ARTICLE
ocl.2011.0389
Auteur(s) : Nicolas Blondeau blondeau@ipmc.cnrs.fr
Université de Nice Sophia Antipolis,
28 Avenue de Valrose,
06103 Nice Cedex 2,
France;
Institut de Pharmacologie Moléculaire et Cellulaire,
CNRS,
UMR 6097,
660 Route des Lucioles,
06560 Valbonne,
France
Stroke and the failure of neuroprotective agent
development
Stroke is the third leading cause of death, annually afflicting
approximately 150,000 French and 780,000 Americans. On average in
the developed countries, stroke strikes once every 40 seconds and
causes death every 4 minutes, with an estimated 25% death rate
within the first week, and 50% of the patient population within 5
years after the brain attack. Among survivors, work capacity is
compromised in 70% of victims, among which 30% need assistance with
self-care. Stroke causes functional control impairment, paralysis,
speech and sensory problems, memory and reasoning deficits, often
leading to long-term disability, dementia and post-stroke
depression. Hence stroke is a global burden that affects all racial
or ethnic groups indiscriminately. Its social and psychological
costs are substantial in developed nations, as well as its economic
cost, which have been estimated to be greater than 70 billion
dollars in 2010 in the USA (Lloyd-Jones et al., 2010,
Rosamond et al., 2008).
In eighty five percent of stroke cases, the neurovascular event
causing the stroke is ischemic, meaning that blood flow to a part
of the brain is disrupted due to occlusion of a blood vessel.
Occlusion deprives the brain of nutrients and oxygen, eliciting a
complex interplay of multiple cellular signaling pathways that
damages the neurovascular unit (neuronal, glial and endothelial
cells (Iadecola, 2004)) within the affected territory. Within the
core of the ischemic territory, blood flow is most severely
restricted, and excitotoxic and necrotic cell death occurs within
minutes. In the periphery of the core, termed the ischemic
penumbra, reduced collateral blood flow buffers the full effects of
the stroke. In this area, primarily apoptosis leads to a slower
rate of cell death (Endres and Dirnagl, 2002).The only therapeutic
available is recombinant tissue plasminogen activator, which
restores cerebral blood flow by disrupting the blood clot causing
vessel occlusion. Unfortunately, due to its restricted application,
thrombolysis it is only perform in approximately 5% of the stroke
population. Other therapeutics aimed at more directly blocking the
cellular ischemic cascade, as identified in numerous preclinical
studies, failed in clinical trials. In 2007 O’Collins reviewed 1026
neuroprotective treatments identified for acute stroke between 1957
and 2003. Of the 114 treatments which were tested (and failed) in
clinical trials, no drug perform any better against all other drugs
when tested against focal models of cerebral ischemia. In addition,
these drugs displayed poor adherence to the series of criteria
determined to identify neuroprotective agents with the best chance
of success in clinical trials by the Stroke Therapy Academic
Industry Roundtable (STAIR). This poor translation from
experimental models to clinical trials raised the question of
whether the best drugs were being chosen to proceed to clinical
trial, leading to consideration of new ideas and recommendations
for the development of strategies in combating stroke.
Regarding translation, much has been written about timing and
dosing, failure to incorporate preclinical information into
clinical trials, as well as acknowledgement that animal data may
not adequately support translation of a neuroprotective drug to
clinical (Jonas et al., 1999). Although animal models may
not faithfully reproduce all multifactorial aspects of strokes in
humans, animal models are representative of important clinically
relevant pathophysiological features of human stroke. Therefore,
the “best in class” drug should be tested and be efficient in
several experimental mode of stroke, as well as in species which
include primates. A second recommendation is to redefine the view
of the pathology as a cerebrovascular and not exclusively as a
neuronal disease. Nowadays, considering only neurobiological
aspects of stroke defies increasing recognition that stroke
triggers both cerebral endothelium dysfunction leading to CBF
alteration, and neuronal, astroglial and oligodendroglial
homeostasis disruption, as well as and microglial activation.
