Blood First Edition Paper
prepublished online January 9, 2003; DOI 10.1182/blood-2002-07-1952

Submitted July 2, 2002
Accepted November 1, 2002

Experience with alemtuzumab plus
rituximab in patients with relapsed and
refractory lymphoid malignancies

Stefan Faderl*, Deborah A Thomas, Susan O'Brien, Guillermo
Garcia-Manero, Hagop M Kantarjian, Francis J Giles, Charles
Koller, Alessandra Ferrajoli, Srdan Verstovsek, Barbara Pro, Michael
Andreeff, Miloslav Beran, Jorge Cortes, William Wierda, Ngoc Tran, and
Michael J Keating

Department of Leukemia, The University of Texas M. D. Anderson Cancer
Center, Houston, TX, USA

* Corresponding author; email: sfaderl@....

We explored the safety and efficacy of rituximab plus alemtuzumab in
patients with relapsed/refractory lymphoid
malignancies. Forty-eight patients have been treated and are assessable
for response (32 CLL, 9 CLL/PLL, 1
PLL, 4 mantle cell leukemia/lymphoma, 2 Richter's transformation). The
overall response rate was 52% (CR 8%,
nPR 4%, PR 40%). With a median follow up of 6.5 months (range 1-20
months), the median time to progression
is 6 months (range 1-20), and median survival 11 months (11+ months for
responders versus 6 months for
non-responders). Most toxicities were  grade 2 and infusion-related.
Infections occurred in 52% of the patients.
CMV antigenemia was positive in 27%, but only 15% of the patients were
symptomatic requiring therapy. The
combination of rituximab and alemtuzumab is feasible, has an acceptable
safety profile, and has clinical activity with
a short course in a poor prognosis group of patients.

I just realized that my post of Thurs. Jan. 16 did not include an
attachment which may have had a virus.  Sorry for any inconvenience I
may have caused U.  Hal Skye.

I have been notified that in my prior post; the fwd. message's
attachment may contain a virus. Please take necessary precautions.   Hal
Skye

Someone with access to the Cll  lists must be sending this message out
at random.  I find it, to say the least,  somewhat disturbing. Has
anyone else received such a message?  The "poster's" name is fictious;
as my reply "to refrain" has been bounced back. If the sender reads this
message, I suggest he (or she) come fwd. with their identity; and cease
and desist sending me  this type of message immediately.   Hal Skye.



[Non-text portions of this message have been removed]

I tried to reach you off-line but my post was bounced back as your
mailbox is full.  We R all waiting impatiently 4 the "big" research
breakthrough to alleviate our condition. Be well.  Hal Skye.

----- Original Message -----
From: Ruth Simpson
To: julie anderson ; judy beaird ; bettyann deweese ; rhonda spencer ; amber
snowden ; karen snowden
Sent: Monday, January 13, 2003 5:49 PM
Subject: Fw: The Lord's Prayer



----- Original Message -----
From: Judy/Larry McCormick
To: Julie ; 3-Marsha ; 3-Jean ; 2-Stephanie ; 2-Ed ; 2-Anita ; 1-Sis&Jeff ;
1-Shari ; 1-Ruth ; 1-Pat&LeRoy ; 1-Mary&Larry ; 1-Marie&Ted ; 1-Louise&Steve ;
1-Lora ; 1-Kathy ; 1-Delories-my sissy/girlfriend ; 1-Daphne&Claude ; 1-Carolyn
; 01-Dale
Sent: Thursday, January 09, 2003 11:07 AM
Subject: The Lord's Prayer


The Lord's Prayer


Stop whatever you are doing for the next 60 seconds.

Just say "The Lords Prayer" for the person that sent you to this site:

Our Father, who art in Heaven, Hallowed be Thy Name, Thy Kingdom Come, Thy Will
be done, on Earth as it is in Heaven. Give us this day, our daily bread and
forgive us our trespasses as we forgive those who trespass against us and lead
us not into temptation but deliver us from all evil. For Thine is the Kingdom,
and the Power, and the Glory, forever and ever. Amen.

Now just send this message to everyone you know.
Within hours, many people will have prayed for you,
and you caused a multitude of people to pray to
God for other people.

Then sit back and watch the power of God work in
your life for doing the thing that you know he LOVES.

If you aren't ashamed to do this, please follow the
instructions. Jesus said, "If you are ashamed of me,
I will be ashamed of you before my Father." Pass this
on only if you believe and mean it. Yes, I do Love my God.
He is my source of existence, my guiding light, my strength,
my savior, my redeemer.

He keeps me functioning each and everyday.
Without Him, I would be be nothing.
Without Him, I am nothing... But with Him
I can do all things through Christ that strengthens me. (Phil 4:13)

This is a simple test. Take 60 seconds & give this a shot!
Let's just see if Satan stops this one!

If you love God and are not ashamed of all the marvelous things
that he has done for you, send this to everyone you know.











[Non-text portions of this message have been removed]

We are currently looking for three CRA's and a CR Project Leader with LEUKEMIA
experience for positions in New Jersey/USA. Below please find detailed job
descriptions. If you meet all of the requirements of a job description and would
like to learn more, please send your resume to jfrese@...
referencing the position you are interested in.

If you know anyone in the industry who might be interested and qualified, I
would appreciate if you could forward this email to them.



Thanks in advance for your cooperation.



Sincerely,



Jeanne Frese - President
Recruiting Services International, Inc.
Email: jfrese@...
Web:  www.recruitingservicesintl.com


Clinical Research Project Leader-Oncology

Job Description: Project management for a Phase 3 study in LEUKEMIA. Will be
involved with a large expanding program of studies and be directly responsible
for the management of HQ (domestic/international), Field based and CRO CRAs as
applicable, in the timely implementation of clinical trials in full compliance
with SOPs and government regulations. Responsible for the timely generation and
finalization of quality data. Results are intended to gain regulatory approval
for drugs/biologics and provide clinical support for marketing objectives.
Responsible for planning, monitoring and tracking clinical studies, reviewing
protocols, and mentoring new CRAs. Oversight of CRO monitors while coordinating
field and in-house clinical monitoring and supervision of day to day activities
and assignments. In association with Project Director(s), will be responsible
for the management of global clinical projects including interaction with
support groups to insure efficient and timely completion of projects. Acts as
liaison with outside vendors. Provides formalized training for new and
entry-level CRAs and supervises the monitoring staff on specific projects.

Requirements: BS degree in Life Sciences is preferred. Nursing background is
helpful. Minimum of 5 years of direct industry CRA monitoring experience
required with a minimum total related clinical research experience of 6 years.
Prior study/CRO management experience required. Prior oncology experience
required (please detail types and amount of experience on submissions). LEUKEMIA
experience preferred. Prior Electronic Data Capture experience preferred. Major
Pharmaceutical experience preferred. Travel requirement: up to 25%. Prior
international experience required.
Job Location: Linden, NJ, USA
Salary Range: $95000 - $105000, plus 6% bonus, plus profit sharing
Excellent benefits including relocation.

CRA - Clinical Research Associate
Major Global Pharmaceutical leader located in central New Jersey is is need of
three (3) In-house CRAs to monitor domestic sites for Non-Small Cell Lung Cancer
(Breast Cancer) or LEUKEMIA programs. Minimum of two year's of direct industry
CRA monitoring experience required with a minimum total related clinical
research experience of three years. Prior oncology experience required,
LEUKEMIA/NSCLC preferred (must detail types and amount of experience in resume).
Major Pharmaceutical experience preferred. Electronic Data Capture experience as
a monitor preferred (this must be a remote data entry system, not a fax based
system). Travel requirement: 50-70% average. BS degree required, preferably in
life sciences. Position is based out of our client's headquarters facility in
central New Jersey.
Job Location: New Brunswick, NJ, USA
Salary Range: up to $85000
Excellent benefits including relocation.

