Immunology,
Endocrine & Metabolic Agents in Medicinal Chemistry
(Formerly 'Current Medicinal Chemistry - Immunology, Endocrine
and Metabolic Agents')
ISSN: 1871-5222
Current Medicinal Chemistry
- Immunology, Endocrine and Metabolic Agents
Volume 5, Number 6, December 2005
Contents
Recent Progress in the Development of
Anti-Diabetic Drugs
Guest Editor:J.Eckel
Editorial Pp.467
Clinical View on the Need to Develop New Anti-Diabetic
Drugs Pp.469
L. Laviola, A. Cignarelli and F. Giorgino
[Abstract]
Insulin Analogs Revisited Pp.475
J. Eckel
[Abstract]
GLP-1, Incretin Mimetics and DPP 4 Inhibitors: New
Ways in the Treatment of Type 2 Diabetes Pp.485
J.J. Meier and M.A. Nauck
[Abstract]
The Mode of Action of the Antidiabetic Drug Glimepiride
Beyond Insulin Secretion Pp.499
G. Müller
[Abstract]
Glucose Transport Regulators Pp.519
M.B. Yakir, A. Gruzman, E. Alpert and S. Sasson
[Abstract]
Serine Kinases as New Drug Targets for the Treatment
of Type 2 Diabetes Pp.529
C.M. Rondinone
[Abstract]
Hematopoietic Stem Cell Transplantation and Graft-Versus-Host
Disease
Guest Editor: T. Iwasaki
Editorial Pp.537
Graft Versus Host Disease Pp.539
J.L.M. Ferrara and S. Mineishi
[Abstract]
A New Bone Marrow Transplantation Method for Prevention
of Graft-Versus-Host Disease Pp.547
S. Ikehara
[Abstract]
In Vitro and In Vivo Sirolimus for
Modulation of Allogeneic Hematopoietic Stem Cell Transplantation
Pp.555
D.H. Fowler and R.E. Gress
[Abstract]
Protective Growth Factors for Graft-Versus-Host Disease
Pp.565
T. Iwasaki
[Abstract]
The Parent-into-F1 Model of Graft-vs-Host
Disease as a Model of In Vivo T Cell Function and
Immunomodulation Pp.575
R.A. Pulaiev, I.A. Puliaeva, A.E. Ryan and C.S. Via
[Abstract]
GVHD: Complication and Challenge to Successful Allogeneic
Hematopoietic Cell Transplantation Pp.100
R.B. Levy
[Abstract]
Abstracts
Recent Progress in the Development of Anti-Diabetic
Drugs
Guest Editor: J. Eckel
[Back to top]
Editorial
Diabetes mellitus is now taking its place as one of the major
threats to human health in the 21st century. In the last two
decades an explosive increase in the number of people diagnosed
with diabetes has been observed worldwide and the global figure
of affected individuals is expected to rise from currently
150 million to 300 million in 2025. This epidemic development
imposes a huge burden on health care systems requiring more
than 10% of the total health budget for the treatment of this
disease. Type 1 diabetes is an autoimmune disease characterized
by a loss of pancreatic ß-cell function and is observed
in 5-10% of the diabetic population. The remainder suffers
from Type 2 diabetes which is a multifactorial heterogeneous
disease linked to a much broader underlying disorder, the
metabolic syndrome. This entity includes several disorders
like hypertension, obesity, dyslipidemia and insulin resistance.
The increased risk for cardiovascular disease in this group
underlies the huge premature morbidity and mortality in the
diabetic population.
Both genetic and environmental factors contribute to the
pathogenesis of Type 2 diabetes, however, this process remains
incompletely understood. Peripheral insulin resistance of
insulin signalling and action combined with impaired pancreatic
ß-cell function finally leads to the clinical manifestation
of Type 2 diabetes. The potential relationship between these
processes and the question on which event initiates the disease
has remained controversial. The epidemic of Type 2 diabetes
can be explained by environmental factors such as sedentary
lifestyle, overly rich nutrition and obesity. Lifestyle intervention
can reduce the incidence of diabetes, however, pancreatic
ß-cell function is already altered at earlier stages
of impaired glucose tolerance (IGT) and intervention at this
stage prevents diabetes in only a fraction of the population.
Further, intensive intervention programmes often show high
relapse rates and pharmacological treatment is required for
the majority of diabetic patients to maintain glycemic control.
