Last year, when the Physician Payment Sunshine Act became law, I recommended that all physicians involved in any sort of financial relationship with the pharmaceutical industry review the data reported about them prior to public posting of the information. Since that posting is due to occur at the end of this month, a reminder is in order.

Under a new bureaucracy created by the Affordable Care Act – formally called the Open Payments program – all manufacturers of drugs, devices, and medical supplies covered by federal health care programs must report any financial interactions with physicians and teaching hospitals to the Centers for Medicare & Medicaid Services (CMS).

Reportable interactions include consulting; food; ownership or investment interest; direct compensation for speakers at education programs; and research. Compensation for conducting clinical trials must be reported, but will not be posted on the website until the product receives approval from the Food and Drug Administration or until 4 years after the payment, whichever is earlier. Payments for trials involving a new indication for an approved drug will be posted immediately.

There are a number of specific exclusions, such as certified and accredited continuing medical education activities funded by manufacturers, and product samples for patient use. Medical students and residents are excluded entirely.

Under the law, you are allowed to review your data and seek corrections before it is published. Publication is scheduled to occur on Sept. 30, so if you have not yet done this, there is no time to waste. Although you will have an additional 2 years to pursue corrections after the online content goes live, any erroneous information will remain on the site until corrections can be made, so the best time to find and fix errors is now.

If you don’t see drug reps, accept sponsored lunches, or give sponsored talks, don’t assume that you won’t be on the website. Check anyway; you might be indirectly involved in a compensation situation that you were not aware of, or you may have been reported in error.

To review your data, register at the CMS Enterprise Portal, and request access to the Open Payments system.

Once you are satisfied that your interactions have been reported accurately, the question of what effect the law will have on research, continuing education, and private practice remains. The short answer is that no one knows. Much will depend on how the public interprets the data – if they take notice at all.

Sunshine laws have been in effect for several years in six states: California, Colorado, Massachusetts, Minnesota, Vermont, and West Virginia; plus the District of Columbia. (Maine repealed its law in 2011.) Observers disagree on their impact. Studies in Maine and West Virginia showed no significant public reaction or changes in prescribing patterns, according to a 2012 article in Archives of Internal Medicine (Arch. Intern. Med. 2012;172:819-21).

Potential effects on physician-patient interactions are equally unclear. Do patients think less of doctors who accept the occasional industry-sponsored lunch for their employees? Do they think more of doctors who speak at meetings or conduct industry-sponsored clinical research? There are no objective data, as far as I know.

My guess is that attorneys, activists, and the occasional reporter will data-mine the website on a regular basis, and perhaps use their findings as ammunition in any agenda that they might be pushing, but few patients will ever bother to visit. Nevertheless, you should review each year’s reportage to ensure the accuracy of anything posted about you.

The data must be reported to CMS by March 31 each year, so you will need to set aside time each April or May to review it. If you have many or complex industry relationships, you should probably contact each company in January or February and ask to see the data before it is submitted. Then, review it again once CMS gets it, to be sure nothing was changed. A free app is available to help physicians track payments and other reportable industry interactions; search for "Open Payments" at your favorite app store.

Maintaining accurate financial records has always been important, but it will be even more so now, to effectively dispute any inconsistencies. While the extra work may turn out to have been unnecessary, it is still a prudent precaution, given the possible consequences of any increased government or public scrutiny that may (or may not) result.

Dr. Eastern practices dermatology and dermatologic surgery in Belleville, N.J. He is the author of numerous articles and textbook chapters, and is a long-time monthly columnist for Skin & Allergy News.

Last year, when the Physician Payment Sunshine Act became law, I recommended that all physicians involved in any sort of financial relationship with the pharmaceutical industry review the data reported about them prior to public posting of the information. Since that posting is due to occur at the end of this month, a reminder is in order.

Under a new bureaucracy created by the Affordable Care Act – formally called the Open Payments program – all manufacturers of drugs, devices, and medical supplies covered by federal health care programs must report any financial interactions with physicians and teaching hospitals to the Centers for Medicare & Medicaid Services (CMS).

Reportable interactions include consulting; food; ownership or investment interest; direct compensation for speakers at education programs; and research. Compensation for conducting clinical trials must be reported, but will not be posted on the website until the product receives approval from the Food and Drug Administration or until 4 years after the payment, whichever is earlier. Payments for trials involving a new indication for an approved drug will be posted immediately.

There are a number of specific exclusions, such as certified and accredited continuing medical education activities funded by manufacturers, and product samples for patient use. Medical students and residents are excluded entirely.

Under the law, you are allowed to review your data and seek corrections before it is published. Publication is scheduled to occur on Sept. 30, so if you have not yet done this, there is no time to waste. Although you will have an additional 2 years to pursue corrections after the online content goes live, any erroneous information will remain on the site until corrections can be made, so the best time to find and fix errors is now.

If you don’t see drug reps, accept sponsored lunches, or give sponsored talks, don’t assume that you won’t be on the website. Check anyway; you might be indirectly involved in a compensation situation that you were not aware of, or you may have been reported in error.

To review your data, register at the CMS Enterprise Portal, and request access to the Open Payments system.

Once you are satisfied that your interactions have been reported accurately, the question of what effect the law will have on research, continuing education, and private practice remains. The short answer is that no one knows. Much will depend on how the public interprets the data – if they take notice at all.

Sunshine laws have been in effect for several years in six states: California, Colorado, Massachusetts, Minnesota, Vermont, and West Virginia; plus the District of Columbia. (Maine repealed its law in 2011.) Observers disagree on their impact. Studies in Maine and West Virginia showed no significant public reaction or changes in prescribing patterns, according to a 2012 article in Archives of Internal Medicine (Arch. Intern. Med. 2012;172:819-21).

Potential effects on physician-patient interactions are equally unclear. Do patients think less of doctors who accept the occasional industry-sponsored lunch for their employees? Do they think more of doctors who speak at meetings or conduct industry-sponsored clinical research? There are no objective data, as far as I know.

My guess is that attorneys, activists, and the occasional reporter will data-mine the website on a regular basis, and perhaps use their findings as ammunition in any agenda that they might be pushing, but few patients will ever bother to visit. Nevertheless, you should review each year’s reportage to ensure the accuracy of anything posted about you.

The data must be reported to CMS by March 31 each year, so you will need to set aside time each April or May to review it. If you have many or complex industry relationships, you should probably contact each company in January or February and ask to see the data before it is submitted. Then, review it again once CMS gets it, to be sure nothing was changed. A free app is available to help physicians track payments and other reportable industry interactions; search for "Open Payments" at your favorite app store.

Maintaining accurate financial records has always been important, but it will be even more so now, to effectively dispute any inconsistencies. While the extra work may turn out to have been unnecessary, it is still a prudent precaution, given the possible consequences of any increased government or public scrutiny that may (or may not) result.

Dr. Eastern practices dermatology and dermatologic surgery in Belleville, N.J. He is the author of numerous articles and textbook chapters, and is a long-time monthly columnist for Skin & Allergy News.

Last year, when the Physician Payment Sunshine Act became law, I recommended that all physicians involved in any sort of financial relationship with the pharmaceutical industry review the data reported about them prior to public posting of the information. Since that posting is due to occur at the end of this month, a reminder is in order.