[Non-text portions of this message have been removed]

Guy,

You don't need to type the http to get to a website.  I
only type www.whatever.whatever.  or
www.whatever@....

Gretchen

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BMJ 2003;326:106 ( 11 January )
Letters
Why are miraculous cures mainly of cancer?

EDITOR---In his personal view Westcott asks whether
miracles can happen.1 Many of the apparently well
authenticated cases of miraculous cures seem to be of
cancer. Occasionally cases of spontaneous remission of
cancer occur outside a religious context. This implies
that in certain rare circumstances an effect, probably
immune mediated, can happen that results in complete
remission. The psychological state of the patient is
undoubtedly relevant through well known connections
between the nervous system and the immune system.

The claim that this is evidence of divine intervention
is harder to sustain. If this were the case we would
presumably hear convincing accounts of cures in cases
where spontaneous recovery does not occur. This need
not be as dramatic as regrowth of an amputated limb:
recovery of the integrity of the optic nerve in a
patient with visual loss from glaucoma would do.

Such cases do not seem to occur, which suggests to me
that the cancer cures, no matter how impressive and
gratifying, are events that can be accommodated in the
framework of the natural world.

Anthony Campbell, retired consultant physician, Royal
London Homoeopathic Hospital.
London N14 5NN ac@...

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(These drugs are primarily used in arthritis)

LYMPHOMA NEWSLINE

Article # 649

               Date: 1/7/2003

Etanercept and Infliximab May Be Associated with
Development of Lymphoma

January 2, 2003 (Reuters) -

NEW YORK - The tumor necrosis factor (TNF) antagonists
etanercept and infliximab may be associated with
lymphoproliferative disorders, according to a review
of MedWatch reports.

Dr. M. Miles Braun and colleagues, from the U.S. Food
and Drug Administration (FDA) and the National Cancer
Institute (NCI) in Rockville, MD, identified 26
reports of lymphoma subsequent to the initiation of
anti-TNF therapy between May 1999 and December 2000.
Between November 2001 and September 2002, another 68
cases reported to the FDA's passive postmarket adverse
event reporting system were classified as having a
"probable or possible" association with these two
medications.

In the December issue of Arthritis and Rheumatism, the
researchers thoroughly reviewed data from the earlier
cohort. The indication for TNF antagonist use was
rheumatoid arthritis in 18 of the 26 cases, psoriatic
arthritis for two and Crohn's disease for five cases.
For one case the indication was not specified.

Among the 18 patients given etanercept, lymphoma was
diagnosed a median of eight weeks (range two to 52
weeks) after starting therapy. The median duration of
treatment with infliximab before diagnosis was six
weeks (range two to 44 weeks) for seven of the eight
cases.

"Currently available data do not permit us to draw
definitive conclusions regarding whether these TNF
antagonists were the proximate cause of the reported
lymphomas, whether these neoplasms developed as part
of the natural history of the underlying medical
conditions, or whether they occurred as a complication
related to other immunosuppressive medications to
which these patients were exposed," the investigators
write.

Further implicating the antagonists, however, was the
"striking" observation that the latent period was
quite similar to that associated with lymphomas that
develop following immunosuppressive therapy for
patients who receive organ transplants, the
investigators note.

Dr. Braun's group identified two patients previously
treated for lymphoma who relapsed "very quickly" after
being started on anti-TNF therapy. Therefore, they
suggest that such individuals be considered ineligible
for such treatment, at least until this issue is
clarified.

They also found that in two patients, one treated with
etanercept and one with infliximab, there was
regression of their lymphoma once treatment was
discontinued. Patients should be monitored for
"spontaneous remission" after withdrawal of the agent
to see if cytotoxic chemotherapy can be avoided, "if
the patient's clinical condition permits," they add.

Finally, Dr. Braun's group urges clinicians to report
similar cases to MedWatch with as much clinical detail
as possible.

Arthritis Rheum 2002;46:3151-3158.

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Actually, both http://cll.ucsd.edu and
http://www.cll.ucsd.edu work.

The old site address was the former.  It was pretty
much an unutilized resource.

Nice to see UC San Diego and the consortium spend some
money getting this going.  It indeed is a very good
resource.


--- Guy Rich <grich101@...> wrote:
> Minor glitch in the address below.  Should be
> http://www.cll.ucsd.edu/
> Thanks for the info, Gretchen. Looks like a good
> site.
>
> Guy Rich
>
> ----- Original Message -----
> From: "Nelson or Gretchen Cover"
> <ncoverjr@...>
> To: <CLLResearch@yahoogroups.com>
> Sent: Saturday, January 11, 2003 8:49 AM
> Subject: Re: [CLLResearch] CLL Consortium site
> address
>
>
> > OK. I got unlazy.  Here is the consortium website
> address
> > for those who don't want to search for it:
> >
> > www.cll.uscd.edu
> >
> > Gretchen Cover
> >
>
>
>


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Minor glitch in the address below.  Should be http://www.cll.ucsd.edu/
Thanks for the info, Gretchen. Looks like a good site.

Guy Rich

----- Original Message -----
From: "Nelson or Gretchen Cover" <ncoverjr@...>
To: <CLLResearch@yahoogroups.com>
Sent: Saturday, January 11, 2003 8:49 AM
Subject: Re: [CLLResearch] CLL Consortium site address


> OK. I got unlazy.  Here is the consortium website address
> for those who don't want to search for it:
>
> www.cll.uscd.edu
>
> Gretchen Cover
>

OK. I got unlazy.  Here is the consortium website address
for those who don't want to search for it:

www.cll.uscd.edu

Gretchen Cover

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I just checked out the website. If you have an older
monitor, the slide show may not be clear. I found it worked
best by clicking on the slide show icon at the bottom and
then clicking on full screen.  You can then click on the
tornado icon on the bottom right corner of the slide show
or click the arrow keys under the slide show to change
slides.

Quite frankly, the best thing was to go to the public
website listed on one of the slides. (I forgot to write it
down to post).  It had links and other useful information
for CLL.

Gretchen Cover

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Study Suggests Way to Boost Blood-Platelet Supply
Fri January 10, 2003 05:34 PM ET

NEW YORK (Reuters Health) - New research hints at a
possible way to extend the shelf-life of platelets,
tiny blood cells that are used in millions of
transfusions each year, yet often go to waste because
they cannot be refrigerated.

Scientists have long puzzled over why chilling renders
platelets useless for transfusion--a fact that makes
the cells different from other blood products, and all
transplantable tissue.

Now researchers at Harvard University and Brigham and
Women's Hospital in Boston, Massachusetts believe they
have discovered why: Chilling platelets causes a
change on the blood cells' surface that ultimately
makes them targets for removal after they are
transfused into the recipient.

The scientists speculate that making specific changes
to the platelets could permit the cells to be chilled,
yet still function normally after transfusion.
Dr. Karin M. Hoffmeister and her colleagues report
their findings in the January 10th issue of the
journal Cell.
Platelets are necessary for normal blood clotting and
protect against blood loss by clumping together at the
site of a vessel injury. Platelet deficiency due to
bone marrow failure can lead to life-threatening
bleeding, and less severe deficiencies can spur
bleeding after surgery or injury. Platelet
transfusion--performed more than 4 million times in
the US each year--can counter these problems.

