Download Issue #13 October 2011 In This Issue Workplace Giving Steroids

Issue #13
October 2011
In This Issue
Workplace Giving
Steroids & Vitamin D
Coming Soon...
The Diamond Blackfan Anemia Foundation (DBAF) is committed to
keeping you updated and connected to the entire DBA community.
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DBA Fact
Oral Steroids Linked to Severe Vitamin
D Deficiency in Nationwide Study
Get All the News
DBAF Journal Club
(reprinted with permission from Albert Einstein School of
Medicine)
Workplace Giving
September 29, 2011 (BRONX, NY) - People taking oral steroids are
twice as likely as the general population to have severe vitamin D
deficiency, according to a study of more than 31,000 children and
adults by scientists at Albert Einstein College of Medicine of Yeshiva
University. Their findings, in the September 28 online edition of The
Journal of Clinical Endocrinology and Metabolism, suggest that
physicians should more diligently monitor vitamin D levels in
patients being treated with oral steroids.
The Diamond Blackfan Anemia Foundation
relies on the support of our friends and
families to continue our mission of
supporting DBA patients, families, and
research.
Once again we are asking for your help.
Many employers and companies offer their
employees an opportunity to donate to an
organization through a payroll deduction
program or participate in a matching gift
program. The payroll deduction programs
"When doctors write that prescription for steroids
and they're sending the patients for lab
tests, they should also get thevitamin D
level measured," said study lead author
Amy Skversky, M.D., M.S., assistant
professor of pediatrics at Einstein and
Montefiore Medical Center, the
University Hospital for Einstein.
Amy Skversky, M.D., M.S.
The severe vitamin D deficiency
assessed in this study (defined as levels
below 10 nanograms per milliliter of blood) is known to be
associated with osteomalacia (softening of the bones), rickets
and United Way payroll designation
programs make donating easy. The
matching gift programs are a great way to
double your contribution! The DBA
Foundation is a 501(c)(3) organization and
is eligible to take advantage of these
generous company-based programs.
(softening of bones in children) and clinical myopathy (musc le
weakness). While there is much debate on the issue, vitamin D
levels between 20 and 50 ng/ml are generally considered adequate
for bone and overall health in healthy individuals. Steroids have
been shown to cause vitamin D deficiency, possibly by increasing
levels of an enzyme that inactivates the vitamin.
To find out if your employer participates in
a charitable giving program, it's as easy as
visiting your Human Resources Department
or checking the company's website. The
DBAF is happy to assist you in filling out the
necessary paperwork.
Smaller studies involving people often prescribed steroids (i.e.,
children with asthma and patients with Crohn's disease and lupus)
have found significantly reduced vitamin D levels in these patients.
To further assess this association between steroid use and vitamin
D levels, the Einstein researchers carried out the first-ever study of a
large, nationally representative sample of people.
The researchers examined data collected from participants who had
participated in the National Health and Nutrition Examination Survey
Over the last few years, donations received 2001-2006. About one percent of the participants answered "yes"
through payroll deductios and matched gifts when asked if they had used oral steroids during the previous 30
days.
have markedly increased. We are grateful
to our donors and their employers for their
continued support. We encourage
everyone to take advantage of these
workplace options to help maximize your
charitable giving.
Please contact the DBA Foundation for
further information at
DBAFoundation@juno.com
THANK YOU!
Upcoming Events
DBA Fishing Tournament
October 9, 2011
1:00 - 5:00pm
Four Oaks, NC
Contact:
Tracy Adams
tda101194@yahoo.com
Blood Drive & DBA Fundraiser
Eleven percent of the self-reported steroid users had severely low
vitamin D levels compared with a severe vitamin D deficiency of 5
percent for people not taking steroids - a two-fold increased risk for
severe vitamin D deficiency. The risk was particularly pronounced
for steroid users under 18, who were 14 times more likely to have a
severe vitamin D deficiency compared with young non-steroid users.
(Participants who reported using inhaled steroids were not included
in the steroid-user group.)