Under a new bureaucracy created by the Affordable Care Act – formally called the Open Payments program – all manufacturers of drugs, devices, and medical supplies covered by federal health care programs must report any financial interactions with physicians and teaching hospitals to the Centers for Medicare & Medicaid Services (CMS).

Reportable interactions include consulting; food; ownership or investment interest; direct compensation for speakers at education programs; and research. Compensation for conducting clinical trials must be reported, but will not be posted on the website until the product receives approval from the Food and Drug Administration or until 4 years after the payment, whichever is earlier. Payments for trials involving a new indication for an approved drug will be posted immediately.

There are a number of specific exclusions, such as certified and accredited continuing medical education activities funded by manufacturers, and product samples for patient use. Medical students and residents are excluded entirely.

Under the law, you are allowed to review your data and seek corrections before it is published. Publication is scheduled to occur on Sept. 30, so if you have not yet done this, there is no time to waste. Although you will have an additional 2 years to pursue corrections after the online content goes live, any erroneous information will remain on the site until corrections can be made, so the best time to find and fix errors is now.

If you don’t see drug reps, accept sponsored lunches, or give sponsored talks, don’t assume that you won’t be on the website. Check anyway; you might be indirectly involved in a compensation situation that you were not aware of, or you may have been reported in error.

To review your data, register at the CMS Enterprise Portal, and request access to the Open Payments system.

Once you are satisfied that your interactions have been reported accurately, the question of what effect the law will have on research, continuing education, and private practice remains. The short answer is that no one knows. Much will depend on how the public interprets the data – if they take notice at all.

Sunshine laws have been in effect for several years in six states: California, Colorado, Massachusetts, Minnesota, Vermont, and West Virginia; plus the District of Columbia. (Maine repealed its law in 2011.) Observers disagree on their impact. Studies in Maine and West Virginia showed no significant public reaction or changes in prescribing patterns, according to a 2012 article in Archives of Internal Medicine (Arch. Intern. Med. 2012;172:819-21).

Potential effects on physician-patient interactions are equally unclear. Do patients think less of doctors who accept the occasional industry-sponsored lunch for their employees? Do they think more of doctors who speak at meetings or conduct industry-sponsored clinical research? There are no objective data, as far as I know.

My guess is that attorneys, activists, and the occasional reporter will data-mine the website on a regular basis, and perhaps use their findings as ammunition in any agenda that they might be pushing, but few patients will ever bother to visit. Nevertheless, you should review each year’s reportage to ensure the accuracy of anything posted about you.

The data must be reported to CMS by March 31 each year, so you will need to set aside time each April or May to review it. If you have many or complex industry relationships, you should probably contact each company in January or February and ask to see the data before it is submitted. Then, review it again once CMS gets it, to be sure nothing was changed. A free app is available to help physicians track payments and other reportable industry interactions; search for "Open Payments" at your favorite app store.

Maintaining accurate financial records has always been important, but it will be even more so now, to effectively dispute any inconsistencies. While the extra work may turn out to have been unnecessary, it is still a prudent precaution, given the possible consequences of any increased government or public scrutiny that may (or may not) result.

Dr. Eastern practices dermatology and dermatologic surgery in Belleville, N.J. He is the author of numerous articles and textbook chapters, and is a long-time monthly columnist for Skin & Allergy News.

In my last column, I addressed the question of whether or not to outsource your practice’s social media efforts. While some medical practices do their own social media, others simply don’t have the time, resources, or desire to do it themselves. That’s where social media consultants come in. Hiring the right consultant offers numerous benefits such as devising a strategic plan that aligns with your practice’s unique goals, as well helping you develop and market your personal brand.

Last time, I offered guidelines to help you choose the right consultant for your practice. This time, I’ll offer some pitfalls to avoid when choosing a social media consultant or agency. If a consultant promises any of the following, be skeptical:

• Thousands of followers in just a few weeks! Authentic social media takes time because it’s about building relationships. There are digital programs that let you buy followers, but I don’t recommend them. It’s much better to have a smaller, genuine, truly engaged target audience than a huge, inauthentic one. Building a genuine target audience takes longer to cultivate, but it is far more effective in the long run.

• Your videos will go viral! We’ve all seen videos that have gone viral (many involve grumpy cats, which I don’t recommend using for your brand). Chances are if you’re making a 2-minute video on how to treat rosacea or ringworm, it won’t go viral. (Unless it involves a grumpy cat.) Instead, focus on realistic expectations. Your consultant should offer creative ways to market your brand, whether it’s video or text. But getting hung up on going viral is like waiting to win the lottery. It’s better to regularly create and share high-quality content that over time will garner an audience.

• You’ll double your patients in weeks! The number one way physicians acquire new patients is through word of mouth. Social media is word of mouth enhanced by technology, so it has the potential to grow your patient base. But it takes time. If acquiring new patients is one of your goals, then be certain that your consultant creates a realistic plan to achieve that goal.

• We’re your one-stop shop! Although I advocate using social media to market your practice, I believe it should be only one spoke in your marketing wheel. Traditional forms of marketing, such as newspaper and magazine advertisements, newsletters, and local radio and television appearances, still offer real benefits for many practices. If someone is trying to convince you to abandon all your other marketing efforts, be cautious.

• We’ve had 100% success with all of our clients! Would you believe your fellow doctor if he said he hadn’t had a patient complaint in 3 years? I didn’t think so. Don’t believe a consultant who tells you he’s never made mistakes or had an unhappy client. Ask what a consultant has learned from negative and positive experiences. What insight have they gleaned from that unsuccessful experience? How can these insights help when devising your strategy?

With these guidelines in place, you’re putting your practice and your reputation in safer hands.

Dr. Benabio is a partner physician in the department of dermatology of the Southern California Permanente Group in San Diego and a volunteer clinical assistant professor at the University of California, San Diego. Dr. Benabio is @dermdoc on Twitter.

In my last column, I addressed the question of whether or not to outsource your practice’s social media efforts. While some medical practices do their own social media, others simply don’t have the time, resources, or desire to do it themselves. That’s where social media consultants come in. Hiring the right consultant offers numerous benefits such as devising a strategic plan that aligns with your practice’s unique goals, as well helping you develop and market your personal brand.

Last time, I offered guidelines to help you choose the right consultant for your practice. This time, I’ll offer some pitfalls to avoid when choosing a social media consultant or agency. If a consultant promises any of the following, be skeptical:

• Thousands of followers in just a few weeks! Authentic social media takes time because it’s about building relationships. There are digital programs that let you buy followers, but I don’t recommend them. It’s much better to have a smaller, genuine, truly engaged target audience than a huge, inauthentic one. Building a genuine target audience takes longer to cultivate, but it is far more effective in the long run.

• Your videos will go viral! We’ve all seen videos that have gone viral (many involve grumpy cats, which I don’t recommend using for your brand). Chances are if you’re making a 2-minute video on how to treat rosacea or ringworm, it won’t go viral. (Unless it involves a grumpy cat.) Instead, focus on realistic expectations. Your consultant should offer creative ways to market your brand, whether it’s video or text. But getting hung up on going viral is like waiting to win the lottery. It’s better to regularly create and share high-quality content that over time will garner an audience.