Therefore the research and medical community had now moved towards
a more integrative view of stroke taking in consideration the
protection of all cell types within the entire neurovascular unit
(fundamentally comprising endothelium, astrocyte and neuron). In
order to be considered as a good candidate for a clinical trial,
stroke treatment must have clear and demonstrable efficacy on all
the neurovascular unit cells or at least must be carefully
considered in terms of its actions on all cell types and
neurovascular functions. Thus, an experimental drug should be
better tested for safety and efficacy not only in neurons but also
on cerebral endothelial cells, astrocytes, oligodendrocytes,
microglia and so on (Lo and Rosenberg, 2009). A large body of basic
research over the past two decades shows that ischemic stroke
causes brain damage by multiple pathways, implicating mechanisms
like excitotoxicity, oxidative stress and programmed cell death.
The failure of stroke trials which targeted one or only a few of
these pathways suggests that targeting a single element of a single
pathway may not yield sufficient neuroprotection. Consequently, an
emerging view is that combination or « multi » therapy,
or discovering drugs exhibiting multimodal actions at multiple cell
types, is required to address the multifactorial nature of stroke.
Therefore, molecules that provoke multiple protective and
regenerative mechanisms should be particularly attractive
therapeutic agents (Lo, 2008; Minnerup and Schabitz, 2009;
Zaleska, et al., 2009). A pertinent and effective
experimental approach to identify such candidates would be to
better understand how the brain protects itself against ischemia,
through the study of brain preconditioning.
Brain preconditioning is an innovative approach in discovery of
novel cerebroprotective strategies against ischemic stroke
This cellular and adaptative biological process conferring
resistance to ischemia is called preconditioning. Particularly
within the last two decades, preconditioning has attracted much
interest within the clinical and basic neuroscientist communities,
primarily due to promotion of protection and regeneration against
stroke through direct and/or indirect mechanisms, involving
multiple cell types. Therefore preconditioning is considered
pleiotropic in nature. Ischemic preconditioning of the brain, heart
and other organs refers to an endogenous protective process that is
induced by a sublethal ischemia and which increases the tissue
tolerance to a subsequent, normally lethal ischemia. Since its
original description in the brain by Kitagawa in 1990, (Kitagawa
et al., 1990), non-ischemic peconditioners including various
sublethal insults like epilepsy, endotoxins, anoxia, hyperthermia
and spreading depression were shown to also induce delayed
tolerance to normally lethal forms of themselves, and additionally
tolerance to ischemia, also named “cross-tolerance” (Plamondon
et al., 1999; Tauskela and Blondeau, 2009).
A concern that potential clinical applications of brain
preconditioning may be very limited due to the requirement of
bringing neurons to the “brink of death” during preconditioning,
has been circumvented by discoveries that preconditioning and its
tolerance to ischemia may be induced or mimicked pharmacologically
by chemicals like adenosine and KATP channel agonists
(Blondeau et al., 2000). Several other compounds including
3-nitropropionic acid and the glutamate receptor agonist,
N-methyl-D-aspartate (NMDA) have been investigated in both in
vivo and in vitro models of preconditioning (Tauskela
and Blondeau, 2009). Moreover, retrospective case-control studies
showed a clinical correlate of the experimental preconditioning
paradigm, suggesting that patients with a history of transient
ischemic attack (TIA) exhibit a decreased morbidity after stroke
(O’Duffy et al., 2007; Weih et al., 1999), strongly
suggesting that preconditioning is a pertinent and effective
experimental concept in the human brain. Finally, with the recent
demonstration that preconditioning can also be induced by a variety
of natural product like polyunsaturated fatty acid and
lysophospholipids, preconditioning studies provide an innovative
approach for the discovery of novel cerebroprotective strategies
(Blondeau et al., 2002a; Blondeau et al., 2002b).
Preconditioning induces two different temporal windows of
protection against ischemia: the first window known as “rapid
preconditioning” occurs within minutes after the stimulus used for
induction of preconditioning and only lasts for around 1 h,
whereas the delayed window produces a more robust state of
protection that usually develops 24 h after preconditioning
induction, peaks at 72 hours fades 7 days later. In general, a two-
to four-day interval between preconditioning and lethal ischemia
provides the greatest protection, at least in the rodent brain.