However, Hoffmeister's team point out, it's estimated
that up to half of the US platelet supply goes to
waste because of its short, 5-day shelf-life at room
temperature.

Platelets are able to stick to blood vessel damage
spots, in part, because they have receptors on their
surface that bind to von Willebrand factor (vWf), a
protein that also arrives at the site of vessel
injury.
In the new study, the researchers found that chilling
causes these vWf receptors to form clusters on the
platelets' surface. This, in turn, causes a receptor
on white blood cells in the liver called CR3 to target
and remove the platelets from the blood circulation.
However, in mice that lacked the CR3 receptor, chilled
platelets did not disappear from circulation and were
able to function normally.

All of this suggests that altering the vWf receptors
on platelets could allow the cells to be refrigerated
without harming their usefulness for transfusion,
according to the researchers.

In a statement, study co-author Dr. Thomas P. Stossel
said: "Refrigeration of platelets could significantly
impact platelet transfusion technology by increasing
available platelet supplies."
SOURCE: Cell 2003;112:87-97.


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Mol Cancer Ther 2002 Dec;1(14):1321-6

2-[4-(7-chloro-2-quinoxalinyloxyphenoxy]-propionic
acid (XK469), an inhibitor of topoisomerase (Topo)
IIbeta, up-regulates Topo IIalpha and enhances Topo
IIalpha-mediated cytotoxicity.

Mensah-Osman EJ, Al-Katib AM, Wu HY, Osman NI,
Mohammad RM.

Division of Hematology and Oncology, Department of
Internal Medicine, Karmanos Cancer Institute, Detroit,
Michigan 48201, USA.

Topoisomerase (Topo) IIalpha has proven to be an
adequate anticancer target for tumors expressing this
enzyme. In this study, we elucidated the effect of
2-[4-(7-chloro-2-quinoxalinyloxyphenoxy]-propionic
acid (XK469; a new Topo IIbeta inhibitor) in the
modulation of Topo IIalpha levels and sensitivity to
Topo IIalpha poisons.

We demonstrate by Western blot analysis that indolent
B-cell tumors express undetectable levels of this
enzyme and are refractory to the effects of Topo
IIalpha poisons such as VP16. Using the Waldenstrom's
macroglobulinemia (WM) cell line WSU-WM, we show that
XK469 induced the expression of Topo IIalpha protein
by 24 h compared with control. Immunofluorescence
studies by confocal microscopy using a specific
monoclonal antibody against Topo IIalpha supported the
immunoblot findings with high intensity staining in
XK469-exposed cells.

To determine the effect of up-regulating Topo IIalpha
on sensitivity of Topo IIalpha-directed inhibitors,
WSU-WM cells were exposed to simultaneous, sequential,
and reverse order XK469 and VP16. We demonstrate that
24 h of exposure to XK469 before VP16 resulted in a
maximum synergistic response. In contrast,
simultaneous or reverse order exposure resulted in an
antagonistic effect.

A similar trend was observed with cells obtained from
chronic lymphocytic leukemia patients, but not in
normal lymphocytes. This increase in VP16 sensitivity
after 24 h of XK469 exposure was associated with
VP16-dependent DNA cleavage, as demonstrated by
formation of a smeared DNA band in a SDS-KCL DNA
cleavage assay.

From this study, we concluded that XK469 up-regulates
Topo IIalpha levels and consequently sensitizes
indolent malignant B cells to the cytotoxic effect of
VP16 in a schedule-dependent manner.

PMID: 12516965 [PubMed - in process]


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Blood First Edition Paper
prepublished online January 9, 2003

Submitted August 1, 2002
Accepted December 23, 2002

Acadesine activates AMPK and induces apoptosis in
B-cell chronic lymphocytic leukemia cells but not in T
lymphocytes

Clara Campas, Jose M Lopez, Antonio F Santidrian,
Montserrat Barragan, Beatriz Bellosillo, Dolors
Colomer, and Joan Gil*
Unitat de Bioquimica, Departament de Ciencies
Fisiologiques II, Universitat de Barcelona, Barcelona,
Spain
Unitat d'Hematopatologia, Institut d'Investigacions
Biomediques August Pi i Sunyer (IDIBAPS), Hospital
Clinic, Barcelona, Spain
* Corresponding author; email:
joangil@...
<mailto:joangil@...>.

Acadesine, 5-aminoimidazole-4-carboxamide (AICA)
riboside, induced apoptosis in B-cell chronic
lymphocytic leukemia (B-CLL) cells in all samples
tested (n=70). The IC50* for B-CLL cells was 380 ± 60
µM (n=5).

The caspase inhibitor Z-VAD.fmk completely blocked
acadesine-induced apoptosis, which involved the
activation of caspases -3, -8 and -9 and cytochrome c
release.

Incubation of B-CLL cells with acadesine induced the
phosphorylation of AMP-activated protein kinase
(AMPK), indicating that it is activated by acadesine.
Nitrobenzylthioinosine (NBTI), a nucleoside transport
inhibitor, 5-iodotubercidin, an inhibitor of adenosine
kinase, and adenosine completely inhibited
acadesine-induced apoptosis and AMPK phosphorylation,
demonstrating that incorporation of acadesine into the
cell and its subsequent phosphorylation to AICA
ribotide (ZMP) are necessary to induce apoptosis.

Inhibitors of protein kinase A and MAP kinases did not
protect from acadesine-induced apoptosis in B-CLL
cells. Moreover, acadesine had no effect on p53 levels
or phosphorylation, suggesting a p53-independent
mechanism in apoptosis triggering.

Normal B lymphocytes were as sensitive as B-CLL cells
to acadesine-induced apoptosis. However, T cells from
B-CLL patients were only slightly affected by
acadesine at doses up to 4 mM. AMPK phosphorylation
did not occur in T cells treated with acadesine.
Intracellular levels of ZMP were higher in B-CLL cells
than in T cells when both were treated with 0.5 mM
acadesine, suggesting that ZMP accumulation is
necessary to activate AMPK and induce apoptosis.

These results suggest a new pathway involving AMPK in
the control of apoptosis in B-CLL cells and raise the
possibility of using acadesine in B-CLL treatment.

*NOTE The IC50 is the inhibitory concentration of a
drug needed to inhibit 50% of cell growth or to kill
50% of the cells.

Acadesine is used in cardiac care. It is a purine
nucleoside analog. Prototype adenosine regulating
agent; enhances endogenous adenosine levels in
ischemic tissue


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Blood First Edition Paper
prepublished online January 9, 2003

Submitted October 3, 2002
Accepted November 27, 2002

Marrow frequency of rat long-term repopulating cells:
evidence that marrow hematopoietic stem cell
concentration may be inversely proportional to species
body weight

Kenneth F McCarthy*
, Hilton Head Island, SC, USA
* Corresponding author; email: mcneth@...
<mailto:mcneth@...>.

As measured by the long-term repopulating cell (LTRC)
assay, only a few hematopoietic stem cells (HSC), or
perhaps a single HSC, are required to totally
repopulate the lympho-hematopoietic tissues of
lethally irradiated mice, cats, and humans, raising
the question as to why large mammals require more
marrow cells to either rescue them from lethal
irradiation, or establish a long term hematopoietic
graft than do small mammals.

An explanation might be that HSC marrow frequency
across species is not constant, but decreases as
species body weight increases.