• You’ll double your patients in weeks! The number one way physicians acquire new patients is through word of mouth. Social media is word of mouth enhanced by technology, so it has the potential to grow your patient base. But it takes time. If acquiring new patients is one of your goals, then be certain that your consultant creates a realistic plan to achieve that goal.

• We’re your one-stop shop! Although I advocate using social media to market your practice, I believe it should be only one spoke in your marketing wheel. Traditional forms of marketing, such as newspaper and magazine advertisements, newsletters, and local radio and television appearances, still offer real benefits for many practices. If someone is trying to convince you to abandon all your other marketing efforts, be cautious.

• We’ve had 100% success with all of our clients! Would you believe your fellow doctor if he said he hadn’t had a patient complaint in 3 years? I didn’t think so. Don’t believe a consultant who tells you he’s never made mistakes or had an unhappy client. Ask what a consultant has learned from negative and positive experiences. What insight have they gleaned from that unsuccessful experience? How can these insights help when devising your strategy?

With these guidelines in place, you’re putting your practice and your reputation in safer hands.

Dr. Benabio is a partner physician in the department of dermatology of the Southern California Permanente Group in San Diego and a volunteer clinical assistant professor at the University of California, San Diego. Dr. Benabio is @dermdoc on Twitter.

In my last column, I addressed the question of whether or not to outsource your practice’s social media efforts. While some medical practices do their own social media, others simply don’t have the time, resources, or desire to do it themselves. That’s where social media consultants come in. Hiring the right consultant offers numerous benefits such as devising a strategic plan that aligns with your practice’s unique goals, as well helping you develop and market your personal brand.

Last time, I offered guidelines to help you choose the right consultant for your practice. This time, I’ll offer some pitfalls to avoid when choosing a social media consultant or agency. If a consultant promises any of the following, be skeptical:

• Thousands of followers in just a few weeks! Authentic social media takes time because it’s about building relationships. There are digital programs that let you buy followers, but I don’t recommend them. It’s much better to have a smaller, genuine, truly engaged target audience than a huge, inauthentic one. Building a genuine target audience takes longer to cultivate, but it is far more effective in the long run.

• Your videos will go viral! We’ve all seen videos that have gone viral (many involve grumpy cats, which I don’t recommend using for your brand). Chances are if you’re making a 2-minute video on how to treat rosacea or ringworm, it won’t go viral. (Unless it involves a grumpy cat.) Instead, focus on realistic expectations. Your consultant should offer creative ways to market your brand, whether it’s video or text. But getting hung up on going viral is like waiting to win the lottery. It’s better to regularly create and share high-quality content that over time will garner an audience.

• You’ll double your patients in weeks! The number one way physicians acquire new patients is through word of mouth. Social media is word of mouth enhanced by technology, so it has the potential to grow your patient base. But it takes time. If acquiring new patients is one of your goals, then be certain that your consultant creates a realistic plan to achieve that goal.

• We’re your one-stop shop! Although I advocate using social media to market your practice, I believe it should be only one spoke in your marketing wheel. Traditional forms of marketing, such as newspaper and magazine advertisements, newsletters, and local radio and television appearances, still offer real benefits for many practices. If someone is trying to convince you to abandon all your other marketing efforts, be cautious.

• We’ve had 100% success with all of our clients! Would you believe your fellow doctor if he said he hadn’t had a patient complaint in 3 years? I didn’t think so. Don’t believe a consultant who tells you he’s never made mistakes or had an unhappy client. Ask what a consultant has learned from negative and positive experiences. What insight have they gleaned from that unsuccessful experience? How can these insights help when devising your strategy?

With these guidelines in place, you’re putting your practice and your reputation in safer hands.

Dr. Benabio is a partner physician in the department of dermatology of the Southern California Permanente Group in San Diego and a volunteer clinical assistant professor at the University of California, San Diego. Dr. Benabio is @dermdoc on Twitter.

Recently, Federal Practitioner talked with Benjamin Powers, MD, and Suman Kambhampati, MD, about factors that come into play when treating patients with chronic myelogenous leukemia (CML) and the dramatic improvements in treatment that have been made. To find out more about these factors and improvements, read Blast Phase Chronic Myelogenous Leukemia from the August 2014 issue.

Dr. Powers is a fellow and Dr. Kambhampati is an associate professor of medicine, both in the Department of Internal Medicine, Division of Hematology/Oncology, at the University of Kansas Medical Center in Kansas City, Kansas. Dr. Kambhampati is also a staff physician in the Hematology/Oncology Division at the Kansas City VAMC in Kansas City, Missouri.

Recently, Federal Practitioner talked with Benjamin Powers, MD, and Suman Kambhampati, MD, about factors that come into play when treating patients with chronic myelogenous leukemia (CML) and the dramatic improvements in treatment that have been made. To find out more about these factors and improvements, read Blast Phase Chronic Myelogenous Leukemia from the August 2014 issue.

Dr. Powers is a fellow and Dr. Kambhampati is an associate professor of medicine, both in the Department of Internal Medicine, Division of Hematology/Oncology, at the University of Kansas Medical Center in Kansas City, Kansas. Dr. Kambhampati is also a staff physician in the Hematology/Oncology Division at the Kansas City VAMC in Kansas City, Missouri.

Recently, Federal Practitioner talked with Benjamin Powers, MD, and Suman Kambhampati, MD, about factors that come into play when treating patients with chronic myelogenous leukemia (CML) and the dramatic improvements in treatment that have been made. To find out more about these factors and improvements, read Blast Phase Chronic Myelogenous Leukemia from the August 2014 issue.

Dr. Powers is a fellow and Dr. Kambhampati is an associate professor of medicine, both in the Department of Internal Medicine, Division of Hematology/Oncology, at the University of Kansas Medical Center in Kansas City, Kansas. Dr. Kambhampati is also a staff physician in the Hematology/Oncology Division at the Kansas City VAMC in Kansas City, Missouri.

Sickled and normal red cells

Credit: Graham Beards

Scientists have discovered that manipulating gene regulation can cause red blood cells to produce fetal hemoglobin, a finding that may have implications for sickle cell disease (SCD) and other hemoglobinopathies.

The researchers used protein-engineering techniques to force chromatin fiber into looped structures that contact DNA at specific sites to preferentially activate genes that regulate hemoglobin.

The team described the work in Cell. The research was previously presented at the 2013 ASH Annual Meeting.

Key to the researcher’s method is a developmental transition that normally occurs in the blood of newborns. A biological switch regulates a changeover from fetal hemoglobin to adult hemoglobin as it begins to silence the genes that produce fetal hemoglobin.

Hematologists have long known that SCD patients with elevated levels of fetal hemoglobin have a milder form of the disease.

“This observation has been a major driver in the field to understand the molecular basis of the mechanisms that control the biological switch, with the ultimate goal to reverse it,” said study author Gerd A. Blobel, MD, PhD, of The Children’s Hospital of Philadelphia in Pennsylvania.

In previous research, his team used bioengineering techniques to adapt zinc-finger proteins to latch onto specific DNA sites far apart on a chromosome. The chromatin loop that results transmits regulatory signals for specific genes.