Increasing this interval generally reduces benefits, although in
some studies a delay of up to two weeks could still result in some
ischemic tolerance. Longer stimulation with low stimulation by
non-ischemic preconditioners, while still not inducing toxicity,
may generate more robust ischemic tolerance. All these facts, the
molecular sensors, transducers and effectors of preconditioning
have been already elegantly described in high-impact reviews
(Kirino 2002; Dirnagl et al., 2003; Gidday, 2006;
Obrenovitch, 2008). These reviews also underline key conceptual
differences between preconditioning and neuroprotection strategy,
notably the time frame and mechanism of protection. Preconditioning
activates endogenous pro-survival responses, including genetic
remodeling, to suppress the toxic signaling effects, whereas drug
therapies are mostly designed to directly inhibit toxic signaling
pathways occurring post-stroke. Thus preconditioning requires a
certain delay in order to attain the subsequent maximal protection,
so it is often inadequately perceived as a preventive strategy.
The preventive strategies in stroke are aimed to decrease
stroke incidence
The poor translation from experimental models to clinical trials
has led to adoption of additional strategies in combating stroke,
most notably drawing attention to the importance of prevention. The
prevention or/and treatment of the risk factors has emerged as a
priority to reduce the occurrence of stroke. Some risk factors
cannot be modifiable, such as a family history of cerebrovascular
diseases, aging, male sex, and Hispanic or Black race (Allen and
Bayraktutan, 2008). But the other risk factors including
cardiovascular complications (atrial fibrillation, valvular heart
disease, ischemic cardiomyopathy and carotid stenosis for example),
hypertension, diabetes, hypercholesterolemia, cigarette smoking,
increased inflammatory markers, dyslipidemia, and obesity may be
addressed by life-style changes and pharmacologicals, to
prevent or minimize the possibility of having a stroke.
Modifiable risk factors often coexist and have been estimated to
account for 60%-80% of stroke incidence in the general population
(Allen and Bayraktutan, 2008; Moskowitz et al., 2010), and
are often associated with improper nutrition causing imbalance in
essential vitamins and nutriments. Many clinical and epidemiologic
studies have shown that deficiency in vitamins, nutriments, and
essential omega-3 polyunsaturated fatty acids may be risk factors
of stroke per se. Low levels of fruits and vegetables in
diet or improper omega-3 intake, both in the form of α-Linolenic
Acid (ALA) and the Long Chain derivatives (LC-n-3),
Eicosa-Pentaenoic-Acid (EPA) and Docosa-Hexaenoic-Acid (DHA), are a
risk factor for cardiovascular and cerebral diseases, including
coronary heart disease and stroke (Dauchet et al., 2005; de
Goede et al., 2011; Riediger et al., 2009;
Simopoulos, 2008).
Importantly, besides reducing the risk of stroke, these factors
may exhibit a protective role against stroke-induced damage, a
field of study of potentially major relevance but inadequately
addressed. Several epidemiologic studies in cerebral diseases
identified beneficial effects of diets rich in omega-3
poly-unsaturated fatty acids (PUFAs) by consumption of seafood
(rich in LC-n-3: EPA and DHA) and/or vegetable oils rich in
precursor (ALA), suggesting that omega-3 PUFAs may have a
neuroprotective role. This notion received mechanistic support with
the discovery that omega-3 activates the neuronal potassium TREK-1
channel, leading to neuronal membrane hyperpolarization.
Hyperpolarization of synaptic terminals decreases glutamate release
while blocking NMDA receptor activation at the post-synaptic level,
a protective strategy with proven efficiency in animal model of
stroke (Fink et al., 1998; Lauritzen et al., 2000).
Besides providing acute neuroprotection, our laboratories evaluate
the possibly that omega-3 FA may also act as a preconditioner
against ischemia. By fulfilling multiple requirements of
prevention, acute protection and preconditioning, acting at
multiple cell types, omega-3 FA may indeed be recognized as a
“best-in class” therapeutic against stroke.
Omega-3 α-linolenic acid as an acute treatment in experimental
model of cerebral ischemia and stroke
During the acute phase of ischemic injury, glutamate
excitotoxicity and hyperactivation of its receptors are the major
destructive mechanisms within the core and surrounding penumbra.
Chronologically, glutamate release-driven neuronal death occurs
within minutes to hours following cerebral ischemia, so
therapeutics aiming to inhibit this acute phase must be
administered very shortly after the ischemic insult. Of relevance,
this time course may match the first protection window occurring
within minutes to hours after the induction of “rapid
preconditioning”. The time constraints of acute neuroprotection may
be difficult to achieve in clinical practice, but testing a drug in
both paradigms is important in estimating its neuroprotective
capacity. We have therefore investigated neuroprotection by ALA and
DHA in an in vivo transient model of global ischemia, in
which neuronal death of CA1 hippocampal pyramidal cells is mainly
driven by glutamate excitotoxicity (Pulsinelli and Brierley, 1979).