This hypothesis was tested by comparing the LTRC
marrow concentration of mice to that of rats.
Specifically, histocompatible AKR/J, Thy 1.1 marrow
was transferred to 7 Gy irradiated C3H/HeN, Thy 1.2
mice, while histocompatible Norway Black marrow (NBr),
RT 7.2 marrow was transferred to 7 Gy irradiated RT
7.1 Lewis rats. The recipients were scored for
successful grafts 6 to 20 weeks later. By limiting
dilution analysis, a value of 1 LTRC per 47,700 marrow
cells was calculated for mice, but only 1 LTRC per
502,000 marrow cells was calculated for rats.

Viewed in the context of marrow grafting in larger
mammals, these results suggest that species with
greater body mass have lower marrow HSC frequency.


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Blood First Edition Paper
prepublished online January 9, 2003;

Submitted October 18, 2002
Accepted December 23, 2002

Ligation of OX40 (CD134) regulates graft-versus-host
disease (GVHD) and graft rejection in allogenic bone
marrow transplant (BMT) recipients

Bruce R Blazar*, Arlene H Sharpe, Andy I Chen, Angela
Panoskaltsis-Mortari, Christopher Lees, Hisaya Akiba,
Hideo Yagita, Nigel Killeen, and Patricia A Taylor
Department of Pediatrics, Division of Bone Marrow
Transplantation, University of Minnesota Cancer
Center, Minneapolis, MN, USA
Department of Pathology, Bringham and Women's
Hospital, Boston, MA, USA
Department of Immunology, Juntendo University School
of Medicine, Tokyo, Japan
Department of Microbiology and Immunology, University
of California, San Francisco, CA, USA
* Corresponding author; email: blaza001@...
<mailto:blaza001@...>.

OX40 (CD134) is expressed on activated T-cells; its
ligand, OX40 ligand (OX40L) is expressed on dendritic
cells, B-cells, and activated endothelial cells.

To determine how OX40/OX40L interaction affects GVHD,
we utilized antagonistic anti-OX40L mAbs or OX40-/-
donor or OX40L-/- recipient mice. Similar degrees of
GVHD reduction were observed with each approach.

Despite the fact that OX40 is upregulated on both CD4+
and CD8+ T-cells isolated during GVHD, the major
effects of OX40 ligation were on CD4+ and not CD8+
T-cell-mediated alloresponses as assessed in both GVHD
and engraftment model systems. GVHD inhibition by
blockade of the OX40:OX40L pathway did not require
CD28 signaling.

Some studies have indicated OX40 is essential for
inducing Th2 responses. However, in vivo blockade of
OX40/OX40L interactions reduced GVHD mortality induced
by either Stat-6-/- (Th2-defective) or Stat-4-/-
(Th1-defective) MHC disparate splenocytes, indicating
that the GVHD ameliorating effects did not require
Stat-4 or Stat-6 signaling. Although OX40L has been
reported to be expressed on activated T-cells, no
effects on GVHD were observed when OX40L-/- vs
OX40L+/+ T-cells were infused in different models.

These data provide insights as to the mechanism(s)
responsible for OX40/OX40L regulation of GVHD.


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Folks:

As has been mentioned, the CLL Research Consortium has
(finally!) improved their website.

One non-improvement:  The list of the docs is not in
the old 'members' place.  The new url for the members
of the consortium is:

http://cll.ucsd.edu/Presentations/CRC_Overview_files/frame.htm

This is a power point presentation, so the links don't
work.


I'd recommend everyone bop over to the site and check
it out.  The news section seems up-to-date, and there
is info on trials, etc.

A vast improvement!

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Vaccine, Vol. 21 (7-8) (2003) pp. 798-801
© 2002 Elsevier Science Ltd. All rights reserved.

Short communication

Towards new immunotherapies: targeting recombinant
cytokines to the immune system using live attenuated
Salmonella

Claudia D. Rosenkranz a,b, Damasia Chiara a, Caroline
Agorio a,d, Adriana Baz c, Marcela F. Pasetti b,
Fernanda Schreiber a, Silvia Dematteis c, Miguel
Martinez d, Marcelo B. Sztein b and Jose A.
Chabalgoity a * jachabal@...
a Laboratory for Vaccine Research, Department of
Biotechnology, Instituto de Higiene, Facultad de
Medicina, Avda. A. Navarro 3051, Montevideo, CP 11200,
Uruguay
b Center for Vaccine Development, Departments of
Pediatrics and Medicine, University of Maryland School
of Medicine, 685 West Baltimore Street, Room 480,
Baltimore, MD 21201, USA
c Cátedra de Inmunología, Instituto de Higiene,
Facultad de Química, Avda. A. Navarro 3051,
Montevideo, CP 11200, Uruguay
d Melanoma Unit, Department of Medicine, Hospital de
Clínicas, Facultad de Medicina, Montevideo, CP 11200,
Uruguay
Abstract

We have used Salmonella as a delivery system for
eukaryotic expression plasmids encoding cytokines, and
assessed its capacity to modulate immune responses in
different experimental models.

Plasmids encoding mouse IL-4 and IL-18 under
cytomegalovirus promoter were constructed and
transformed into live attenuated Salmonella enterica
serovar Typhi strain CVD 908-htrA, and Salmonella
enterica serovar Typhimurium strain SL3261.

We have shown that systemic as well as mucosal
immunization with such constructs can influence the
antibody and cytokine responses to the Salmonella
carrier and to co-administered bystander antigens, as
well as the specific immune response elicited during a
parasitic infection. Further, we have shown that oral
cytokine-therapy using Salmonella as gene vector
induce antitumoral effect as demonstrated by extended
survival time in melanoma-bearing mice.

This approach may be particularly suited for the
development of new immunotherapies with applications
in parasitic infections and cancer, were alterations
of the host's immune responses are usually found, and
therapy-induced modulation of the immune response is
likely to be required.

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Interphase Cytogenetic Abnormalities in Chronic
Lymphocytic Leukemia May Predict Response to
Rituximab1

John C. Byrd2, Lisa Smith, Marcy L. Hackbarth, Ian W.
Flinn, Donn Young, John H. Proffitt and Nyla A.
Heerema

The Division of Hematology-Oncology [J. C. B., L. S.],
and Departments of Biostatistics [D. Y.] and Pathology
[N. A. H.], Ohio State University, Columbus Ohio
43210; Vysis Incorporated, Downers Grove, Illinois [M.
L. H., J. H. P.]; and Division of Hematologic
Malignancies, The Johns Hopkins University, Baltimore,
Maryland [I. W. F.]

Select cytogenetic abnormalities such as
del(17)(p13.1) and del(11)(q22-q23)predict rapid
disease progression and inferior survival in chronic
lymphocytic leukemia (CLL). We sought to determine the
impact of the four most common interphase cytogenetic
abnormalities in 28 CLL patients relative to response
to three-times-a-week rituximab therapy.

Abnormalities were noted in 25 of the 28 patients to
include del(13)(q14.3) [n = 16 (57%)], del(11)(q22.3)
[n = 10 (36%)], +12 [n = 6 (21%)], del(17)(p13.1) [n =
5 (18%)], and normal [n = 3 (11%)]. Only a minority of
each of these occurred as sole abnormalities.

To categorize patients into one specific group, we
used the hierarchical order del(17)(p13.1) >
del(11)(q22.3) > trisomy 12 > del(13)(q14.3) to
prioritize. Response to rituximab was noted to vary by
cytogenetic group: del(17)(p13.1), 0% [n = 5];
del(11)(q22.3), 66% [n = 9]; del(13)(q14.3), 86% [n =
7]; +12, 25% [n = 4], and normal, 0% [n = 3]. Response
was significantly lower (P = 0.05) in patients with
del(17)(p13.1) as compared with those with other
abnormalities.