Oral agents like sulfonylureas, metformin or thiazolidinediones
are cornerstones of diabetes therapy, however, one third of
patients is not adequately controlled by these compounds,
highlighting an urgent need for the development of new antidiabetic
drugs.
In April 2005 the U.S. Food and Drug Administration has approved
exenatide as adjunctive therapy to improve blood sugar control
in patients with type 2 diabetes who have not achieved adequate
control on metformin or sulfonylurea. Exenatide is the first
in a new class of drugs called incretin mimetics and exhibits
many of the same effects as the human incretin hormone GLP-1.
This hormone regulates blood sugar by multiple effects on
the stomach, liver, pancreas and brain. Exenatide is an excellent
example for continuous improvement of anti-diabetic therapies
by development of new drugs.
Improved understanding of the complex pathways that lead
to insulin resistance in liver and muscle and to dysfunction
of the pancreatic ß-cell will be an invaluable tool
for defining new drug targets and developing novel anti-diabetic
compounds in the future. In addition, the pharmacological
modulation of direct targets of insulin action like glucose
transport may pave the way to alternative approaches for maintaining
normoglycemia in a diabetic patient. Future availability of
novel anti-diabetic compounds and the combination of these
drugs will offer multiple therapeutic options for the different
clinical phenotypes of diabetic patients.
[Back to top]
Clinical View on the Need to Develop New Anti-Diabetic
Drugs
L. Laviola, A. Cignarelli and F. Giorgino
Type 2 diabetes mellitus is a chronic metabolic disorder
that results from defects in both insulin secretion and insulin
action. Type 2 diabetic individuals are also characterized
by reduced β
-cell mass likely due to increased cellular apoptosis.
Traditional strategies to treat diabetes have been developed
with the main purpose of reducing hyperglyce-mia, and include
insulin sensitizers, α
-glucosidase inhibitors, and β
-cell secretagogues. However, available drugs do not
fully correct the phenotypic abnormalities in diabetes (e.g.,
insulin resistance, insulin deficiency) and have limited toler-ability.
Additionally, several available therapies are associated with
weight gain or enhanced risk of hypoglycemia. Thus, newer
approaches are urgently required. Particular emphasis should
be placed on developing pharmacological interventions that
are dependent on physiological responses and adequately target
underlying defects, such as obesity, in-sulin resistance,
increased glucose output from the liver, secretory dysfunction,
or apoptosis of the β-cell. Individual phenotypic and
genetic characterization of the diabetic patients will allow
to define more and more personalized and effective algorithms
for the treatment of hyperglycemia.
[Back to top]
Insulin Analogs Revisited
Jürgen Eckel
Insulin analogs have largely replaced conventional insulin
preparations and extensive clinical studies have confirmed
the beneficial action profile of these artificial insulin
molecules. Tight blood sugar control is a major goal of intensified
insulin therapy and this can be obtained much more efficiently
when using insulin analogs. Currently, three rapid-acting
insulin analogs are in clinical use based on either a change
of the amino acid sequence (insulin lispro) or exchanges of
one (insulin aspart) or two (insulin glulisine) amino acids.
Insulin glargine was the first long-acting insulin analog
with a well documented low risk of nocturnal hypoglycemia.
Insulin detemir is the most recent insulin analog with a long-acting
profile based on esterification with a fatty acid. For all
insulin analogs safety considerations are mandatory and must
take into account both the IGF-I and the insulin receptor.
Enhanced mitogenic activity and a tumorigenic potential of
an insulin analog may involve increased IGF-I receptor signaling
and/or sustained insulin receptor activation. Both insulin
and IGF-I receptors are involved in the regulation of tumor
cell growth. Further, insulin/IGF-hybrid receptors are abundant
in these cells and additional studies will be needed to assess
the role of these receptors in the long-term action profile
and safety of insulin analogs.
[Back to top]
GLP-1, Incretin Mimetics and DPP 4 Inhibitors: New Ways
in the Treatment of Type 2 Diabetes
Juris J. Meier and Michael A. Nauck
The incretin hormone glucagon-like peptide 1 (GLP-1) is produced
by post-translational processing of the proglucagon gene in
intestinal L-cells. Owing to its glucose-dependent insulinotropic
effect, a potential in the treatment of type 2 diabetes has
been suggested already 20 years ago. However, rapid enzymatic
inactivation of GLP-1 in vivo and the need for parenteral
administration have obviated its earlier therapeutic application.