Seven days after a 20 min global ischemia, only 15% of the CA1
neurons survived the ischemic challenge, while the injection of ALA
(i.c.v., 10 μM/5 μL) within 30 min post-ischemia allowed
80% of the CA1 neurons to survive. ALA was also protective when
administered intravenously (i.v., 500 nmol/kg) 30 minutes
before or after the ischemic challenge (figure 1A).
However, in this model, EPA and DHA had less pronounced and
reproducible protective effects (Lauritzen et al., 2000). We
therefore decided to focus our investigation on the omega-3
precursor rather than on the long chain derivates. To clearly
establish that ALA could inhibit glutamate excitotoxicity we tested
its protective potential in an in vivo model of seizure
induced by the administration of the glutamate analog kainic acid,
and in an in vitro model of glutamate stress. In
vivo, using the same dosage paradigms as for ischemia, ALA was
neuroprotective when injected i.v. either 30 min before or after KA
treatment (Lauritzen et al., 2000). In vitro, the
same range of concentrations known to be protective both in
vivo with i.c.v. injection and in vitro on granule
cells, prevented hippocampal neuronal death triggered by the
addition of an excitotoxic concentration of glutamate (50 mM) for
24 hours (Blondeau et al., 2009). In all these models a
saturated fatty acid, palmitic acid, failed to induce any
beneficial effects, underlying the importance of the omega-3
polyunsaturated class of fatty acids.
ALA effect on the vascular tone and CBF was investigated.
As previously discussed, the failures of therapeutics targeting
only neurons and the hyperacute nature of glutamate release-driven
neuronal death in ischemia lead the scientific community to
identify drugs that could also help restoring and/or preserving the
cerebral blood flow (CBF). The in vivo and in vitro
neuroprotective 10 μM and 100 μM concentrations of ALA
induced an increase of the diameter of the basilar, but not of the
carotid artery (Blondeau et al., 2007). In both mice and
rats (figure
1B) ALA acted as a vasoactive drug, leading to an
approximately 30% increase of the diameter of the basilar artery
ex vivo, accounting for a 20% increase of the in vivo
CBF observed within 30 min post-injection (i.v. neuroprotective
dose of 500 nmol/kg). Since ALA did not dilate carotid arteries
with elastic properties, the omega-3 induced relaxation appears to
be specific to cerebral resistance arteries such as those of the
cerebral vascular bed, without affecting the systemic blood
pressure. Therefore, both the increased resistance to glutamate
hyperexcitability and vasodilation capacity of brain arteries that
increases collateral flow and reduce CBF loss in the penumbra,
after ALA injection, may potentially contribute to protection
against ischemic stroke. Thus, we investigated the effect of
α-linolenic acid in the middle cerebral artery occlusion (MCAO)
model, using the intraluminal suture technique ascribed to be the
closest model to human stroke.
The compatibility of ALA post-treatment to the clinical
setting was addressed by investigating two clinically relevant
parameters. The window of intervention to efficiently reduce the
infarct volume 24 hours post-MCAO was characterized, and a delivery
protocol was designed to improve the long-term survival rate. ALA
significantly reduced the infarct volume when injected up to
6 h after reperfusion onset (Heurteaux et al., 2006).
Maximal protection was achieved using 500 nmol/kg injected
2 h post-ischemia, and the window of intervention faded by 12
hours after the onset of reperfusion (figure 1C).
The ALA-induced neuroprotection correlated with a decrease in
cytopathological features of cell injury, DNA-fragmentation and
pro-apoptotic Bax protein up-regulation. For all parameters used as
a measure of the degree of protection, the natural omega-3
precursor efficiency was similar to riluzole, a chemical
neuroprotectant currently in clinical use for amyotrophic lateral
sclerosis. In contrast, the saturated palmitic fatty acid failed to
reduce the infarct volume when injected 2 hours after reperfusion.