These data suggest that interphase cytogenetics in CLL
may be predictive of a response to rituximab therapy
and provide support for additional studies validating
risk-adapted therapy in this disease.

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Psychiatric and Clinical Neurosciences
Volume 57 Issue 1 Page 91  - February 2003

Psychological factors and survival after bone marrow
transplantation in patients with leukemia

Rie Akaho, MD, PhD1, Tsukasa Sasaki, MD, PhD1,2,
Shin-Ichiro Mori, MD3, Hideki Akiyama, MD, PhD3, Miyo
Yoshino, MSc1, Katsuko Hagiya, MSc1, Kazuyuki
Nakagome, MD, PhD4 and Hisashi Sakamaki, MD, PhD3

Abstract
Psychological factors may be associated with the
outcome of cancer treatment, including bone marrow
transplantation (BMT). However, studies on the issue
have provided controversial results.

In the present study, effects of mood status on the
outcome was studied through a follow-up period of 1-3
years as well as in shorter periods (3 and 8 months)
post-BMT in 72 Japanese patients with leukemia.
Psychological status was evaluated 2 weeks before BMT
using Profile of Mood States (POMS).

The most major factor abstracted from the POMS
subscales (Factor 1, mainly comprising anxiety,
depression, anger, fatigue and confusion) was
associated with disease-free survival rate at 3 months
post-BMT. However, the factor most significantly
associated with the outcome was gender.

Females had better outcome than males through the
period of 1-3 years as well as at 8 months post-BMT.
When analyzed by gender, Factor 1 was associated with
poor prognosis at 3 and 8 months in males. In females,
however, Factor 1 was not significantly associated
with the prognosis.

The present results suggest an association between
mood status pre-BMT and prognosis post-BMT in a
gender-specific manner.

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Blood First Edition Paper
prepublished online January 9, 2003;

Submitted October 21, 2002
Accepted December 23, 2002

Chronic lymphocytic leukemia B cells expressing AID
display a dissociation between class switch
recombination and somatic hypermutation

Pablo Oppezzo, Francoise Vuillier, Yuri Vasconcelos,
Gerard Dumas, Christian Magnac, Beatrice
Payelle-Brogard, Otto Pritsch, and Guillaume Dighiero*

Unite d'Immuno-hematologie, Institut Pasteur, Paris,
France
Department of Hematology, Universidad Federal de Sao
Paulo, Sao Paulo, SP, Brazil
Department of Biochemistry, Facultad de Medicina,
Montevideo, Uruguay
* Corresponding author; email: dighiero@...
<mailto:dighiero@...>.

In B-cells, somatic hypermutation (SHM) and class
switch recombination (CSR) depend on the
activation-induced deaminase (AID) gene product,
although its precise mode of action remains unknown.
Since some chronic lymphocytic leukemia (CLL) B-cells
can undergo CSR without SHM, it constitutes a useful
model to dissect AID function.

In this work, we have studied AID expression, the pres
ence of mutations in pre-switch µ DNA region, CSR and
the SHM in 65 CLL patients.

Our results demonstrate that: 1) unmutated CLL B-cells
can constitutively express AID and its expression is
associated to the presence of mutations in the
pre-switch region and clonally related
isotype-switched transcripts and 2) in CLL without
constitutive AID expression, its induction upon
stimulation results in pre-switch mutations and CSR
process.

Our results show a dissociation between SHM and CSR in
CLL and suggest that, in this disease, AID would
require additional help to carry out SHM process.



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Mercurial Effects of Fish-Rich Diets

Janet Raloff

In the spring of 2000, one of Jane M. Hightower's
patients had been concerned about hair loss, so the
internist referred the woman to a specialist in her
building. That dermatologist probed the woman's
medical history but could find no explanation. That
is, until she suddenly recalled a radio broadcast
about mercury poisoning in people who had been eating
lots of fish from tainted lakes. Their symptoms
included hair loss.

Although the individual pieces of sushi are small, a
meal of such bite-size seafood morsels
could deliver a substantial dose of mercury, depending
on the fish species selected and the
waters from which they were pulled.
So, the dermatologist asked her patient if she ate
much fish. Indeed, the woman said, she loved it. The
doctor quickly arranged for the woman to get a blood
test and then faxed the results back to Hightower.
After reviewing the findings, which suggested the
patient's mercury concentrations were in fact somewhat
elevated, Hightower put the document atop the papers
in her in-box.

Which is where it was still sitting, when a patient
came in complaining, "My house is poisoning me!"
Hightower listened as the woman described how she
sometimes felt so enervated that she could barely
summon the will to get out of bed. Other times,
especially while traveling abroad for months on end,
the woman felt fine.

Oh yes, one other thing: The patient's thinning hair
had become such a problem that the woman turned to
Rogaine. She told Hightower she had been using this
antibalding drug for 2 years.

Glancing at the in-box and her other patient's mercury
data, Hightower asked whether her new patient ate much
fish. "And she said, 'Yes, as a matter of fact—nine
times a week,'" Hightower recalls.

This "serendipitous" pairing of cases launched the
doctor on a quest to understand whether a taste for
fish might be poisoning any of her other patients.
For the next year, Hightower formally surveyed the
fish-consumption patterns of every person who came
through her practice. Among those 720 people, 123
appeared to be eating fairly high concentrations of
fish.

She then convinced 113 of these fish eaters—several of
whom also showed symptoms indicative of possible
mercury poisoning—to get tested for the metal. All but
seven had blood drawn for testing. The remainder,
including several children, submitted only their hair
for testing.
Most of tested individuals exhibited elevated mercury
concentrations despite having little or no known
exposure to mercury besides eating fish, report
Hightower and Dan Moore of the California Pacific
Medical Center, also in San Francisco, in an upcoming
issue of Environmental Health Perspectives.

Among the patients who had blood tests, 89 percent had
blood concentrations exceeding 5 micrograms per liter
( m g/L). Indeed, 16 percent had blood concentrations
over 20 mg/L of blood—and 4 individuals surpassed 50
mg/L.
Because fetal exposure to mercury can later play out
as IQ deficits, the National Academy of Sciences in
2000 recommended that women of childbearing age should
try to keep mercury concentrations in their blood to
less than 5 mg/L(or hair concentrations to below 1
mg/L). They didn't address other parts of the
population.

Hightower advised all her patients with blood or hair
values well above those cutoffs to pare fish from
their diets over the next few months. And though
follow-up blood tests showed that their bodies indeed
began shedding mercury, the drop was slow. In some
cases, even 21 weeks later, the patients' mercury
concentrations remained elevated well above the NAS
guideline figures.

Among adults, most symptoms abated as their blood
concentrations dropped. Alas, Hightower says, that
didn't spare one child, who initially was screened
with nearly 15 times the NAS recommended ceiling
concentrations for mercury. Hightower notes that this
boy had experienced a documented "mental decline"
during the 4 years he had regularly been eating not
only canned tuna but also fresh tuna and salmon
steaks. Though his parents eventually purged fish from
his diet, the boy retains a significant neurological
impairment, Hightower says.

Since her initial study ended, she has continued to
evaluate fish consumption in her patients. Another 60
or so of them turned out to be at risk for subtle
mercury poisoning. Perhaps most troubling, Hightower
told Science News Online, was that her patients—much
like herself—had viewed fish as a healthy food. Study
after study had extolled the heart benefits of
fish-rich diets. She asked: How could her patients
have been so seriously misled? Why weren't they aware
that this food can also serve as the vehicle for a
potent poison?
In a Nov. 20 letter to President George Bush, she
asked for actions to help consumers avoid unnecessary
exposure. For instance, she requested that the
government continue testing fish for mercury tainting
and that the results—and any necessary fish advisories
about mercury—"be readily available where fish are
sold."