In addition to its effects on insulin secretion, GLP-1 suppresses
glucagon secretion, decelerates gastric emptying and increases
satiety leading to reduced food intake and weight loss. In
the light of these features, GLP-1 appears to be an ideal
candidate for the treatment of type 2 diabetes. Today, a number
of different GLP-1 analogues or derivatives (the so called
“incretin mimetics”) with more favourable pharmacokinetic
profiles have been generated. Exenatide (Byetta; Eli Lilly
& Co), a synthetic GLP-1 receptor agonist suitable for
twice daily s.c. injection, has now been approved by the FDA
for the add-on therapy of patients with type 2 diabetes with
insufficient metabolic control during metformin and/or sulfonylurea
treatment. A number of other incretin mimetics are currently
being studied in clinical trials. An alternative strategy
to enhance the ac-tion of endogenous GLP-1 is inhibition of
its enzymatic degradation by specific inhibitors of the protease
DPP 4 (DPP 4 inhibitors), which are absorbed after oral ingestion.
Reductions in HbA1c-levels during treatment with incretin
mimetics and DPP 4 inhibitors were in the order of 0.5-1 %.
Major advantages of using incretin mimetics compared to other
antidiabetic drugs available include the lack of a risk for
hypoglycaemia due to the strict glucose-dependence of insuli-notropic
and glucagonostatic GLP-1 actions as well as weight reduction
by several kg despite their insulinotropic mode of action.
Therefore, incretin mimetics and DPP 4 inhibitors seem to
be useful new tools for the future treatment of type 2 diabetes.
[Back to top]
The Mode of Action of the Antidiabetic Drug Glimepiride-Beyond
Insulin Secretion
Günter Müller
During the past 10 years a multitude of clinical and observational
studies have confirmed the efficacy of the antidiabetic drug,
glimepiride, in lowering fasting and postprandial blood glucose
in lean and obese type 2 diabetic patients even after a single
administration per day, only, as well as its high safety and
patient’s compliance. Additional findings obtained in
these studies suggested a number of clinical advantages compared
to other sulfonylurea drugs on the market (e.g. glibenclamide),
in particular, the lower risk for hypoglycemia, weight gain
and atherosclerotic vascular disease as well as the less pronounced
hyperinsulinemia. Studies investigating the molecular basis
underlying the clinical profile of glimepiride provide strong
evidence for multiple molecular targets/mechanisms for the
blood glucose-lowering effect of glimepiride operating at
both pancreatic β-cells
and extrapancreatic cells. (i) Interaction with the sulfonylurea
receptor, SUR, at the ß-cell plasma membrane triggers
insulin release. (ii) Interaction with lipid rafts, DIGs,
at the plasma membrane of adipose and muscle cells induces
the insulin-mimetic activity via the activation of
a glyco-sylphosphatidylinositol-specific phospholipase, redistribution
of signaling components and positive cross-talk down-stream
to the insulin signaling cascade. (iii) Interference with
additional molecular mechanisms in extrapancreatic cells (e.g.
regulation of adipocytokine release from and differentiation
of adipocytes), relying on or independent of SUR and DIGs,
contributes to the insulin-sensitizing activity of glimepiride.
Differences in the engagement of these tar-gets/mechanisms
between glimepiride and glibenclamide are compatible with
the more favorable blood glucose-lowering profile and the
lower risk for weight gain, hypoglycemic incidences and cardiovascular
side effects. The mo-lecular and clinical findings with glimepiride
raise doubts that the potential of sulfonylureas for the therapy
of type 2 diabetic patients has already been fully explored
and feeds the hope for more efficient and nevertheless safe
antidiabetic drugs derived from this “old” pharmacophore
class in the future.