Interestingly, a single ALA injection providing the best cerebral
protection at 24 hours post-stroke had no beneficial effect on the
long-term survival rate. To achieve a 3-fold improvement in the
survival rate at 10 days and one month post-ischemia, repeated
injections were required (Blondeau et al., 2009, Heurteaux
et al., 2006). This data suggested that the reduction of
glutamate excitotoxicity was insufficient to reduce long-term
mortality rates. Indeed, excitotoxicity suppression may instead
only delay neuronal death, by failing to prevent later stages of
cell death including apoptosis and associated inflammatory events,
events known to cause progressive tissue damage hours to days or
weeks later. Nevertheless, the beneficial effects caused by
repeated injections spaced several days apart implied that ALA
triggered other beneficial mechanisms. Preclinical data indicate
that pharmacological therapies that enhance brain-repair processes
substantially improve functional recovery when given during the
later recovery phase of stroke. The concept underlying these
restorative therapies is the pleiotropic targeting of many
parenchymal cell types including neural stem cells, cerebral
endothelial cells, astrocytes, oligodendrocytes, and neurons leads
to enhancement of neurotrophic factor production, endogenous
neurogenesis, angiogenesis, and synaptogenesis in ischemic brain
tissue (Zhang and Chopp, 2009). These events collectively improve
stroke outcome including neurological function.
To evaluate long-term benefits, the effect of subchronic ALA
administration on neuronal plasticity was investigated. An
increase in neurogenesis was observed, following three sequential
injections performed using the same time course and dose that
improved long-term survival rate post-stroke (Blondeau et
al., 2009). Subchronic ALA treatment significantly increased
the number of proliferating immature neurons, as identified by the
colocalization of incorporated BrdU, a DNA synthesis marker, in
dividing progenitor cells and DCX, a microtubule-associated protein
specifically expressed in all migrating neuronal precursors. These
immature neurons identified 3 days after the last injection
survived and matured by 21 days after the last ALA injection
(figure
2A), suggesting that the repeated ALA injections
triggered the induction of neurogenesis. The upregulation of key
proteins involved in synaptic functions, synaptophysin-1, VAMP-2,
and SNAP-25 as well as proteins supporting glutamatergic
neurotransmission, V-GLUT1 and V-GLUT2, also indicated that ALA
subchronic treatment promoted synaptogenesis (figure 2B).
These effects correlated with an increase in BDNF protein levels
both in vivo, following subchronic ALA treatment and in
vitro using neural stem cells and hippocampal cultures
(Blondeau et al., 2009). Altogether these results imply a
pleiotropic effect of ALA, which could target different brain cell
types and combine acute neuroprotection, CBF regulation and
long-term repair/compensatory plasticity to protect from stroke.
This pleiotropism parallels brain preconditioning findings of
combined neuroprotective, regenerative and anti-inflammatory
effects.
Omega-3 α-linolenic acid as a preconditioner in experimental
model of cerebral ischemia and stroke
As a proof a concept that ALA could be a “natural”
preconditioner against cerebral ischemia, we tested whether ALA
preconditioning could trigger the late phase of tolerance against
two models of excitotoxicity-driving neuronal death by global
ischemia and kainic acid injection. ALA injection (i.v., 500
nmol/kg) 3 days before 6 min global ischemia or kainic acid-induced
epileptic seizure almost fully prevented the CA1 neurodegeneration
(Blondeau et al., 2002b). The narrow temporal window of
cerebral protection conferred by ALA preconditioning parallels
findings observed using preconditioning by ischemia or epileptic
activity. Similarities in signal transduction pathways activated
with ischemia and other well-established chemical preconditioners,
confirmed that ALA may be studied as a new natural preconditioner
of the brain. For example, ALA preconditioning induced the
neuroprotective HSP70 heat shock protein within a similar time
frame and neuronal localization shared by ischemic, epileptic and
adenosine and Katp channel openers preconditioning
(Blondeau et al., 2000; Blondeau et al., 2002b). In
addition, preconditioning by ALA, ischemic, kainic acid-induced
epileptiform activity rapidly increased the expression of the
transcription factor nuclear factor-κB. NFκB is an ubiquitously
expressed inducible regulator of a broad range of genes that play
pivotal roles in cell death and survival pathways. The three
different preconditionings increased NFkB DNA-binding activity and
nuclear translocation of p65 and p50 subunits of NFkB in a similar
manner and cellular compartmentalization (Blondeau et al.,
2001). Pretreatment with the NFkB inhibitor diethyldithiocarbamate
or kB-decoy DNA suppressed the increased DNA-binding activity and
the nuclear translocation of NFkB, leading to the loss of the
preconditioning-induced neuroprotection against an otherwise lethal
ischemic or epileptic challenge. Thus the functions of the pathways
established by ALA preconditionings are similar to those observed
in the other preconditioning that are required for the development
of brain tolerance. ALA preconditioning was also demonstrated in
mice, since ALA subchronic treatment 3 days before a transient
focal ischemia significantly reduced the infarct volume (Blondeau
et al., 2009). The similarities in the narrow window of
cerebral protection, as well as overlap in signal transduction
pathways, activated by ischemia and other well-established chemical
preconditioners, clearly demonstrates that ALA can trigger the
ubiquitous pleiotropic protective signaling pathways important to
brain preconditioning.