In their current work, the researchers custom-designed zinc fingers to flip the biological switch in hematopoietic stem cells, reactivating the genes expressing fetal hemoglobin at the expense of the genes expressing adult hemoglobin.

The team achieved these results in cultured blood cells from adult mice and adult humans.

The researchers are now planning to test the approach in animal models of SCD. If this strategy corrects the disease in animals, it may set the stage to move to human trials.

Dr Blobel also noted that, in principle, the forced chromatin looping approach could be applied to other hemoglobin-related disorders, such as certain forms of thalassemia.

Sickled and normal red cells

Credit: Graham Beards

Scientists have discovered that manipulating gene regulation can cause red blood cells to produce fetal hemoglobin, a finding that may have implications for sickle cell disease (SCD) and other hemoglobinopathies.

The researchers used protein-engineering techniques to force chromatin fiber into looped structures that contact DNA at specific sites to preferentially activate genes that regulate hemoglobin.

The team described the work in Cell. The research was previously presented at the 2013 ASH Annual Meeting.

Key to the researcher’s method is a developmental transition that normally occurs in the blood of newborns. A biological switch regulates a changeover from fetal hemoglobin to adult hemoglobin as it begins to silence the genes that produce fetal hemoglobin.

Hematologists have long known that SCD patients with elevated levels of fetal hemoglobin have a milder form of the disease.

“This observation has been a major driver in the field to understand the molecular basis of the mechanisms that control the biological switch, with the ultimate goal to reverse it,” said study author Gerd A. Blobel, MD, PhD, of The Children’s Hospital of Philadelphia in Pennsylvania.

In previous research, his team used bioengineering techniques to adapt zinc-finger proteins to latch onto specific DNA sites far apart on a chromosome. The chromatin loop that results transmits regulatory signals for specific genes.

In their current work, the researchers custom-designed zinc fingers to flip the biological switch in hematopoietic stem cells, reactivating the genes expressing fetal hemoglobin at the expense of the genes expressing adult hemoglobin.

The team achieved these results in cultured blood cells from adult mice and adult humans.

The researchers are now planning to test the approach in animal models of SCD. If this strategy corrects the disease in animals, it may set the stage to move to human trials.

Dr Blobel also noted that, in principle, the forced chromatin looping approach could be applied to other hemoglobin-related disorders, such as certain forms of thalassemia.

Sickled and normal red cells

Credit: Graham Beards

Scientists have discovered that manipulating gene regulation can cause red blood cells to produce fetal hemoglobin, a finding that may have implications for sickle cell disease (SCD) and other hemoglobinopathies.

The researchers used protein-engineering techniques to force chromatin fiber into looped structures that contact DNA at specific sites to preferentially activate genes that regulate hemoglobin.

The team described the work in Cell. The research was previously presented at the 2013 ASH Annual Meeting.

Key to the researcher’s method is a developmental transition that normally occurs in the blood of newborns. A biological switch regulates a changeover from fetal hemoglobin to adult hemoglobin as it begins to silence the genes that produce fetal hemoglobin.

Hematologists have long known that SCD patients with elevated levels of fetal hemoglobin have a milder form of the disease.

“This observation has been a major driver in the field to understand the molecular basis of the mechanisms that control the biological switch, with the ultimate goal to reverse it,” said study author Gerd A. Blobel, MD, PhD, of The Children’s Hospital of Philadelphia in Pennsylvania.

In previous research, his team used bioengineering techniques to adapt zinc-finger proteins to latch onto specific DNA sites far apart on a chromosome. The chromatin loop that results transmits regulatory signals for specific genes.

In their current work, the researchers custom-designed zinc fingers to flip the biological switch in hematopoietic stem cells, reactivating the genes expressing fetal hemoglobin at the expense of the genes expressing adult hemoglobin.

The team achieved these results in cultured blood cells from adult mice and adult humans.

The researchers are now planning to test the approach in animal models of SCD. If this strategy corrects the disease in animals, it may set the stage to move to human trials.

Dr Blobel also noted that, in principle, the forced chromatin looping approach could be applied to other hemoglobin-related disorders, such as certain forms of thalassemia.

The proteasome inhibitor carfilzomib (Kyprolis) did not meet its primary endpoint in the phase 3 FOCUS trial, according to the drug’s developers.

Single-agent carfilzomib did not improve overall survival compared to an active control regimen of corticosteroids plus optional cyclophosphamide in patients with relapsed and refractory multiple myeloma (MM).

This result raises questions about carfilzomib’s chances for regulatory approval around the world.

However, the companies developing the drug, Amgen and its subsidiary Onyx Pharmaceuticals, Inc., said results of the phase 3 ASPIRE trial should be sufficient to support carfilzomib’s approval.

At present, carfilzomib has accelerated approval from the US Food and Drug Administration for the treatment of MM patients who have received at least 2 prior therapies, including bortezomib and an immunomodulatory agent, and have demonstrated disease progression on or within 60 days of completing their last therapy.

That approval was based on response rates observed with carfilzomib. For the drug to gain full approval, it must demonstrate a clinical benefit.

The FOCUS trial

For the FOCUS trial, researchers enrolled 315 patients with relapsed and advanced refractory MM.

Patients were randomized to receive carfilzomib or an active control regimen consisting of low-dose dexamethasone, or equivalent corticosteroids, plus optional cyclophosphamide.

Nearly all patients in the control arm received cyclophosphamide. Patients were heavily pretreated and had received a median of 5 treatment regimens prior to study entry.

The trial’s primary endpoint was overall survival, and there was no significant difference between the 2 treatment arms. The hazard ratio was 0.975.

Treatment discontinuation due to adverse events and on-study deaths were comparable between the treatment arms. The rate of cardiac events in the carfilzomib arm was consistent with the current US label.

However, there was an increase in the incidence of renal adverse events of all grades observed in the carfilzomib arm compared to the active control arm and the label.

Full prescribing information for carfilzomib is available at www.kyprolis.com.

Amgen and Onyx said detailed results from the FOCUS trial will be submitted for presentation at an upcoming scientific meeting.

The proteasome inhibitor carfilzomib (Kyprolis) did not meet its primary endpoint in the phase 3 FOCUS trial, according to the drug’s developers.

Single-agent carfilzomib did not improve overall survival compared to an active control regimen of corticosteroids plus optional cyclophosphamide in patients with relapsed and refractory multiple myeloma (MM).

This result raises questions about carfilzomib’s chances for regulatory approval around the world.

However, the companies developing the drug, Amgen and its subsidiary Onyx Pharmaceuticals, Inc., said results of the phase 3 ASPIRE trial should be sufficient to support carfilzomib’s approval.

At present, carfilzomib has accelerated approval from the US Food and Drug Administration for the treatment of MM patients who have received at least 2 prior therapies, including bortezomib and an immunomodulatory agent, and have demonstrated disease progression on or within 60 days of completing their last therapy.

That approval was based on response rates observed with carfilzomib. For the drug to gain full approval, it must demonstrate a clinical benefit.

The FOCUS trial

For the FOCUS trial, researchers enrolled 315 patients with relapsed and advanced refractory MM.

Patients were randomized to receive carfilzomib or an active control regimen consisting of low-dose dexamethasone, or equivalent corticosteroids, plus optional cyclophosphamide.