[Back to top]
Glucose Transport Regulators
M. Ben-Yakir, A. Gruzman, E. Alpert and S. Sasson
The prevalence of Type 2 diabetes (Non-Insulin-Dependent
Diabetes Mellitus) increases at an alarming rate in the world’s
population, reaching an epidemic proportion. Moreover, impaired
glucose tolerance and insulin resistance are being diagnosed
nowadays in a growing subpopulation of obese children and
adolescents, mostly in Western societies. This adds to the
concern that not only the number of NIDDM patients will increase
dramatically to over 300 millions within 20 years, but also
that overt diabetes and diabetes-related complications will
develop earlier in life. The main goal of pharmacological
therapy of diabetic patients is to reduce blood glucose levels
to the normal range. Indeed, most diabetic patients require
oral antihyperglycemic drug therapy; yet, the relatively high
rate of failure of these drugs and the chronic nature of the
disease, which is associated with progressive dysfunction
and exhaustion of pancreatic insulin-producing β-cells,
lead in many cases to insulin therapy. Most available antihyperglycemic
drugs sensitize β-cells to secrete insulin or overcome
peripheral insulin resistance by sensitizing insulin-responsive
tissues towards insulin. Nevertheless, genuine insulin mimetic
drugs or drugs aimed at directly augmenting the glucose transport
system in insu-lin-sensitive tissues are still being sought.
This review describes briefly current molecular targets for
antihyperglycemic drugs and discusses potential compounds
that may act as insulin-mimetics or enhancers. In addition,
a novel concept is introduced for the development of carbohydrate
derivatives that may augment glucose transport in insulin-sensitive
tis-sues in an insulin-independent manner.
[Back to top]
Serine Kinases as New Drug Targets for the Treatment of
Type 2 Diabetes
Cristina M. Rondinone
Protein phosphorylation is the most common mechanism of protein
function regulation. Protein kinases are key signaling enzymes
that participate in the regulation of multiple cellular responses.
Insulin regulates whole-body glucose homeostasis by modulating
the activities of protein kinases in its target tissues: muscle,
liver and fat. Defects in insulin's ability to modulate protein
kinase activity lead to 'insulin resistance' or impaired insulin
action. Recently, many serine kinases have been involved in
the pathogenesis of obesity, metabolic syndrome and diabetes.
These include the discovery of c-Jun N-terminal kinase (JNK),
I kappa beta kinase (IKK), protein kinase C (PKC) theta, glycogen
synthase kinase 3 (GSK3), S6 kinase-1 (S6K1) and 5'AMP-activated
protein kinase (AMPK) as critical regulators of insulin ac-tion
and glucose homeostasis. In this review, the mechanisms underlying
kinases-induced insulin resistance, the impact of blocking
this pathway in obesity and diabetes and the status of small
molecule inhibitors will be discussed. It is ex-pected that
elucidation of the molecular mechanisms underlying regulation
and specificity may prompt novel approaches for the pharmacological
modulation of protein kinase activities involved in metabolic
diseases. This review will give de-tail on recent discoveries
and highlight emerging kinase targets that hold potential
to reduce insulin resistance and nor-malize blood glucose.
Hematopoietic Stem Cell Transplantation and Graft-Versus-Host
Disease
Guest Editor: T. Iwasaki
[Back to top]
Editorial
Graft-versus-host disease (GVHD) is a devastating complication
of allogeneic hematopoietic stem cell transplanta-tion (HSCT).
Although significant progress in the treatment of GVHD has
been made, several obstacles remain in overcoming this complication.
Animal models have been critical to our understanding of the
pathophysiology of GVHD, and multiple clinical approaches
have been taken, based on experimental animal models. This
volume brings together contributions from experts in the fields
of HSCT and GVHD research, reviewing GVHD pathophysiology
and GVHD therapy.
Ferrara et al. review the pathophysiology of acute GVHD,
considering this disorder as a three-step process in which
the innate and adaptive immune systems interact. Ikehara reviews
a new HSCT method, intra-bone marrow transplantation, by which
GVHD is prevented even when donor lymphocyte infusion is carried
out. Fowler and Gress review the role of sirolimus in allogeneic
HSCT, and they describe a new adoptive Th2 cell therapy using
sirolimus. Iwasaki reviews novel therapies aimed at protecting
against GVHD by using protective growth factors, focusing
on hepatocyte growth factor and sphingosine-1-phosphate. Via
et al. review the parent-into-F1 model of GVHD that is useful
for studying immune responses in non-myeloablative conditioning
regimens, chronic GVHD, and autoimmunity. Finally, Levy reviews
approaches to regulate experimental as well as clinical GVHD
during three different stages, including the use of CD4+CD25+
regulatory T cells. We gratefully acknowledge the generous
efforts of all of these contributors. I hope this book will
prove valuable to those who are working in the fields of hematology
and oncology.