Omega-3 α-linolenic acid as preconditioner in the diet to
prevent stroke-induced damage: from preconditioning toward
nutraceutical
The overall properties of ALA may fulfill criteria necessary to
rank this omega-3 PUFA as a good neuroprotectant, or at least as a
crucial molecule for brain resistance. ALA is a fatty acid
qualified of “essential”, because its synthesis is not performed by
the human organism and must therefore be provided by diet. This
could explain in part why the severe deficiency in omega-3 intake
that has been reported in numerous epidemiologic studies may weaken
the brain, representing an important risk factor in the development
and/or deterioration of certain neuropathologies and neurovascular
diseases, like stroke. In the context of stroke treatment, the
rationale of supplementation with a non-ischemic preconditioner
like ALA has seemed promising to investigate, especially since no
detrimental effects of ALA have been documented as far as we are
aware. An unobtrusive method of increasing ALA intake would be to
increase levels in the daily diet. We addressed this important
hypothesis by investigating whether ALA supplementation achieved
using a diet enriched in rapeseed oil, a rich source of ALA as the
only source of lipids, decreased infarct volumes in stroked mice. A
diet enriched with ALA (0,75% by weight) significantly reduced
mortality rate, infarct size induced by 60 min of middle carotid
artery occlusion and increased the probability of spontaneous
reperfusion in the post-ischemic period (Nguemeni et al.,
2010). Figure
3 shows that the ALA-enriched diet decreased the total
infarct volume by 35 to 45% (total infarct, cortical infarct). The
reduction of the focal ischemic lesion was similar in rats
supplemented with high dietary levels of long-chain omega-3 (1.75%
by weight) over 6 weeks (Relton et al., 1993). This result
implies that lower levels of supplementation may be required when
using precursors compared to long-chain derivatives. Since the
neuronal protection obtained with supplementation achieved
force-feeding fish oil rich in long-chain omega-3 is controversial
(Bas et al., 2007; Ozen et al., 2008), ALA provided
by vegetable rapeseed oil should be considered as an interesting
alternative to long-chain omega-3 derivates from fish oil. Finally,
a drastic reduction of lipid peroxidation levels was also observed
in the ischemic brain of animals fed the ALA enriched diet,
suggesting that beneficial effects of ALA have not yet been
exhaustively categorized (Nguemeni et al., 2010).
Conclusion
To conclude, this review supports α-linolenic acid as an omega-3
precursor exhibiting interesting potential therapeutic value
against stroke. Moreover, a new perspective in the preconditioning
field is offered. Specifically, a novel approach to precondition
the brain against ischemia may be to implement existing or novel
nutraceuticals. Indeed, one could view nutraceuticals as “natural
preconditioners” which target the brain to its increase resistance
against devastating insults such as stroke. Ultimately, the future
of preconditioning largely depends upon successful translation of
important findings to daily life and the clinical arena.
Development of strategies achieved using functional food may
represent an important avenue to achieve this goal.
Acknowledgments
Ideas discussed here are based in part on the author's
presentation at the 2011 Journées CHEVREUL – Lipids and Brain 2 The
French Society for the Study of Lipids in Paris. I am grateful to
GLN, ONIDOL, the “Fondation de la Recherche Médicale” and CNRS for
their support. I wish to thank Dr Joseph Tauskela for his critical
reading of the manuscript. I am also grateful to Pr Bernadette
Delplanque and Dr Catherine Heurteaux for many helpful discussions.
Finally, I thank all our past and present team members who have
contributed to the data discussed in the review.
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