impaired by
the
overexpression of PTP1B.85 Interestingly, we recently observed
the
up-regulation of receptor protein tyrosine phosphatasek (RPTP-
k)
with the inhibition of Bcr-Abl in BV173 cells treated with the
Figure 4. Signaling pathways activated in BCR-ABL –positive
cells. Note that this
is a simplified diagram and that many more associations
between Bcr-Abl and
signaling proteins have been reported.
Table 1. Substrates of BCR-ABL
Protein Function Reference
P62DOK Adapter 74
Crkl Adapter 73
Crk Adapter 13
Shc Adapter 75
Talin Cytoskeleton/cell membrane 76
Paxillin Cytoskeleton/cell membrane 77
74. Fak Cytoskeleton/cell membrane 78
Fes Myeloid differentiation 79
Ras-GAP Ras-GTPase 80
GAP-associated proteins Ras activation? 214
PLCg Phospholipase 80
PI3 kinase (p85 subunit) Serine kinase 127
Syp Cytoplasmic phosphatase 83
Bap-1 14-3-3 protein 24
Cbl Unknown 81
Vav Hematopoietic differentiation 82
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tyrosine kinase inhibitor STI571,86 which suggests that the
75. oppo-
site effect may also occur. Thus, though the pivotal role of Bcr-
Abl
tyrosine kinase activity is clearly established, much remains to
be
learned about the significance of tyrosine phosphatases in the
transformation process.
Activated signaling pathways and biologic properties
of BCR-ABL–positive cells
Three major mechanisms have been implicated in the malignant
transformation byBcr-Abl, namely altered adhesion to stroma
cells
and extracellular matrix,87 constitutively active mitogenic
signal-
ing88 and reduced apoptosis89 (Figure 5). A fourth possible
mechanism is the recently described proteasome-mediated
degrada-
tion of Abl inhibitory proteins.66
Altered adhesion properties
CML progenitor cells exhibit decreased adhesion to bone
marrow stroma cells and extracellular matrix.87,90 In this sce-
nario, adhesion to stroma negatively regulates cell proliferation,
and CML cells escape this regulation by virtue of their
perturbed
adhesion properties. Interferon-a (IFN-a), an active therapeutic
agent in CML, appears to reverse the adhesion defect.91 Recent
data suggest an important role forb-integrins in the interaction
between stroma and progenitor cells. CML cells express an
adhesion-inhibitory variant ofb1 integrin that is not found in
normal progenitors.92 On binding to their receptors, integrins
are
capable of initiating normal signal transduction from outside to
76. inside93; it is thus conceivable that the transfer of signals that
normally inhibit proliferation is impaired in CML cells. Because
Abl has been implicated in the intracellular transduction of such
signals, this process may be further disturbed by the presence of
a large pool of Bcr-Abl protein in the cytoplasm. Furthermore,
Crkl, one of the most prominent tyrosine-phosphorylated pro-
teins in Bcr-Abl–transformed cells,73 is involved in the regula-
tion of cellular motility94 and in integrin-mediated cell adhe-
sion95 by association with other focal adhesion proteins such as
paxillin, the focal adhesion kinase Fak, p130Cas,96 and Hef1.97
We recently demonstrated that Bcr-Abl tyrosine kinase up-
regulates the expression ofa6 integrin mRNA,86 which points to
transcriptional activation as yet another possible mechanism by
which Bcr-Abl may have an impact on integrin signaling. Thus,
though there is sound evidence that Bcr-Abl influences integrin
function, it is more difficult to determine the precise nature of
the biologic consequences, and, at least in certain cellular
systems, integrin function appears to be enhanced rather than
reduced by Bcr-Abl.98
Activation of mitogenic signaling
Ras and the MAP kinase pathways.Several links between
Bcr-Abl and Ras have been defined. Autophosphorylation of
tyrosine 177 provides a docking site for the adapter molecule
Grb-2.57 Grb-2, after binding to the Sos protein, stabilizes Ras
in its
active GTP-bound form. Two other adapter molecules, Shc and
Crkl, can also activate Ras. Both are substrates of Bcr-Abl73,99
and
bind Bcr-Abl through their SH2 (Shc) or SH3 (Crkl) domains.