But they ate pricey fish. . .

That fish can serve as a dietary vehicle for bringing
mercury to the dinner table is hardly new. Mercury is
the most commonly cited basis for state warnings that
locally caught fish might be dangerous to consumers'
health.

American lobster is among the shellfish species that
tends to carry mercury, typically about 0.3 parts per
million, according to FDA data. Though roughly
comparable to the mercury tainting of tuna steaks, it
carries only about a third as much as swordfish or
shark. By contrast, its mercury load is generally
about twice the concentration typical of crab or
canned tuna.
However, Hightower says, those advisories generally
addressed only freshwater species caught by
noncommercial anglers from especially tainted waters.
Her patients were eating primarily marine fish.
Moreover, these bankers, scientists, physicians,
business executives, investment brokers, and Internet
entrepreneurs weren't hauling in their own catch of
the day. They either ordered it from the counter of a
local food retailer or from the menus of
white-tablecloth restaurants.

A message that federal health officials have failed to
effectively communicate to the public, she says, is
that many large, predatory, and long-lived oceanic
species also accumulate plenty of heavy metals,
including mercury. Many of Hightower's patients noted
that they had been selecting precisely these large,
predatory marine species because they tasted least
fishy and their bones were easy to remove.

Overall, elevated mercury readings among her patients
tended to correlate most strongly with any consumption
of swordfish. However, many with high mercury scores
also ate plenty of tuna—especially steaks—and salmon.
The heart of the matter

In her readings on health effects of mercury,
Hightower ran across a 1999 Italian study in the
Journal of the American College of Cardiology. It
described finding highly elevated concentrations of
mercury in heart—but not other muscle—of patients who
had died from heart failure related to a condition
known as idiopathic dilated cardiomyopathy. Because
none of the patients had known elevated exposures to
mercury, the data hinted that heart muscle might
selectively accumulate the metal, leading to its
selective poisoning.

On November 28, the New England Journal of Medicine
published two epidemiological studies offering further
support for a heart sensitivity to methylmercury—the
organic form of the metal found in fish.

In one international study probing cardiovascular
risks, Eliseo Guallar of the Johns Hopkins Medical
Institutions and his colleagues correlated risk of
first heart attack with toenail concentrations of
mercury and concentrations of a fish oil
(docosahexaenoic acid, or DHA) in body fat. Their data
came from 684 men who had had a heart attack and
another 724 who hadn't.

In this study, increasing concentrations of mercury in
toenails—which serve as a relatively long-term record
of exposure—were "directly associated" with increasing
risk of heart attack, the study found, whereas DHA
concentrations in body fat appeared protective against
heart attack. Guallar and his colleagues say that
their data suggest that mercury tainting of fish
diminishes the cardioprotective effect normally
associated with heavy consumption of DHA and oily
fish.

The authors noted that they had not collected
information on the sources of mercury or DHA among
their participants—nor data on fish intake. However,
they noted, the substantial DHA concentrations
measured in some subpopulations of the participants
would suggest their mercury likely derived from
consumption of marine fish.

To date, health advisories against eating
mercury-tainted fish have tended to focus on pregnant
women and children, with a goal of protecting the
neurological development in youngsters, Guallar's
group observes. "Our results raise the possibility
that this advice should be extended to the general
adult population," the researchers say. They recommend
that people should not eschew fish, just judiciously
choose species that are not likely to be heavily
contaminated.
According to a table of data that the U.S. Food and
Drug Administration compiled nearly 2 years ago,
tilefish, swordfish, shark, and king mackerel lead the
list with mean mercury concentrations of between 0.7
and 1.4 parts per million (ppm). Although the agency
had fewer samples from a number of other popular
marine species, among them red snapper, moonfish,
orange roughy, marine bass, and marlin also tended to
be fairly heavily tainted, typically averaging 0.4 to
0.6 ppm.
FDA reported somewhat lower—but still far from
negligible—mercury tainting in grouper, tuna, halibut,
pollock, cod, whitefish, and herring. All were down in
the 0.2 to 0.15 ppm range. Canned tuna had less
contamination than fresh or frozen. Some shellfish
also fall in that category, with lobster containing
more mercury than crab.

Seafood with the least mercury contamination includes
tilapia, salmon, shrimp, oysters, clams, sole, and
flounder.
Bon appetit!

References:
Bolger, P.M., and B.A. Schwetz. 2002. Mercury and
health. New England Journal of Medicine 347(Nov.
28):1736.
Frustaci, A., et al. 1999. Marked elevation of
myocardial trace elements in idiopathic dilated
cardiomyopathy compared with secondary cardiac
function. Journal of the American College of
Cardiology 33(May):1578-1583.
Guallar, E., et al. 2002. Mercury, fish oils, and the
risk of myocardial infarction. New England Journal of
Medicine 347(Nov. 28):1747-1754. Abstract available at
<http://content.nejm.org/cgi/content/abstract/347/22/1747>.
Hightower, J.M., and D. Moore. In press. Mercury
levels in high-end consumers of fish. Environmental
Health Perspectives. Abstract available at
<http://ehpnet1.niehs.nih.gov/docs/2003/5837/abstract.html>.
Yoshizawa, K., et al. 2002. Mercury and the risk of
coronary heart disease in men. New England Journal of
Medicine 347(Nov. 28):1755-1760. Abstract available at
<http://content.nejm.org/cgi/content/abstract/347/22/1755>.

Further Readings:
2002. Mercury associated with risk of heart attack.
Johns Hopkins University press release. Nov. 27.

Available at
<http://www.jhsph.edu/Press_Room/Press_Releases/fish_mercury.html>.
Center for Food Safety and Applied Nutrition, Office
of Seafood. 2001. References: Consumer advisory on
methylmercury in commercial seafood. U.S. Food and
Drug Administration (May). Available at
<http://www.cfsan.fda.gov/~dms/hgpdftoc.html>.
Raloff, J. 2001. Landfills make mercury more toxic.
Science News 160(July 7)4. Available at
<http://www.sciencenews.org/20010707/fob1.asp>.
______. 2001. A dietary cost of our appetite for gold.
Science News Online (May 12). Available at
<http://www.sciencenews.org/20010512/food.asp>.
______. 2000. China: A mercury megapolluter. Science
News 158(July 29):77.
______. 2000. Methylmercury's toxic toll. Science News
158(July 29):77.
______. 1991. Mercurial risks from acid's reign.
Science News 139(March 9):152.
Sources:
Center for Food Safety and Nutrition
Food and Drug Administration
5100 Paint Branch Parkway
College Park, MD 20740-3835
Web site: <http://www.cfsan.fda.gov/>
Eliseo Guallar
Welch Center for Prevention, Epidemiology, and
Clinical Research
Johns Hopkins Medical Institutions
2024 E. Monument Street, Suite 2-639
Baltimore, MD 21205-2223
Jane M. Hightower
2100 Webster Street, Suite 418
San Francisco, CA 94115
Kazuko Yoshizawa
Harvard School of Public Health
Boston, MA 02115

Science News Online

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Purdue Researchers Design Fishes' Diets To Make You
Healthier

WEST LAFAYETTE, Ind. -- Farm-raised fish eating
specially formulated diets high in fatty acids could
improve people's health and also satisfy different
palates, according to Purdue University researchers
who are concocting designer menus for aquatic
creatures.