Nearly all patients in the control arm received cyclophosphamide. Patients were heavily pretreated and had received a median of 5 treatment regimens prior to study entry.

The trial’s primary endpoint was overall survival, and there was no significant difference between the 2 treatment arms. The hazard ratio was 0.975.

Treatment discontinuation due to adverse events and on-study deaths were comparable between the treatment arms. The rate of cardiac events in the carfilzomib arm was consistent with the current US label.

However, there was an increase in the incidence of renal adverse events of all grades observed in the carfilzomib arm compared to the active control arm and the label.

Full prescribing information for carfilzomib is available at www.kyprolis.com.

Amgen and Onyx said detailed results from the FOCUS trial will be submitted for presentation at an upcoming scientific meeting.

The proteasome inhibitor carfilzomib (Kyprolis) did not meet its primary endpoint in the phase 3 FOCUS trial, according to the drug’s developers.

Single-agent carfilzomib did not improve overall survival compared to an active control regimen of corticosteroids plus optional cyclophosphamide in patients with relapsed and refractory multiple myeloma (MM).

This result raises questions about carfilzomib’s chances for regulatory approval around the world.

However, the companies developing the drug, Amgen and its subsidiary Onyx Pharmaceuticals, Inc., said results of the phase 3 ASPIRE trial should be sufficient to support carfilzomib’s approval.

At present, carfilzomib has accelerated approval from the US Food and Drug Administration for the treatment of MM patients who have received at least 2 prior therapies, including bortezomib and an immunomodulatory agent, and have demonstrated disease progression on or within 60 days of completing their last therapy.

That approval was based on response rates observed with carfilzomib. For the drug to gain full approval, it must demonstrate a clinical benefit.

The FOCUS trial

For the FOCUS trial, researchers enrolled 315 patients with relapsed and advanced refractory MM.

Patients were randomized to receive carfilzomib or an active control regimen consisting of low-dose dexamethasone, or equivalent corticosteroids, plus optional cyclophosphamide.

Nearly all patients in the control arm received cyclophosphamide. Patients were heavily pretreated and had received a median of 5 treatment regimens prior to study entry.

The trial’s primary endpoint was overall survival, and there was no significant difference between the 2 treatment arms. The hazard ratio was 0.975.

Treatment discontinuation due to adverse events and on-study deaths were comparable between the treatment arms. The rate of cardiac events in the carfilzomib arm was consistent with the current US label.

However, there was an increase in the incidence of renal adverse events of all grades observed in the carfilzomib arm compared to the active control arm and the label.

Full prescribing information for carfilzomib is available at www.kyprolis.com.

Amgen and Onyx said detailed results from the FOCUS trial will be submitted for presentation at an upcoming scientific meeting.

ALL cells in the bone marrow

Two genes appear to play a key role in acute lymphoblastic leukemia (ALL), particularly for patients who also have Down syndrome.

Researchers found evidence suggesting that 2 in 3 cases of ALL among patients with Down syndrome may be caused by mutations in RAS or JAK2, but the mutations tend not to occur together.

The group therefore believes that if we can begin to identify which of the genes is mutated in ALL patients, we can tailor therapy accordingly.

“We believe our findings are a breakthrough in understanding the underlying causes of leukemia, and, eventually, we hope to design more tailored and effective treatment for this cancer, with less toxic drugs and less side effects,” said study author Dean Nizetic, MD, PhD, a professor at both Queen Mary University of London in the UK and Lee Kong Chian School of Medicine in Singapore.

He and his colleagues reported their findings in Nature Communications.

The researchers conducted full-exome or targeted sequencing in 42 samples from 39 patients with ALL and Down syndrome. The team found similar recurrence rates for driver mutations in RAS (15/42), JAK2 mutations (12/42), and P2RY8-CRLF2 fusions (14/42).

Together, RAS and JAK2 mutations drove two-thirds of the ALL cases, though the mutations were almost completely mutually exclusive (P=0.016).

The researchers also noted that, in two-thirds of patients with relapsed ALL, there was a switch from a primary JAK2- or PTPN11-mutated subclone to a RAS-mutated subclone in relapse.

Moving forward, the team plans to conduct more studies to determine how else RAS and JAK2 might affect children who have ALL, with or without Down syndrome.

ALL cells in the bone marrow

Two genes appear to play a key role in acute lymphoblastic leukemia (ALL), particularly for patients who also have Down syndrome.

Researchers found evidence suggesting that 2 in 3 cases of ALL among patients with Down syndrome may be caused by mutations in RAS or JAK2, but the mutations tend not to occur together.

The group therefore believes that if we can begin to identify which of the genes is mutated in ALL patients, we can tailor therapy accordingly.

“We believe our findings are a breakthrough in understanding the underlying causes of leukemia, and, eventually, we hope to design more tailored and effective treatment for this cancer, with less toxic drugs and less side effects,” said study author Dean Nizetic, MD, PhD, a professor at both Queen Mary University of London in the UK and Lee Kong Chian School of Medicine in Singapore.

He and his colleagues reported their findings in Nature Communications.

The researchers conducted full-exome or targeted sequencing in 42 samples from 39 patients with ALL and Down syndrome. The team found similar recurrence rates for driver mutations in RAS (15/42), JAK2 mutations (12/42), and P2RY8-CRLF2 fusions (14/42).

Together, RAS and JAK2 mutations drove two-thirds of the ALL cases, though the mutations were almost completely mutually exclusive (P=0.016).

The researchers also noted that, in two-thirds of patients with relapsed ALL, there was a switch from a primary JAK2- or PTPN11-mutated subclone to a RAS-mutated subclone in relapse.

Moving forward, the team plans to conduct more studies to determine how else RAS and JAK2 might affect children who have ALL, with or without Down syndrome.

ALL cells in the bone marrow

Two genes appear to play a key role in acute lymphoblastic leukemia (ALL), particularly for patients who also have Down syndrome.

Researchers found evidence suggesting that 2 in 3 cases of ALL among patients with Down syndrome may be caused by mutations in RAS or JAK2, but the mutations tend not to occur together.

The group therefore believes that if we can begin to identify which of the genes is mutated in ALL patients, we can tailor therapy accordingly.

“We believe our findings are a breakthrough in understanding the underlying causes of leukemia, and, eventually, we hope to design more tailored and effective treatment for this cancer, with less toxic drugs and less side effects,” said study author Dean Nizetic, MD, PhD, a professor at both Queen Mary University of London in the UK and Lee Kong Chian School of Medicine in Singapore.

He and his colleagues reported their findings in Nature Communications.

The researchers conducted full-exome or targeted sequencing in 42 samples from 39 patients with ALL and Down syndrome. The team found similar recurrence rates for driver mutations in RAS (15/42), JAK2 mutations (12/42), and P2RY8-CRLF2 fusions (14/42).

Together, RAS and JAK2 mutations drove two-thirds of the ALL cases, though the mutations were almost completely mutually exclusive (P=0.016).

The researchers also noted that, in two-thirds of patients with relapsed ALL, there was a switch from a primary JAK2- or PTPN11-mutated subclone to a RAS-mutated subclone in relapse.

Moving forward, the team plans to conduct more studies to determine how else RAS and JAK2 might affect children who have ALL, with or without Down syndrome.