[Back to top]
Graft Versus Host Disease
J.L.M. Ferrara and S. Mineishi
The pathophysiology of acute graft versus host disease (GVHD)
can be considered as a three-step process where the innate
and adaptive immune systems interact (Fig. 1). The three steps
are: 1) tissue damage to the recipient by the radiation/chemotherapy
pre-transplant conditioning regimen, 2) donor T cell activation
and clonal expansion, and 3) cellular and inflammatory factors.
This schema underscores the importance of mononuclear phagocytes
and other accessory cells to the development of GVHD after
complex interactions with cytokines secreted by activated
donor T cells. In step 1, the conditioning regimen (irradiation
and/or chemotherapy) leads to damage and activation of host
tissues throughout the body and the secretion of inflammatory
cytokines Tumor Necrosis Factor (TNFα)
and Interleukin (IL-1). These cytokines may enhance donor
T cell recognition of host alloantigens by increasing expression
of major histocompatibility complex (MHC) antigens and other
molecules on host antigen presenting cells (APCs). Inflammatory
cytokines may also stimu-late chemokine release, recruiting
donor T cells into host target organs. In step 2, host APCs
present alloantigen (an HLA-peptide complex) to the donor
T cells. Co-stimulatory signals are required for T cell activation
and these signals further activate APCs which in turn enhance
T cell stimulation, characterized by cellular proliferation
and the secretion of cytokines. IL-2 expands the T cell clones
and induces cytotoxic T cell (CTL) responses; whereas, IFNγ
has multiple effects, including the priming of mononuclear
phagocytes to produce TNFα
and IL-1. In step 3, effector functions of mononuclear phagocytes
and neutrophils are triggered through a secondary signal provided
by mediators such as lipopolysaccharides (LPS) that leak through
the intestinal mucosa damaged during step 1. This inflammation,
along with direct lysis of target cells by CTL, causes pathologic
changes in target organs. Risk factors, as well as strategies
to prevent GVHD, can be conceptualized according to this three-step
model and will be reviewed in this article.
[Back to top]
A New Bone Marrow Transplantation Method for the Prevention
of Graft-Versus-Host Disease
Susumu Ikehara
A new bone marrow transplantation (BMT) method, “intra-bone
marrow (IBM)-BMT” has recently been developed. This
method was found to prevent not only graft-versus-host (GvH)
reaction but also host-versus-graft (HvG) reaction, since
IBM-BMT can efficiently recruit donor-derived stromal cells
(including mesenchymal stem cells: MSCs), which produce immunosuppressive
cytokines. This paper shows that IBM-BMT prevents GvHD even
when donor lym-phocyte infusion (DLI) is carried out, and
that the combination of IBM-BMT + DLI not only prevents GvHD
but also in-hibits the growth of solid tumors in mice. In
addition, it has been shown that IBM-BMT will be applicable
to the treat-ment of various intractable diseases.
[Back to top]
In Vitro and In Vivo Sirolimus for Modulation
of Allogeneic Hematopoi-etic Stem Cell Transplantation
Daniel H. Fowler and Ronald E. Gress
An ability to modulate three distinct yet inter-related immune
processes is required for successful allogeneic hematopoietic
stem cell transplantation (HSCT): reduction in graft-versus-host
reactivity that initiates graft-versus-host-disease (GVHD),
inhibition of host-versus-graft reactivity that causes allograft
rejection, and enhancement of graft-versus-leukemia (GVL)
and graft-versus-tumor (GVT) effects that primarily account
for the curative capacity of alloge-neic HSCT. Each of these
inter-related processes is susceptible to modulation by sirolimus,
which restricts receptor and nutrient mediated signaling in
multiple cell types through inhibition of the central regulatory
molecule, mammalian tar-get of rapamycin (mTOR). In experimental
models, sirolimus beneficially: (1) prevents GVHD; (2) prevents
graft rejec-tion; and (3) directly mediates anti-tumor responses
in tumors with constitutive activation of the phosphoinositide-3
kinase (PI3K) pathway that lies upstream to mTOR. However,
sirolimus detrimentally may: (1) abrogate GVL and GVT effects;
(2) reduce function of APC populations; and (3) inhibit hematopoiesis.