The
relevance of Ras activation by Crkl is, however, questionable
because it appears to be restricted to fibroblasts.100 Moreover,
direct
77. binding of Crkl to Bcr-Abl is not required for the
transformation of
myeloid cells.101 Circumstantial evidence that Ras activation is
important for the pathogenesis of Ph-positive leukemias comes
from the observation that activating mutations are uncommon,
even
in the blastic phase of the disease,102 unlike in most other
tumors.
This implies that the Ras pathway is constitutively active, and
no
further activating mutations are required. There is still dispute
as to
which mitogen-activated protein (MAP) kinase pathway is
down-
stream of Ras in Ph-positive cells. Stimulation of cytokine
receptors such as IL-3 leads to the activation of Ras and the
subsequent recruitment of the serine–threonine kinase Raf to the
cell membrane.103 Raf initiates a signaling cascade through the
serine–threonine kinases Mek1/Mek2 and Erk, which ultimately
leads to the activation of gene transcription.104 Although some
data
indicate that this pathway may be activated only in v-abl– but
not in
BCR-ABL–transformed cells,105 this view has recently been
chal-
lenged.106 Moreover, activation of the Jnk/Sapk pathway by
Bcr-Abl has been demonstrated and is required for malignant
transformation107; thus, signaling from Ras may be relayed
through
the GTP–GDP exchange factor Rac108 to Gckr (germinal center
kinase related)109 and further down to Jnk/Sapk (Figure 6).
There is
also some evidence that p38, the third pillar of the MAP kinase
pathway, is also activated in BCR-ABL–transformed cells, and
there are other pathways with mitogenic potential. In any case,
the
78. signal is eventually transduced to the transcriptional machinery
of
the cell.
It is also possible that Bcr-Abl uses growth factor pathways in a
more direct way. For example, association with thebc subunit of
the IL-3 receptor110 and the Kit receptor111 has been observed.
Interestingly, the pattern of tyrosine-phosphorylated proteins
seenFigure 5. Mechanisms implicated in the pathogenesis of
CML.
Figure 6. Signaling pathways with mitogenic potential in BCR-
ABL –trans-
formed cells. The activation of individual paths depends on the
cell type, but the
MAP kinase system appears to play a central role. Activation of
p38 has been
demonstrated only in v-abl–transformed cells, whereas data for
BCR-ABL–
expressing cells are missing.
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in normal progenitor cells after stimulation with Kit ligand is
79. similar to the pattern seen in CML progenitor cells.112 Dok-1
(p62DOK), one of the most prominent phosphoproteins in this
setting, forms complexes with Crkl, RasGAP, and Bcr-Abl. In
fact,
there may be a whole family of related proteins with similar
functions—for example, the recently described Dok-2
(p56DOK2).113
Somewhat surprisingly, p62DOK is essential for transformation
of
Rat-1 fibroblasts but not for growth-factor independence of my-
eloid cells114; thus, its true role remains to be defined.
Jak-Stat pathway.The first evidence for involvement of the Jak-
Stat pathway came from studies in v-abl–transformed B cells.62
Consti-
tutive phosphorylation of Stat transcription factors (Stat1 and
Stat5) has
since been reported in several BCR-ABL–positive cell lines115
and in
primary CML cells,116 and Stat5 activation appears to
contribute to
malignant transformation.117Although Stat5 has pleiotropic
physiologic
functions,118 its effect in BCR-ABL–transformed cells appears
to be
primarily anti-apoptotic and involves transcriptional activation
of
Bcl-xL.119,120 In contrast to the activation of the Jak-Stat
pathway by
physiologic stimuli, Bcr-Abl may directly activate Stat1 and
Stat5
without prior phosphorylation of Jak proteins. There seems to
be
specificity for Stat6 activation by P190BCR-ABL proteins as
opposed to
80. P210BCR-ABL.115 It is tempting to speculate that the
predominantly
lymphoblastic phenotype in these leukemias is related to this
peculiarity.