Preparing pills for a trial

Credit: Esther Dyson

The US Food and Drug Administration (FDA) has granted fast track designation for AG-221 to treat acute myelogenous leukemia (AML) patients with mutated isocitrate dehydrogenase-2 (IDH2).

AG-221 is an IDH2 inhibitor under evaluation in a phase 1 trial of patients with advanced hematologic malignancies.

Results from this trial were presented at the 19th Congress of the European Hematology Association, which took place in Milan in June.

The FDA’s fast track drug development program is designed to expedite clinical development and submission of a new drug application (NDA) for drugs with the potential to treat serious or life-threatening conditions and address unmet medical needs.

Fast track designation facilitates meetings between the FDA and the company developing a drug to discuss all aspects of development to support approval. It also affords the developer the opportunity to submit sections of an NDA on a rolling basis as data become available, so the FDA does not have wait for the entire NDA submission before beginning its review.

AG-221 also recently received orphan designation as a treatment for AML. The FDA grants orphan status to support the development of drugs for underserved patient populations or rare disorders that affect fewer than 200,000 people in the US.

Orphan designation affords the drug’s developer certain benefits, including market exclusivity upon regulatory approval, exemption of FDA application fees, and tax credits for qualified clinical trials.

Phase 1 trial results

Thus far in the phase 1 study, AG-221 has proven active and well-tolerated in patients with AML, myelodysplastic syndromes (MDS), and chronic myelomonocytic leukemia (CMML).

The trial included 35 patients with a median age of 68 years (range, 48-81).

Twenty-seven patients had relapsed/refractory AML, 4 had relapsed/refractory MDS, 2 had untreated AML, 1 had CMML, and 1 had granulocytic sarcoma. Thirty-one patients had R140Q IDH2 mutations, and 4 had R172K IDH2 mutations.

The patients received AG-221 at doses ranging from 30 mg BID to 150 mg QD. Patients completed a median of 1 cycle of treatment (range, <1-5+) and a mean of 2 cycles.

The drug was generally well-tolerated, largely prompting grade 1 or 2 adverse events. Grade 3 or higher events included thrombocytopenia (n=3), anemia (n=1), febrile neutropenia (n=3), sepsis (n=3), diarrhea (n=1), fatigue (n=1), leukocytosis (n=2), neutropenia (n=1), and rash (n=1).

Four patients had serious events possibly related to treatment. One patient had grade 3 confusion and grade 5 respiratory failure. One patient had grade 3 leukocytosis, grade 3 anorexia, and grade 1 nausea. One patient had grade 3 diarrhea. And 1 patient had grade 3 leukocytosis.

Twenty-five patients were evaluable for response. There were 6 complete responses (CRs), 2 CRs with incomplete platelet recovery, 1 CR with incomplete hematologic recovery, and 5 partial responses. Five patients had stable disease, and 6 had progressive disease.

The most responses occurred among patients who received AG-221 at 50 mg BID, and most responses occurred in cycle 1.

Twelve of the 14 responses are ongoing. Of the 8 patients who achieved a CR or CR with incomplete platelet recovery, 5 have lasted more than 2.5 months (range, 1-4+ months). And the 5 patients with stable disease remain on study.

This study is sponsored by Agios Pharmaceuticals Inc., the company developing AG-221 in collaboration with Celgene.

Preparing pills for a trial

Credit: Esther Dyson

The US Food and Drug Administration (FDA) has granted fast track designation for AG-221 to treat acute myelogenous leukemia (AML) patients with mutated isocitrate dehydrogenase-2 (IDH2).

AG-221 is an IDH2 inhibitor under evaluation in a phase 1 trial of patients with advanced hematologic malignancies.

Results from this trial were presented at the 19th Congress of the European Hematology Association, which took place in Milan in June.

The FDA’s fast track drug development program is designed to expedite clinical development and submission of a new drug application (NDA) for drugs with the potential to treat serious or life-threatening conditions and address unmet medical needs.

Fast track designation facilitates meetings between the FDA and the company developing a drug to discuss all aspects of development to support approval. It also affords the developer the opportunity to submit sections of an NDA on a rolling basis as data become available, so the FDA does not have wait for the entire NDA submission before beginning its review.

AG-221 also recently received orphan designation as a treatment for AML. The FDA grants orphan status to support the development of drugs for underserved patient populations or rare disorders that affect fewer than 200,000 people in the US.

Orphan designation affords the drug’s developer certain benefits, including market exclusivity upon regulatory approval, exemption of FDA application fees, and tax credits for qualified clinical trials.

Phase 1 trial results

Thus far in the phase 1 study, AG-221 has proven active and well-tolerated in patients with AML, myelodysplastic syndromes (MDS), and chronic myelomonocytic leukemia (CMML).

The trial included 35 patients with a median age of 68 years (range, 48-81).

Twenty-seven patients had relapsed/refractory AML, 4 had relapsed/refractory MDS, 2 had untreated AML, 1 had CMML, and 1 had granulocytic sarcoma. Thirty-one patients had R140Q IDH2 mutations, and 4 had R172K IDH2 mutations.

The patients received AG-221 at doses ranging from 30 mg BID to 150 mg QD. Patients completed a median of 1 cycle of treatment (range, <1-5+) and a mean of 2 cycles.

The drug was generally well-tolerated, largely prompting grade 1 or 2 adverse events. Grade 3 or higher events included thrombocytopenia (n=3), anemia (n=1), febrile neutropenia (n=3), sepsis (n=3), diarrhea (n=1), fatigue (n=1), leukocytosis (n=2), neutropenia (n=1), and rash (n=1).

Four patients had serious events possibly related to treatment. One patient had grade 3 confusion and grade 5 respiratory failure. One patient had grade 3 leukocytosis, grade 3 anorexia, and grade 1 nausea. One patient had grade 3 diarrhea. And 1 patient had grade 3 leukocytosis.

Twenty-five patients were evaluable for response. There were 6 complete responses (CRs), 2 CRs with incomplete platelet recovery, 1 CR with incomplete hematologic recovery, and 5 partial responses. Five patients had stable disease, and 6 had progressive disease.

The most responses occurred among patients who received AG-221 at 50 mg BID, and most responses occurred in cycle 1.

Twelve of the 14 responses are ongoing. Of the 8 patients who achieved a CR or CR with incomplete platelet recovery, 5 have lasted more than 2.5 months (range, 1-4+ months). And the 5 patients with stable disease remain on study.

This study is sponsored by Agios Pharmaceuticals Inc., the company developing AG-221 in collaboration with Celgene.

Preparing pills for a trial

Credit: Esther Dyson

The US Food and Drug Administration (FDA) has granted fast track designation for AG-221 to treat acute myelogenous leukemia (AML) patients with mutated isocitrate dehydrogenase-2 (IDH2).

AG-221 is an IDH2 inhibitor under evaluation in a phase 1 trial of patients with advanced hematologic malignancies.

Results from this trial were presented at the 19th Congress of the European Hematology Association, which took place in Milan in June.

The FDA’s fast track drug development program is designed to expedite clinical development and submission of a new drug application (NDA) for drugs with the potential to treat serious or life-threatening conditions and address unmet medical needs.