The paper is titled "Association of Glucocorticoid Use and Low 25Hydroxyvitamin D Levels: Results from the National Health and
Nutrition Examination Survey (NHANES): 2001-2006." Co-authors
include senior author Michal Melamed, M.D., M.H.S., Matthew
Abramowitz, M.D., M.S., and Frederick Kaskel, M.D., Ph.D., all at
Einstein; and Juhi Kumar, M.D., M.P.H. at Weill Cornell Medical
Center. This research was funded by the National Institute of
Diabetes and Digestive and Kidney Diseases and the National
Institutes of Health and National Center for Research Resources,
both part of the National Institutes of Health.
October 14, 2011
Schumacher Elementary School
1:00 - 7:00pm
Liberty, MO
Contact:
Lea Ann Soto
mustangsoto@hotmail.com
Kevin J. Gately Foundation
Golf Outing
October 17, 2011
Black Swan Country Club
Georgetown, MA
Contact:
KJGFoundation@gmail.com
617-240-3094
Shopping Day for DBA
Retail Therapy for a Cure
October 19, 2011
11:00am - 6:30pm
Acworth, GA
Contact:
Kathi Vroman
kavroman@aol.com
Jack's Fight for a Cure
DBA Dinner & Dance Gala
to benefit DBAC
November 11, 2011
Orangeville Agricultural Center
Orangeville, Ontario
Canada
Contact:
Janet Pereira
janet@jacksfightforacure.com
Ongoing Fundraisers
Mixed Bags Designs
Contact:
Vickie Lamb
Use Code: 69293
To order online visit:
Coming Soon to a Window Near You!
Coming soon! This awesome 5" x 5"
window sticker will be available to
display on your car, windows, and
mirrors. Help spread our message
and support our mission.
Michelle Holdren, mother to 11
month old Ethan, will be announcing
details shortly. Thanks, Michelle!
How Can YOU Help?
The DBAF is reaching out to our families and
friends to help us to grow and to fulfill our
mission. Your gifts of time, talents, and
treasure are appreciated and necessary for
our continued success.
If you have a talent or area of expertise that
you feel may benefit the DBAF, please
contact us at DBAFoundation@juno.com. We welcome your ideas!
Donating is easy and all contributions are tax-deductable. Please
visit our Donate Page for details. If you are interested in organizing a
fundraiser to benefit the DBAF, please contact us at
DBAFoundation@juno.com. THANK YOU!
Take the Challenge ~ Show Us Your
Logo
T-shirts, hats, coffee
mugs, face paintings,
tattoos, bags, pumpkins ...
our logo is showing up
everywhere! We are
thrilled that our beautiful
logo is proudly being worn
and displayed by patients,
families, and friends.
http://www.mixedbagdesigns.com/
Maddy Lapierre, mom to
DBA patient Mark
Lapierre, dedicated her
time and talent to craft a
beautiful hand-made quilt
for Camp Sunshine. DBA
patients and families
signed their names and
messages of gratitude and
appreciate in every quilted
heart, and proudly presented it to Camp Sunshine. The quilt, made
with love, will wrap many Camp families in DBA compassion and
warm wishes. Thank you Maddy for making this treasured gift
possible.
Wristbands Available
Contact:
Twila Edwards
twilak@cox.net
Here's the challenge: we'd like to
see how many places we can show
off our logo! Snap a picture sporting
our logo and send us your story. Draw it,
print it out, wear it, wave it, tattoo it,
carve it... be creative! Take us to school,
on vacation, to the hospital, on a plane,
to the game, in your home... anywhere!
Show us your logo! Send your photos
and stories to
DBAFoundation@juno.com.
DBA Fact #6
Tribute Cards Available
(2 styles)
In honor of...
Our Facebook page posts DBA facts written
by DBA nurse, Ellen Muir, RN, MSN, CPON.
We are pleased to share these facts with our
patients and families. Thanks, Ellen!
In memory of...
Contact:
Dawn Baumgardner
dbaumgardner@dbafoundation.org
716.674.2818
We have been working closely with an adult
endocrinologist, Dr. Irwin Klein, at the
Feinstein Institute for Medical Research, who
has done a lot of research studying heart
disease in relation to thyroid dysfunction.