As such, utility of interventions that in-hibit mTOR will
depend upon the balance of beneficial vs. detrimental effects
generated. Recent clinical trials indicate that sirolimus
can indeed yield a favorable balance to this equation, as
the drug appears to prevent GVHD without marked impairment
of alloengraftment or anti-tumor effects. However, sirolimus
therapy is limited by drug toxicity and a relatively narrow
therapeutic window. This limitation may be overcome in part
through in vitro usage of sirolimus for allograft
T cell engineering in clinical trials now in progress.
[Back to top]
Protective Growth Factors for Graft-Versus-Host Disease
Tsuyoshi Iwasaki
Graft-versus-host disease (GVHD) has been the primary limitation
to the wide application of allogeneic hematopoietic stem cell
transplantation (HSCT). GVHD is initiated by activation of
donor T cells recognizing host tissue antigens, with subsequent
dysregulated inflammatory cytokine production by monocytes
and macrophages. These inflammatory cytokines are crucial
for the pathogenesis of acute GVHD and these inflammatory
manifestations are recognized as clinical acute GVHD. This
paper presents a brief review of the mechanisms underlying
inflammatory cytokine responses during acute GVHD and various
strategies aimed at the prevention of acute GVHD. As cytokines
and growth factors that are protective against GVHD are also
produced during inflammatory cytokine responses, the factors
contributing to the protection against GVHD are also reviewed.
Attention has focused on the mechanisms responsible for the
protection against GVHD conferred by hepatocyte growth factor
and sphingosin-1-phosphate, which are abundantly stored in
platelets. These factors are produced during inflammation
and tissue injury and regulate immune, hematopoietic and regenerative
responses. Novel therapies aimed at protection against GVHD
using protective growth factors are discussed, although in
most cases, their clinical relevance has not been established.
Carefully designed clinical trials are awaited to evaluate
their usefulness in the prevention and management of GVHD.
[Back to top]
The Parent-into-F1 Model of Graft-vs-Host Disease as a
Model of In Vivo T Cell Function and Immunomodulation
R.A. Pulaiev, I.A. Puliaeva, A.E. Ryan and C.S. Via
Since its description roughly 30 years ago, the parent-into-F1
model of graft-vs.-host disease has provided insights
into the mechanisms of in vivo T cell activation
and the pathogenesis of autoimmune conditions. A new and emerging
role for the P→F1 model is one of identifying agents
with immunomodulatory activity and defining in vivo mechanisms
that promote cell mediated or antibody mediated immune responses.
Because F1 mice are not irradiated prior to donor cell transfer,
the P→F1 model has in the past not been strictly analogous
to human hematopoetic stem cell transplantation. However with
the advent of newer non-myeloablative conditioning regimens,
the model may assume more relevance. In this article, we first
provide a review of relevant earlier fundamental observations
followed by a summary of recent work from our laboratory in
which acute and chronic GVHD in this model have been used
not only to study normal T cell responses in vivo
but also to define mechanisms important in the pathogenesis
of autoimmunity and immunomodulation.
[Back to top]
GVHD: Complication and Challenge to Successful Allogeneic
Hematopoietic Cell Transplantation
Robert B. Levy
Graft vs. host disease (GVHD) represents the major obstacle
to more widespread clinical application of allogeneic hematopoietic
cell transplants and experimentally provides perhaps the most
important model for immunologists to study the significance
and regulation of allogeneic T cell responses in situ.
The sensitivity of induction to donor T cell numbers, the
target tissues ‘attacked’ in the host and the
clinical sequelae associated with the pathogenesis of GVHD
in the mouse remarkably parallel that which occurs in humans
and thus has provided an extremely useful tool to dissect
the underlying cells and mechanisms involved in this complex
disorder. This review describes the general features of GVHD
followed by a description of the three stages which define
this response. Approaches being developed to regulate experimental
as well as clinical GVHD during these different stages are
then discussed. We conclude that advances towards the targeting
of each stage of the process are raising hope that clinicians
will one day be able to control both the ‘light’
and ‘dark’ sides of GVHD. The challenge to refine
and implement such approaches at the bedside necessitates
continued interactions and collaborative efforts between laboratories
dedicated to applying the underlying cellular and molecular
biology of hematolymphoid cells to transplantation together
with clinician scientists motivated by the goal to perform
hematopoietic cell transplants without fear of complications.
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