Fast track designation facilitates meetings between the FDA and the company developing a drug to discuss all aspects of development to support approval. It also affords the developer the opportunity to submit sections of an NDA on a rolling basis as data become available, so the FDA does not have wait for the entire NDA submission before beginning its review.

AG-221 also recently received orphan designation as a treatment for AML. The FDA grants orphan status to support the development of drugs for underserved patient populations or rare disorders that affect fewer than 200,000 people in the US.

Orphan designation affords the drug’s developer certain benefits, including market exclusivity upon regulatory approval, exemption of FDA application fees, and tax credits for qualified clinical trials.

Phase 1 trial results

Thus far in the phase 1 study, AG-221 has proven active and well-tolerated in patients with AML, myelodysplastic syndromes (MDS), and chronic myelomonocytic leukemia (CMML).

The trial included 35 patients with a median age of 68 years (range, 48-81).

Twenty-seven patients had relapsed/refractory AML, 4 had relapsed/refractory MDS, 2 had untreated AML, 1 had CMML, and 1 had granulocytic sarcoma. Thirty-one patients had R140Q IDH2 mutations, and 4 had R172K IDH2 mutations.

The patients received AG-221 at doses ranging from 30 mg BID to 150 mg QD. Patients completed a median of 1 cycle of treatment (range, <1-5+) and a mean of 2 cycles.

The drug was generally well-tolerated, largely prompting grade 1 or 2 adverse events. Grade 3 or higher events included thrombocytopenia (n=3), anemia (n=1), febrile neutropenia (n=3), sepsis (n=3), diarrhea (n=1), fatigue (n=1), leukocytosis (n=2), neutropenia (n=1), and rash (n=1).

Four patients had serious events possibly related to treatment. One patient had grade 3 confusion and grade 5 respiratory failure. One patient had grade 3 leukocytosis, grade 3 anorexia, and grade 1 nausea. One patient had grade 3 diarrhea. And 1 patient had grade 3 leukocytosis.

Twenty-five patients were evaluable for response. There were 6 complete responses (CRs), 2 CRs with incomplete platelet recovery, 1 CR with incomplete hematologic recovery, and 5 partial responses. Five patients had stable disease, and 6 had progressive disease.

The most responses occurred among patients who received AG-221 at 50 mg BID, and most responses occurred in cycle 1.

Twelve of the 14 responses are ongoing. Of the 8 patients who achieved a CR or CR with incomplete platelet recovery, 5 have lasted more than 2.5 months (range, 1-4+ months). And the 5 patients with stable disease remain on study.

This study is sponsored by Agios Pharmaceuticals Inc., the company developing AG-221 in collaboration with Celgene.

Researcher in the lab

Credit: Rhoda Baer

Indirectly targeting the prosurvival protein Mcl-1 can reverse chemoresistance in lymphoma and other cancer cells, investigators have reported in The Journal of Biological Chemistry.

The team found that targeting an enzyme known as protein phosphatase 2A (PP2A) inhibited Mcl-1 dephosphorylation, which prompted the loss of Mcl-1 in chemoresistant Burkitt lymphoma cells.

“These findings may lead to a new target for chemoresistant cancer cells,” said Ruth W. Craig, PhD, of Geisel School of Medicine at Dartmouth in Hanover, New Hampshire.

“These cells are resistant to multiple types of standard chemotherapeutic agents because of [Mcl-1] overexpression. However, Mcl-1 expression plummets when we inhibit [PP2A], and then cancer cells subsequently die.”

Dr Craig and her colleagues found that PP2A can be inhibited to stop the removal of phosphate groups from a regulatory motif in Mcl-1 referred to as the PEST region (enriched with amino acids proline, glutamic acid, serine, and threonine).

And inhibiting the removal of phosphate groups, such as at threonine-163 and serine-159, targets the Mcl-1 protein for rapid destruction.

To reach this conclusion, the investigators studied BL41-3 cells, a Burkitt lymphoma cell line that overexpresses Mcl-1 and has proven resistant to multiple treatments.

The team exposed BL41-3 cells to 2 different PP2A inhibitors, okadaic acid and calyculin A. Both drugs prompted an increase in phosphorylation at threonine-163 and serine-159, as well as a decrease in Mcl-1 expression.

Further investigation confirmed that PP2A interacts with Mcl-1. And, as with therapeutic targeting, shRNA knockdown of PP2A/Aα increased phosphorylation while decreasing Mcl-1 expression.

Finally, the investigators showed the increase in Mcl-1 phosphorylation and decrease in its expression occurred well before markers of cell death appeared—about 2 to 3 hours before.

“PP2A is a complex multi-subunit enzyme, and we hope to identify more specifically which form of PP2A is involved in dephosphorylating Mcl-1,” Dr Craig said. “This could [provide us with] a more specific way of causing Mcl-1 destruction.”

Researcher in the lab

Credit: Rhoda Baer

Indirectly targeting the prosurvival protein Mcl-1 can reverse chemoresistance in lymphoma and other cancer cells, investigators have reported in The Journal of Biological Chemistry.

The team found that targeting an enzyme known as protein phosphatase 2A (PP2A) inhibited Mcl-1 dephosphorylation, which prompted the loss of Mcl-1 in chemoresistant Burkitt lymphoma cells.

“These findings may lead to a new target for chemoresistant cancer cells,” said Ruth W. Craig, PhD, of Geisel School of Medicine at Dartmouth in Hanover, New Hampshire.

“These cells are resistant to multiple types of standard chemotherapeutic agents because of [Mcl-1] overexpression. However, Mcl-1 expression plummets when we inhibit [PP2A], and then cancer cells subsequently die.”

Dr Craig and her colleagues found that PP2A can be inhibited to stop the removal of phosphate groups from a regulatory motif in Mcl-1 referred to as the PEST region (enriched with amino acids proline, glutamic acid, serine, and threonine).

And inhibiting the removal of phosphate groups, such as at threonine-163 and serine-159, targets the Mcl-1 protein for rapid destruction.

To reach this conclusion, the investigators studied BL41-3 cells, a Burkitt lymphoma cell line that overexpresses Mcl-1 and has proven resistant to multiple treatments.

The team exposed BL41-3 cells to 2 different PP2A inhibitors, okadaic acid and calyculin A. Both drugs prompted an increase in phosphorylation at threonine-163 and serine-159, as well as a decrease in Mcl-1 expression.

Further investigation confirmed that PP2A interacts with Mcl-1. And, as with therapeutic targeting, shRNA knockdown of PP2A/Aα increased phosphorylation while decreasing Mcl-1 expression.

Finally, the investigators showed the increase in Mcl-1 phosphorylation and decrease in its expression occurred well before markers of cell death appeared—about 2 to 3 hours before.

“PP2A is a complex multi-subunit enzyme, and we hope to identify more specifically which form of PP2A is involved in dephosphorylating Mcl-1,” Dr Craig said. “This could [provide us with] a more specific way of causing Mcl-1 destruction.”

Researcher in the lab

Credit: Rhoda Baer

Indirectly targeting the prosurvival protein Mcl-1 can reverse chemoresistance in lymphoma and other cancer cells, investigators have reported in The Journal of Biological Chemistry.