Being that DBA patients who are chronically
transfused have thyroid issues due to iron
Ellen Muir
overload, he has taken an interest in working
with us to prevent thyroid disease as well as cardiac failure due to
thyroid dysfunction. As we know, other endocrine organs are also
affected - pancreas, gonads, pituitary, as well as linear height. Here
is a list of recommended labs to monitor and prevent the devastating
effects of iron overload in the thyroid, heart, and the effects of
diabetes:
total T3
total
T4
TSH
DBA Cookbooks Available
Contact:
T3 uptake (instead of free
T4)
Betty Lightner
betty.lightner@gmail.com
To download your order form:
http://issuu.com/bhivemom/docs/cookboo
k_order_form-pdf
IGF-1(monitors acute fluctuations in insulin action and determines
inadequate insulin treatment or poor control of dietary intake)
NT-proBNP (aids in
diagnosis of left ventricular dysfunction in heart failure)
Antithyroid Abs (Antithyroglobulin and AntiThyroperoxidase)
Fructosamine (useful in situations where the A1C cannot be reliably
measured - as with transfused persons)
Vitamin D
Any questions, please feel free to e-mail me emuir@nshs.edu or call
1-877-DBA-NURSe (322-6877).
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the web and shopping online!
To stay "in the know" and to receive all the DBAF's updates, please
ensure we have your correct contact information. Complete the
secure form at
http://www.dbafoundation.org/registration.php
Help us to reach all our families. If you are aware of other DBA
Just download the GoodSearch - Diamond families in your area, please encourage them to contact to the DBA
Blackfan Anemia Foundation - DBAF toolbar Foundation.
at
http://www.goodsearch.com/toolbar/diamo
nd-blackfan-anemia-foundation-dbaf
Please note that the Diamond Blackfan Anemia Registry
(DBAR) and the Diamond Blackfan Anemia Foundation (DBAF),
are not allowed to share your personal information. It is
necessary to register with both the DBAR and the DBAF.
If you have any questions, or to check on the status of your
information, contact Dawn at DBAFoundation@juno.com.
Journal Club
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This month's Journal Club is not a
Journal Club per se, as no single
manuscript prompted this discourse.
Instead, I will use this space to expand
on a subject that has been raised
before on numerous occasions... p53.
I've mentioned p53 in the context of
how haploinsufficiency for ribosomal
proteins leads to its activation, and
how this could account, in part, for the
premature death of erythroid
progenitors in the marrow of DBA
patients (DBAF newsletters; November
2010, April 2011).
Steven R. Ellis, PhD
Research Director
What then is p53?
:: 716-674-2818
Let us begin with the name. p53... rather dull, don't you think? The p
of p53 stands for protein; so alas, p53 is a protein. Proteins in turn
are polymers of amino acids that fold into complex three
dimensional structures that are capable of a wide range of functions.
These functions include antibodies of the immune system, the light
harvesting proteins of vision, proteins involved in muscle
contraction, thousands of enzymes involved in intermediary
metabolism, ribosomal proteins, and the list goes on and on.
Proteins are capable of a wide range of functions because of the
astronomically large number of structures they can assume. These
structures are ultimately dictated by the order of 20 common amino
acids along the length of a protein as they are polymerized during
protein synthesis. The order of amino acids in a protein is dictated
by the gene encoding that protein. The number of amino acids which
comprise a protein brings me to the 53 in p53's name. The 53 refers
to p53's size, or at least its apparent size, of 53,000 Daltons when
analyzed by a routine laboratory gel electrophoresis technique. It is
composed of 393 amino acids. This size is not unduly large or small
for a protein, and so from a size perspective, p53 is fairly average.
Despite its fairly average size there is really nothing average at all
about what p53 does. To give you a feel for just how important p53
is, a search for p53 in the scientific literature compiled in PubMed
gave 59,781 manuscripts that touched on this protein. For a frame of
reference, a similar search for Diamond Blackfan anemia gave 578
hits.
So, what is the function of p53 within a cell? One of the major
functions for p53 is as a transcription factor. Transcription is the
process by which a sequence of bases in DNA (genes) is converted
to a sequence of bases in RNA. RNA then dictates the sequence of
amino acids in a protein, through a process known as translation.