Fatty acid feed supplements for fish may help people
get government-recommended amounts of health-enhancing
macronutrients, said Paul Brown, a Purdue forestry and
natural resources professor. The additive he is
testing currently is a type of omega-6 fatty acid
called conjugated linoleic acid (CLA), which
researchers have found is a weapon against cancers and
diabetes.
"We found by adding CLA to fishes' diets we can get
more of these fatty acids into the fishes' tissues
than is found in any other animal," said Brown, a
nutritional aquaculturalist. "Meat and milk from
ruminant animals are good sources of CLA, but these
fish retain even higher levels."

Brown's research gains added importance based on a
recent National Academy of Sciences Institute of
Medicine's recommendation that people increase their
consumption of food containing alpha-linoleic acid (an
omega-3 fatty acid) and linoleic acid (an omega-6
fatty acid). The institute set the daily requirements,
or Dietary Reference Intakes, of these macronutrients
necessary to maintain health, and noted that
cold-water fish, such as swordfish, tuna and salmon,
are prime sources of omega-3.
Omega-3 and omega-6 are essential fatty acids, meaning
they are important for health, but the human body
can't produce them. Fish and shellfish already are
good sources of omega-3 fatty acids important for
building cells; for brain, nerve and eye function; and
for lowering risks of high cholesterol, cardiovascular
diseases and cancer.
"Fish have always been the original and standard
measure for good sources of omega-3," Brown said. "But
now we find that we can introduce other fatty acids
into fish. Next we must determine if there is an
optimum ratio of omega-3 and omega-6 fatty acids that
is healthy."
The institute recommended that adult men eat 17 grams
(0.6 ounces) of the omega-6 fatty acid linoleic acid
daily and adult women 12 grams (0.42 ounces), while
they should eat 1.6 grams (0.06 ounces) and 1.1 grams
(0.04 ounces) of the omega-3 fatty acid
alpha-linolenic acid, respectively. The amounts vary
for children and juveniles, and for those over age 50.


The American Heart Association recommends at least two
servings each week of omega-3-rich fatty fish. A
serving should be 3 ounces cooked, about the size of a
deck of cards. In one study, senior citizens who ate
one serving weekly had a 44 percent lower risk of
heart attack, according to the organization.

Special fish diets using additives, such as CLA, and
grains, such as soybeans, can be formulated to produce
designer fish that are high in beneficial fatty acids,
Brown said. The research team is studying different
fish species to chronicle their development on
specialized diets and determine how much of the
nutrients they retain.

Purdue scientists discovered that some fish stay lean
while others become much fatter because they retain
the lipids, or polyunsaturated fat, from the fatty
acids. Two fish models they study have very different
activity and metabolism levels, and differ in the
amount of fat they retain. Eating a high fatty acid
diet in a farm environment turns hybrid striped bass
into little butterballs, while yellow perch stay very
lean, Brown said.

The ability to raise more nutritional fish of a
variety of species should encourage growth of the
aquaculture (fish farm) industry, he said. But fish
are the last major food item still obtained primarily
from the wild.
"The wild fish supply just isn't sufficient to provide
us with the amount necessary for human consumption,"
Brown said. "That was decided in 1989 when we hit
maximum sustainable yield from the world's oceans, yet
the world population is still increasing.

"We have to develop new aquaculture production that
rivals global production of soybeans, pigs and
chickens if we want to keep eating fish and
shellfish."
Since 1985 commercial fishing has annually produced
approximately 90 million metric tons (mmt). In
contrast, aquaculture production has doubled every
decade since 1970. Figures from 1999 show annual
aquaculture production at 42 mmt. Worldwide production
of hogs is approximately 83 mmt yearly and that of
chickens is 46 mmt, according to 1995 figures.
Brown estimates that to keep up with demand, annual
aquaculture production must increase by 40 mmt to as
much as 100 mmt by 2035.

However, the problem of meeting demand isn't just
increasing the amount raised on farms, said Brown, who
does part of his research as a collaborator in
Purdue's Center for Enhancing Foods to Protect Health,
which receives support from the Indiana 21st Century
Research and Technology Fund. The public also must be
educated that aquaculture can produce fish just as
good and possibly healthier than those caught in the
wild.

"The consumer doesn't know to ask the right questions
about fish," he said. "They have the perception that
farm-raised fish or shellfish are inferior products
and don't have the healthy fatty acids people need.
"If they want more omega-3 in their fish, we can put
it in. If they want fish that don't taste fishy, we
can produce fish that don't taste fishy. The public
just needs to say what it wants."


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Blood First Edition Paper
prepublished online January 2, 2003

Submitted August 28, 2002
Accepted December 6, 2002

Non-malignant late effects after allogeneic stem cell
transplantation

Gerard Socie*, Nina Salooja, Amnon Cohen, Attilio
Rovelli, Enric Carreras, Anna Locasciulli, Elisabeth
Korthof, Joachim Weis, Vincent Levy, and Andre
Tichelli
Department of Hematology/Stem Cell Transplantation,
Hospital Saint Louis, Paris, France
Haematology Department, Hammersmith Hospital, London,
United Kingdom
Department of Pediatrics, Saint Paul Hospital, Savona,
Italy
Department of Pediatric Bone Marrow Transplantation,
Ospedale San Gerardo, Monza, Italy
Institute of Hematology, Hospital Clinic, Barcelona,
Spain
Department of Hematology/Stem Cell Transplantation,
San Camillo Hospital, Rome, Italy
Department of Hematology, University Hospital, Leiden,
The Netherlands
Tumor Biology Center, University of Freiburg,
Freiburg, Germany
DBIM, Hospital Saint Louis, Paris, France
Hematology Department, University Hospitals, Basel,
Switzerland
* Corresponding author; email: gsocie@...
<mailto:gsocie@...>.

Large number of patients now survive long term
following stem cell transplantation (SCT). The late
clinical effects of SCT are thus of major concern in
the 21st century.

Secondary malignant diseases are of particular
clinical concern as more patients survive the early
phase after transplantation and remain free of their
original disease. These malignant complications have
been previously reviewed in Blood and recently
updated.

Non-malignant late effects are heterogeneous, and
although often non-life threatening they significantly
impair the quality of life of long-term survivors. The
main aims of this review by the Late Effects working
party of the European Study Group for Blood and Marrow
Transplantation (EBMT) are to present physicians with
an overview of these nonmalignant late complications
and provide some recommendations regarding their
prevention and early treatment.

The major risk factors for non- malignant
complications post SCT are chronic graft-versus-host
disease (c.GvHD) and/or its treatment and the use of
irradiation in the pre-transplant conditioning. The
inter-relationship between c.GvHD, total body
irradiation (TBI), and nonmalignant late effects are
summarized.


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Blood First Edition Paper
prepublished online January 2, 2003

Submitted August 29, 2002
Accepted December 13, 2002

The anti-CD22 ligand blocking antibody, HB22.7, has
independent lymphomacidal properties and augments the
efficacy of 90Y-DOTA-peptide-Lym-1 in lymphoma
xenografts

Joseph M Tuscano*, Robert T O'Donnell, Laird A Miers,
Linda A Kroger, David L Kukis, Kathleen R Lamborn,
Thomas F Tedder, and Gerald L DeNardo
Department of Internal Medicine, University of
California, Davis, Sacramento, CA, USA
Department of Hematolog and Oncology, Verterans
Administration, Northern California Health Care
System, Sacramento, CA, USA
Department of Immunology, Duke University, Durham, NC,
USA
Brain Tumor Research Center, University of California,
SanFrancisco, San Francisco, CA, USA
* Corresponding author; email:
joseph.tuscano@...
<mailto:joseph.tuscano@...>.