The team found that targeting an enzyme known as protein phosphatase 2A (PP2A) inhibited Mcl-1 dephosphorylation, which prompted the loss of Mcl-1 in chemoresistant Burkitt lymphoma cells.

“These findings may lead to a new target for chemoresistant cancer cells,” said Ruth W. Craig, PhD, of Geisel School of Medicine at Dartmouth in Hanover, New Hampshire.

“These cells are resistant to multiple types of standard chemotherapeutic agents because of [Mcl-1] overexpression. However, Mcl-1 expression plummets when we inhibit [PP2A], and then cancer cells subsequently die.”

Dr Craig and her colleagues found that PP2A can be inhibited to stop the removal of phosphate groups from a regulatory motif in Mcl-1 referred to as the PEST region (enriched with amino acids proline, glutamic acid, serine, and threonine).

And inhibiting the removal of phosphate groups, such as at threonine-163 and serine-159, targets the Mcl-1 protein for rapid destruction.

To reach this conclusion, the investigators studied BL41-3 cells, a Burkitt lymphoma cell line that overexpresses Mcl-1 and has proven resistant to multiple treatments.

The team exposed BL41-3 cells to 2 different PP2A inhibitors, okadaic acid and calyculin A. Both drugs prompted an increase in phosphorylation at threonine-163 and serine-159, as well as a decrease in Mcl-1 expression.

Further investigation confirmed that PP2A interacts with Mcl-1. And, as with therapeutic targeting, shRNA knockdown of PP2A/Aα increased phosphorylation while decreasing Mcl-1 expression.

Finally, the investigators showed the increase in Mcl-1 phosphorylation and decrease in its expression occurred well before markers of cell death appeared—about 2 to 3 hours before.

“PP2A is a complex multi-subunit enzyme, and we hope to identify more specifically which form of PP2A is involved in dephosphorylating Mcl-1,” Dr Craig said. “This could [provide us with] a more specific way of causing Mcl-1 destruction.”

Red blood cells

Amgen is recalling lots of the erythropoiesis-stimulating agent Aranesp (darbepoetin alfa) that were distributed in several countries outside the US.

The recall applies to 9 lots of Aranesp 500 mcg prefilled syringes from non-US distributors, wholesalers, and hospital pharmacies.

A routine quality examination revealed cellulose and/or polyester particles in a small number of syringes, so Amgen is recalling the 9 lots as a precautionary measure.

To date, there have been no complaints or adverse events that can be attributed to the presence of these particles.

The presence of particulate matter could elicit inflammatory and allergic responses, both chronic and acute, and may be life-threatening.

However, health implications may vary depending on the route of drug administration, the amount of particulate matter injected into the patient, the size of the particles, the patient’s underlying medical condition, and the presence of a right-to-left cardiac shunt.

The products impacted by the recall are Aranesp 500 mcg prefilled syringes. A single lot of Aranesp was packaged for different countries into 9 lots: 1042847, 1044141A, 1044141C, 1044141D, 1046891A, 1046891B, 1047394A, 1047622A, and 1047996A.

The impacted syringes were distributed in Belgium, Denmark, Finland, France, Ireland, Italy, Kuwait, Luxemburg, Russia, Saudi Arabia, Slovenia, Sweden, Switzerland, and the UK.

Consumers in the US who have questions regarding this recall can contact Amgen at 1-800-77-AMGEN (open 24 hours per day, 7 days per week).

Adverse events or quality problems associated with Aranesp can be reported to the US Food and Drug Administration’s MedWatch Adverse Event Reporting Program.

In the US, Aranesp is indicated for the treatment of anemia associated with chronic renal failure, including patients on dialysis and patients not on dialysis, or in patients with non-myeloid malignancies where anemia results from concomitantly administered chemotherapy.

Red blood cells

Amgen is recalling lots of the erythropoiesis-stimulating agent Aranesp (darbepoetin alfa) that were distributed in several countries outside the US.

The recall applies to 9 lots of Aranesp 500 mcg prefilled syringes from non-US distributors, wholesalers, and hospital pharmacies.

A routine quality examination revealed cellulose and/or polyester particles in a small number of syringes, so Amgen is recalling the 9 lots as a precautionary measure.

To date, there have been no complaints or adverse events that can be attributed to the presence of these particles.

The presence of particulate matter could elicit inflammatory and allergic responses, both chronic and acute, and may be life-threatening.

However, health implications may vary depending on the route of drug administration, the amount of particulate matter injected into the patient, the size of the particles, the patient’s underlying medical condition, and the presence of a right-to-left cardiac shunt.

The products impacted by the recall are Aranesp 500 mcg prefilled syringes. A single lot of Aranesp was packaged for different countries into 9 lots: 1042847, 1044141A, 1044141C, 1044141D, 1046891A, 1046891B, 1047394A, 1047622A, and 1047996A.

The impacted syringes were distributed in Belgium, Denmark, Finland, France, Ireland, Italy, Kuwait, Luxemburg, Russia, Saudi Arabia, Slovenia, Sweden, Switzerland, and the UK.

Consumers in the US who have questions regarding this recall can contact Amgen at 1-800-77-AMGEN (open 24 hours per day, 7 days per week).

Adverse events or quality problems associated with Aranesp can be reported to the US Food and Drug Administration’s MedWatch Adverse Event Reporting Program.

In the US, Aranesp is indicated for the treatment of anemia associated with chronic renal failure, including patients on dialysis and patients not on dialysis, or in patients with non-myeloid malignancies where anemia results from concomitantly administered chemotherapy.

Red blood cells

Amgen is recalling lots of the erythropoiesis-stimulating agent Aranesp (darbepoetin alfa) that were distributed in several countries outside the US.

The recall applies to 9 lots of Aranesp 500 mcg prefilled syringes from non-US distributors, wholesalers, and hospital pharmacies.

A routine quality examination revealed cellulose and/or polyester particles in a small number of syringes, so Amgen is recalling the 9 lots as a precautionary measure.

To date, there have been no complaints or adverse events that can be attributed to the presence of these particles.

The presence of particulate matter could elicit inflammatory and allergic responses, both chronic and acute, and may be life-threatening.

However, health implications may vary depending on the route of drug administration, the amount of particulate matter injected into the patient, the size of the particles, the patient’s underlying medical condition, and the presence of a right-to-left cardiac shunt.

The products impacted by the recall are Aranesp 500 mcg prefilled syringes. A single lot of Aranesp was packaged for different countries into 9 lots: 1042847, 1044141A, 1044141C, 1044141D, 1046891A, 1046891B, 1047394A, 1047622A, and 1047996A.

The impacted syringes were distributed in Belgium, Denmark, Finland, France, Ireland, Italy, Kuwait, Luxemburg, Russia, Saudi Arabia, Slovenia, Sweden, Switzerland, and the UK.

Consumers in the US who have questions regarding this recall can contact Amgen at 1-800-77-AMGEN (open 24 hours per day, 7 days per week).

Adverse events or quality problems associated with Aranesp can be reported to the US Food and Drug Administration’s MedWatch Adverse Event Reporting Program.

In the US, Aranesp is indicated for the treatment of anemia associated with chronic renal failure, including patients on dialysis and patients not on dialysis, or in patients with non-myeloid malignancies where anemia results from concomitantly administered chemotherapy.