Transcription factors play a central role in turning genes on and off
in response to a vast array of physiological, developmental, and
environmental signals 1. The p53 protein gets activated through a
variety of signals emanating from various cell stressors including
DNA damage, oxidative stress, oncogenic stress, and yes, now
even ribosome stress. In response to these stress signals, p53
stimulates the expression of a number of genes, some of which
arrest cell division and others of which may function to resolve the
stress imposed on the cell. If the stress is too great for the cell to
resolve, p53 may also initiate a cell death program. In responding to
oncogenic (or cancer promoting) stresses, one can think of the p53
response as putting the brakes on cancer. As such, p53 is classified
as a tumor suppressor. It should come as no surprise therefore that
p53 is frequently inactivated in human cancers.
So having p53 around is a good thing right? Well yes... and no.
Activation of p53 in response to DNA damage or oncogenic stress
protects against cancer. But, it has also been proposed that
activation of p53 in response to oxidative stress plays a role in aging
2
, and as mentioned above, activation of p53 in response to
ribosome stress likely contributes to the pathophysiology of
DBA 3. Consequently, just as in the Goldilocks story, p53 has to be
maintained at levels that are just right... responding to appropriate
signals in its protective role while at the same time being held in
check to temper its contribution to pathogenic states.
To maintain p53 at levels that are "just right" while still allowing p53
to fulfill its critical functions, this remarkable protein is shackled with
numerous levels of control that often have layers of redundancy.
One such level of control is mediated by the protein MDM2, which
modifies p53 with a molecule known as ubiquitin. Ubiquitinated p53
is then directed to cellular garbage disposals where p53 is degraded
4
. The action of MDM2 on p53 keeps p53 levels relatively low in
normal cells that are not exposed to stress. While making and
degrading p53 under non-stressful conditions may seem wasteful,
this control strategy allows for a rapid response in times of stress.
For example, signals resulting from DNA damage disrupt the
MDM2/p53 interaction, so p53 is no longer labeled for degradation
allowing p53 levels to quickly rise in response to this environmental
insult.
The action of MDM2 however, represents only one level of control of
p53 function. In addition to ubiquitination, p53 is subject to a large
number of chemical modifications that also regulate its function.
These modifications include phosphorylation, acetylation,
methylation, sumoylation, and neddylation (yes, neddylation) 1. A
conservative estimate in a recent publication places the number of
confirmed modifications of p53 at 52 5. These various modifications
superimpose additional, sometimes overlapping, layers of control on
p53 and allow its function to be fine tuned to cellular demands. By
dissecting the different signaling pathways that direct these various
modifications it may be possible to develop drugs that target a
specific pathway of p53 activation while leaving others essentially
intact. This approach may allow the development of treatments for
pathologies linked to inappropriate activation of p53 without having
an unduly high risk of promoting cancer.
By targeting the enzymes that modify p53, the DBA community
could tap into a very robust area of drug development. Drugs
targeting enzymes that carry out protein phosphoryation have
transformed certain deadly cancers to chronic diseases 6. Less
specific drugs targeting protein acetylation and methylation have
also shown promise in cancer clinical trials with the hope that these
drugs will show improved success as they are refined to target more
specific modifying enzymes 7.
CONCLUSION
By learning more about the signaling pathway from ribosome stress
to p53 activation, it may be possible to specifically target this
pathway, while leaving other pathways to p53 activation largely
intact, thereby reducing the cancer risks associated with targeting
p53 activation as a possible therapy for DBA.
1. Brooks CL, Gu W. New insights into p53 activation. Cell Res;20:614621.
2. Yi J, Luo J. SIRT1 and p53, effect on cancer, senescence and beyond.
Biochim Biophys Acta;1804:1684-1689.
3. Dutt S, Narla A, Lin K, et al. Haploinsufficiency for ribosomal protein
genes causes selective activation of p53 in human erythroid progenitor cells.
Blood;117:2567-2576.
4. Vucic D, Dixit VM, Wertz IE. Ubiquitylation in apoptosis: a posttranslational modification at the edge of life and death. Nat Rev Mol Cell
Biol;12:439-452.
5. Dai C, Gu W. p53 post-translational modification: deregulated in
tumorigenesis. Trends Mol Med;16:528-536.
6.
Santos FP, Quintas-Cardama A. New drugs for chronic myelogenous
leukemia. Curr Hematol Malig Rep;6:96-103.
7. Wanczyk M, Roszczenko K, Marcinkiewicz K, Bojarczuk K, Kowara M,
Winiarska M. HDACi--going through the mechanisms. Front Biosci;16:340359.