The role of the Ras and Jak-Stat pathways in the cellular
response to growth factors could explain the observation that
BCR-ABLrenders a number of growth factor–dependent cell
lines
factor independent.105,121 In some experimental systems there
is
evidence for an autocrine loop dependent on the Bcr-Abl–
induced
secretion of growth factors,122 and it was recently reported that
Bcr-Abl induces an IL-3 and G-CSF autocrine loop in early
progenitor cells.123 Interestingly, Bcr-Abl tyrosine kinase
activity
may induce expression not only of cytokines but also of growth
factor receptors such as the oncostatin Mb receptor.86 One
should
bear in mind, however, that during the chronic phase, CML
progenitor cells are still dependent on external growth factors
for
their survival and proliferation,124 though less than normal
progeni-
tors.125 A recent study sheds fresh light on this issue.
FDCPmix
cells transduced with a temperature-sensitive mutant ofBCR-
ABL
have a reduced requirement for growth factors at the kinase
permissive temperature without differentiation block.126 This
situa-
tion resembles chronic-phase CML, in which the malignant
clone
has a subtle growth advantage while retaining almost normal
differentiation capacity.
81. PI3 kinase pathway.PI3 kinase activity is required for the
proliferation of BCR-ABL–positive cells.127 Bcr-Abl forms
multi-
meric complexes with PI3 kinase, Cbl, and the adapter
molecules
Crk and Crkl,95 in which PI3 kinase is activated. The next
relevant
substrate in this cascade appears to be the serine–threonine
kinase
Akt.128 This kinase had previously been implicated in anti-
apoptotic signaling.129 A recent report placed Akt in the down-
stream cascade of the IL-3 receptor and identified the pro-
apoptotic
protein Bad as a key substrate of Akt.130 Phosphorylated Bad is
inactive because it is no longer able to bind anti-apoptotic
proteins
such as BclXL and it is trapped by cytoplasmic 14-3-3 proteins.
Altogether this indicates that Bcr-Abl might be able to mimic
the
physiologic IL-3 survival signal in a PI3 kinase-dependent
manner
(see also below). Ship131 and Ship-2,132 2 inositol
phosphatases
with somewhat different specificities, are activated in response
to
growth factor signals and by Bcr-Abl. Thus, Bcr-Abl appears to
have a profound effect on phosphoinositol metabolism, which
might again shift the balance to a pattern similar to physiologic
growth factor stimulation.
Myc pathway. Overexpression of Myc has been demonstrated
in many human malignancies. It is thought to act as a
transcription
factor, though its target genes are largely unknown. Activation
of
82. Myc by Bcr-Abl is dependent on the SH2 domain, and the
overexpression of Myc partially rescues transformation-
defective
SH2 deletion mutants whereas the overexpression of a
dominant-
negative mutant suppresses transformation.133 The pathway
linking
Myc to the SH2 domain of Bcr-Abl is still unknown. However,
results obtained in v-abl–transformed cells suggest that the
signal is
transduced through Ras/Raf, cyclin-dependent kinases (cdks),
and
E2F transcription factors that ultimately activate the MYC pro-
moter.134 Similar results were reported for BCR-ABL–
transformed
murine myeloid cells.135 How these findings relate to human
Ph-positive cells is unknown. It seems likely that the effects of
Myc
in Ph-positive cells are probably not different from those in
other
tumors. Depending on the cellular context, Myc may constitute
a
proliferative or an apoptotic signal.136,137It is therefore likely
that
the apoptotic arm of its dual function is counterbalanced in
CML
cells by other mechanisms, such as the PI3 kinase pathway.
Inhibition of apoptosis
Expression of Bcr-Abl in factor-dependent murine138 and
human122 cell lines prevents apoptosis after growth-factor
with-
drawal, an effect that is critically dependent on tyrosine kinase
activity and that correlates with the activation of Ras.88,139
More-
83. over, several studies showed thatBCR-ABL–positive cell lines
are
resistant to apoptosis induced by DNA damage.89,140 The
underly-
ing biologic mechanisms are still not well understood. Bcr-Abl
may block the release of cytochrome C from the mitochondria
and
thus the activation of caspases.141,142 This effect upstream of
caspase activation might be mediated by the Bcl-2 family of
proteins. Bcr-Abl has been shown to up-regulate Bcl-2 in a Ras-
143
or a PI3 kinase-dependent128 manner in Baf/3 and 32D cells,
respectively. Moreover, as mentioned previously, BclxL is
transcrip-
tionally activated by Stat5 inBCR-ABL–positive cells.119,120
Another link betweenBCR-ABLand the inhibition of apoptosis
might be the phosphorylation of the pro-apoptotic protein Bad.