CD22 is a membrane glycophosphoprotein found on nearly
all normal B-lymphocytes and most B-cell lymphomas.
Recent in vitro studies have identified several
anti-CD22 monoclonal antibodies (mAbs) that block the
interaction of CD22 with its ligand. One of these
mAbs, HB22.7, has been shown to effectively induce
apoptosis in several B-cell lymphoma cell lines.

Lymphoma xenograft studies with Raji-tumored mice were
used to assess the toxicity and efficacy of HB22.7
both alone and with combined modality immunotherapy
(CMIT) with 90Y-DOTA-peptide-Lym-1 radioimmunotherapy
(RIT). The effect of the sequence of these agents on
the combined treatment was assessed by administering
HB22.7 24 hours prior, simultaneously, or 24 hours
after RIT.

Within the groups treated with RIT alone or RIT and
HB22.7 (CMIT), the reduction in tumor volume was the
greatest when HB22.7 was administered simultaneously
and 24 hours after RIT, and in the RIT treatment
groups, this translated into the greatest overall
response and survival, respectively.

Overall survivals at the end of the 84 day CMIT trial
were 67 and 50% in the groups treated with HB22.7
simultaneously and 24 hours after RIT, respectively.
This compared favorably with the untreated and RIT
alone groups which had 38 and 43% surviving at the end
of the trial.

Surprisingly, when compared to untreated controls, and
all other treatment groups, the greatest cure rate and
overall survival was observed in the group treated
with HB22.7 alone with 47% cured and 76% surviving at
the end of the 84 day trial. RIT clearance was not
affected by treatment with HB22.7. When compared to
RIT alone there was no significant additional
hematologic (WBC, RBC, or platelet counts) toxicity
when HB22.7 was added to RIT. Non-hematologic toxicity
(assessed as change in body weight) was also unchanged
when HB22.7 was added to RIT.

Thus the anti-CD22 ligand blocking antibody, HB22.7,
has independent lymphomacidal properties, and augments
the efficacy of 90Y-DOTA-peptide-Lym-1 in lymphoma
xenografts, without significant toxicity.


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(Story says a vaccine may be available in a couple of
years.)

Health & Science: Scientists struggle to solve West
Nile virus mystery

Copyright © 2002 AP
By KATHERINE VOGT, Associated Press

FORT COLLINS, Colo. (December 30, 2002 2:32 p.m. EST)
- Giant beakers filled with blood clutter countertops
and extra refrigerators cramp the hallways at the
federal government's main research center for West
Nile virus.

Scientists at the Centers for Disease Control and
Prevention have had to sharply shift the focus of
their work toward the sometimes fatal disease that is
spreading across most of the country.

The individual labs within the white building are
packed with beakers of blood and other animal
specimens that may carry the virus. Former offices
have been relocated to temporary structures outside to
make room for extra lab space.

Lab officials say their workload increased
dramatically since West Nile virus first appeared in a
few dozen U.S. cases in 1999. Already this year, more
than 3,500 human cases of the mosquito-borne illness
have been confirmed. And recently CDC noted that the
United States had suffered this year the biggest
reported outbreak of West Nile encephalitis in the
world.

"Our workload has been a lot, and there is no sign
that it is going to let up," said John T. Roehrig,
chief of the arbovirus diseases branch of the CDC's
Division of Vector-Borne Infectious Diseases.

West Nile previously received the same attention as
countless diseases affecting the global community.
Now, as the CDC's primary West Nile virus research
facility, up to 90 percent of the lab's time and
resources are devoted to this disease.

About 150 people work at the lab.

The emphasis on West Nile comes while the lab also
tries to address its responsibility for research on
plague and tularemia, both highly infectious agents
with potential for use in bioterrorism.

And with an increased concern about bioterrorism since
the Sept. 11 terrorist attacks, the lab has made a
series of security changes including the installation
of a giant barbed-wire fence around its perimeter.

Roehrig acknowledged that other research projects have
been put on the back burner to make room for West Nile
studies.

"We try to maintain expertise and credibility for all
the diseases we're responsible for. But where we've
had the biggest effect is in our field teams, who are
now responding to West Nile," Roehrig said.

He said lab scientists are trying to develop better
diagnostic testing for West Nile virus. One model,
which detects genetic material from the virus, is
being used in scientific investigations and may one
day be used to screen donated blood for West Nile
virus.

Other research projects include new vaccines for
horses and possibly birds, and studies of how the
virus may be transmitted between humans through breast
milk, blood transfusions and organ donations.

Roehrig said drug companies are investigating a
possible human West Nile vaccine, which he expects to
see within a couple of years.

In the beginning, the Fort Collins lab was responsible
for confirming all human cases of West Nile virus.
Since then, lab workers have trained state and local
agencies to do their own testing when possible.

One of the main lessons learned from the arrival of
West Nile was that state and local health agencies
were far less prepared for an infectious disease
outbreak than they should have been, said Duane J.
Gubler, director of the CDC's Division of Vector-Borne
Infectious Diseases.

He said West Nile is a wake-up call to a public health
system that has grown complacent about vector-borne
infectious diseases since the advent of powerful new
drugs and antibiotics over the last few decades.

"Along with that complacency, we allowed the public
health infrastructure to deteriorate," Gubler said.

Case in point: the aging, cramped lab in Fort Collins.

Built in 1967 to help the CDC deal with arboviral
encephalitis in the western United States, the lab
soon took over research duties for plague, Dengue
fever, Lyme disease and other zoonotic bacterial
infections.

As duties grew, the lab became more crowded. By about
1998, some offices were moved to temporary structures
outside of the main building to make room for more lab
space.

But West Nile virus has the lab busier and more
crowded than ever. The electrical wiring, heating and
cooling systems are antiquated and desperately need to
be replaced.

"We're crowded. We need a new lab. And right now the
plan is to build it," Gubler said.

In the meantime, scientists will learn from changes
the lab has undergone in the last few years.

"One of the main lessons we've taken home from this
experience is that we need to keep an open mind and
expect the unexpected," Gubler said.


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Health & Science: Smallpox vaccine recipients should
wait to give blood, FDA says

Copyright © 2002 AP Online Print Story
The Associated Press

WASHINGTON (December 31, 2002 10:25 a.m. EST) -
Recipients of the smallpox vaccine should not donate
blood for at least three weeks after getting the shot,
the government is warning, because that vaccine
contains a live virus that might enter the blood
supply and endanger other people.

The Food and Drug Administration's blood guidelines
come as the government has begun inoculations expected
to eventually reach millions of military personnel and
health workers. Those two populations also make up the
most faithful blood donors.

Included in the FDA's recommendations, which blood
banks are supposed to implement immediately:

-Recipients of smallpox vaccine should not be allowed
to give blood for 21 days after vaccination or until
the scab at the injection site has fallen off on its
own, whichever is later. Anyone who has scratched off
the scab should not give blood for two months after
vaccination.

-Vaccine recipients who suffer side effects from the
vaccination should not give blood until 14 days after
all those complications have disappeared.

-Blood banks should ask all potential donors if they
suffered any skin lesions or other complications from
close contact with a smallpox vaccine recipient. Those
whose lesions healed on its own can give blood, but
anyone who scratched off a scab cannot donate for
three months after contact with the vaccine recipient.

-Donated blood later found to have been given wrongly
by a vaccine recipient or contact must be destroyed or
used for non-human research. If it already has been
transfused, blood banks may need to alert the patient
and his or her doctor.


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