In
addition to Akt, Raf-1, immediately downstream of Ras,
phosphor-
ylates Bad on 2 serine residues.144,145Two recent studies
provided
evidence that the survival signal provided by Bcr-Abl is at least
partially mediated by Bad and requires targeting of Raf-1 to the
mitochondria.146,147It is also possible that Bcr-Abl inhibits
apopto-
sis by down-regulating interferon consensus sequence binding
protein (ICSBP).148,149 These data are interesting because
ICSBP
knockout mice develop a myeloproliferative syndrome,150 and
hematopoietic progenitor cells from ICSBP2/2 mice show
altered
responses to cytokines.151 The connection to interferona, an
active
84. agent in the treatment of CML, is obvious.
It becomes clear that the multiple signals initiated by Bcr-Abl
have proliferative and anti-apoptotic qualities that are
frequently
difficult to separate. Thus, Bcr-Abl may shift the balance
toward
the inhibition of apoptosis while simultaneously providing a
proliferative stimulus. This is in line with the concept that a
proliferative signal leads to apoptosis unless it is
counterbalanced
by an anti-apoptotic signal,152 and Bcr-Abl fulfills both
require-
ments at the same time. There is, however, controversy. One
report
found 32D cells transfected withBCR-ABLto be more sensitive
to
IR than the parental cells,153 whereas 2 other studies failed to
detect
any difference between CML and normal primary progenitor
cells
with regard to their sensitivity to IR and growth factor with-
drawal.124,154Furthermore, based on results obtained in
transfected
cell systems, it was suggested that Bcr-Abl inhibits apoptosis
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mediated by the Fas receptor/Fas ligand system.155 However,
though there may be a role for this system in mediating the
clinical
response to interferon-a,156 there is no indication that Fas-
triggered
apoptosis is defective in primary CML cells or in “natural”
Ph-positive cell lines.157 Moreover, Bcr-Abl accelerates C2
cer-
amide-induced apoptosis,158 and it does not protect against
natural
killer cell-induced apoptosis.159 These inconsistencies may
reflect
genuine differences between cell lines and primary cells. On the
other hand, it is debatable whether complete growth-factor with-
drawal and IR constitute stimuli that have much physiologic
relevance. To allow for a representative comparison, it would be
crucial to define the signals that induce apoptosis in vivo.
Degradation of inhibitory proteins.
The recent discovery that Bcr-Abl induces the proteasome-
mediated degradation of Abi-1 and Abi-2,66 2 proteins with
inhibitory function, may be the first indication of yet another
way
by which Bcr-Abl induces cellular transformation. Most
compel-
ling, the degradation of Abi-1 and Abi-2 is specific for Ph-
positive
acute leukemias and is not seen in Ph-negative samples of
comparable phenotype. The overall significance of this
observation
remains to be seen, and one must bear in mind that the data
86. refer to
acute leukemias and not to chronic phase CML. It is
nevertheless
tempting to speculate that other proteins, whose level of
expression
is regulated through the proteasome pathway, may also be de-
graded. A good candidate would be the cell cycle inhibitor p27,
but
to our knowledge no data are available yet.
Experimental models of CML
Various experimental systems have been developed to study the
pathophysiology of CML. All of them have their advantages and
shortcomings, and it is probably fair to say that there is still no
ideal
in vitro or in vivo model that would cover all aspects of the
human disease.
Cell lines
Fibroblasts. Fibroblast lines have been used extensively in CML
research because they are easy to manipulate. Fibroblast
transforma-
tion—that is, anchorage-independent growth in soft agar—is the
standard in vitro test for tumorigenicity.160 However, it became
clear that the introduction ofBCR-ABLinto fibroblasts has
diverse
effects, depending on the type of fibroblast used. Thus, though
P210BCR-ABL transforms Rat-1 fibroblasts,161 there is no
such effect
in NIH3T3.162 Moreover, transformation to serum-independent
growth occurs only in few cells (permissive cells163), whereas
most
undergo growth arrest. These observations show that certain
cellular requirements must be met if a cell is to be transformed