|
Current Molecular Medicine
ISSN: 1566-5240
Current Molecular Medicine
Volume 7, Number 5, August 2007
Contents 
Escape Mutations in HIV Infection and its Impact on
CD8+ T Cell
Responses Pp. 446-458
Mariola López, Vincent Soriano and Jose Miguel
Benito
[Abstract]
Gene Profiles within the Adult Subventricular Zone
Niche: Proliferation, Differentiation and Migration of Neural
Progenitor Cells in the Ischemic Brain Pp. 459-462
Rui Lan Zhang, Zheng Gang Zhang and Michael Chopp
[Abstract]
Potential Utility of Telmisartan, an Angiotensin II
Type 1 Receptor Blocker with Peroxisome Proliferator-Activated
Receptor-γ
(PPAR-γ)-Modulating
Activity for the Treatment of Cardiometabolic Disorders
Pp. 463-469
Sho-ichi Yamagishi, Kazuo Nakamura and Takanori Matsui
[Abstract]
Dissecting Cause and Effect in the Pathogenesis of
Psychiatric Disorders: Genes, Environment and Behaviour
Pp. 470-478
Laura Gray and Anthony J. Hannan
[Abstract]
The Wnt/Beta-Catenin Pathway in Wilms Tumors and Prostate
Cancers Pp. 479-489
Benjamin Tycko, Chi-Ming Li and Ralph Buttyan
[Abstract]
Opportunities to Improve the Prevention and Treatment
of Cervical Cancer Pp. 490-503
Richard B.S. Roden, Archana Monie and T.-C. Wu
[Abstract]
Molecular Pathogenesis of Pancreatic Cancer: Advances
and Challenges Pp. 504-521
Thilo Welsch, Jörg Kleeff and Helmut Friess
[Abstract]
Toll-Like Receptors, New Horizons in Sepsis
Pp. 522-531
Saulo F. Saturnino and Marcus V. Andrade
[Abstract]
Abstracts
[Back to top]
Escape Mutations in HIV Infection and its
Impact on CD8+
T Cell Responses
Mariola López, Vincent Soriano and Jose Miguel
Benito
Cellular immune responses play an important role in the control
of HIV replication. Although clear evidence exists on its
influence during acute HIV infection, its role during the
chronic phase of the disease remains controversial. This review
describes the cellular immune responses elicited against HIV
mediated by CD8+
T lymphocytes, and the mechanisms by which these cells are
inefficient to completely control HIV replication and halt
disease progression. The role of escape mutations as one of
the most relevant mechanisms HIV has developed to evade host
cellular immune responses is highlighted.
[Back to top]
Gene Profiles within the Adult Subventricular Zone
Niche: Proliferation, Differentiation and Migration of Neural
Progenitor Cells in the Ischemic Brain
Rui Lan Zhang, Zheng Gang Zhang and Michael Chopp
Focal cerebral ischemia induces neurogenesis in the subventricular
zone (SVZ) of the adult human brain. Neurogenesis is controlled
by proliferation, differentiation, and migration of neural
progenitor cells. This article reviews emerging data that
changes of cell cycle kinetics of neural progenitor cells
induced by stroke contribute to increased neural progenitor
cell proliferation and that gene profiles control proliferation,
differentiation, and migration of neural progenitor cells
within the SVZ niche. A better understanding of gene profiles
that control the biological function of adult SVZ neural progenitor
cells could lead to more selective and effective treatments
to enhance neurogenesis during stroke recovery.
[Back to top]
Potential Utility of Telmisartan, an Angiotensin II
Type 1 Receptor Blocker with Peroxisome Proliferator-Activated
Receptor-γ
(PPAR-γ)-Modulating
Activity for the Treatment of Cardiometabolic Disorders
Sho-ichi Yamagishi, Kazuo Nakamura and Takanori Matsui
The metabolic syndrome is strongly associated with insulin
resistance and consists of a constellation of factors such
as hypertension and hyperlipidemia that raise the risk for
cardiovascular diseases and diabetes mellitus. There is widespread
agreement that the renin-angiotensin system (RAS) plays a
pivotal role in the pathogenesis of insulin resistance and
cardiovascular disease in diabetes. Indeed, large clinical
trials have demonstrated substantial benefit of the blockade
of this system for cardiovascular end-organ protection. Thus
the blockade of the RAS may be a promising strategy for the
treatment of the patients with the metabolic syndrome. Although
several types of angiotensin II type 1 (AT1)
receptor blockers (ARBs) are commercially available for the
treatment of patients with hypertension, we have recently
found that telmisartan (Micardis®) could have
the strongest binding affinity to AT1
receptor. Further, telmisartan is reported to act as a partial
agonist of peroxisome proliferator-activated receptor-γ
(PPAR-γ).
These observations suggest that, due to its unique PPAR-γ-modulating
activity, telmisartan may be one of the most promising sartans
for the treatment of cardiometabolic disorders. In this paper,
we reviewed the potential utility of telmisartan in insulin
resistance and vascular complications in diabetes.
[Back to top]
Dissecting Cause and Effect in the Pathogenesis of
Psychiatric Disorders: Genes, Environment and Behaviour
Laura Gray and Anthony J. Hannan
It has long been established that the development of psychiatric
illness results from a complex interplay between genetic and
environmental factors. Postmortem and genetic linkage studies
have identified a number of promising candidate genes which
have been reinforced by replication and functional studies.
However, the fact that concordance rates for monozygotic twins
rarely approach 100% highlights the involvement of environmental
factors. Whilst epidemiological studies of psychiatric cohorts
have demonstrated potential risk factors, such studies are
clearly limited and in many cases the potential mechanism
linking a given risk factor with pathogenesis remains unclear.
A very powerful method of elucidating the mechanisms underlying
gene-environment interactions is the use of appropriate animal
models of psychiatric pathology. Whilst animals cannot be
used to map the entire complexity of diseases such as schizophrenia,
dissecting the symptom profile into more simply encapsulated
traits or endophenotypes has proved to be a successful approach.
Such endophenotypes provide a measurable link between aetiological
factors and phenotypic outcome. Given the potential for the
careful control and modification of an experimental animal’s
environment, the combination of studies of candidate genes
with investigations of environmental factors is an effective
heuristic tool, allowing examination of behavioural endophenotypes
in conjunction with cellular and molecular outcomes. This
review will consider the extant genetic, molecular, pharmacological
and lesion-based models of psychiatric disorders, and the
relevant methods of environmental manipulation appearing in
the literature. We will discuss studies where such models
have been combined, and the potential for future experimentation
in this area.
[Back to top]
The Wnt/Beta-Catenin Pathway in Wilms Tumors and Prostate
Cancers
Benjamin Tycko, Chi-Ming Li and Ralph Buttyan
Wnt/beta-catenin signaling is constitutively increased in
several major classes of tumors arising from the urogenital
tract. In this review we focus on this pathway mainly in Wilms
tumors and prostate carcinomas, followed by a brief discussion
of its potential role in other types of urological tumors.
Molecular studies in these types of cancers have highlighted
novel components upstream and downstream of this central oncogenic
pathway. Beta-catenin gain-of-function mutations are strongly
linked to WT1 loss-of-function mutations in syndromic
Wilms tumors, and Wnt/beta-catenin signaling increases androgen
receptor mRNA expression and blocks apoptosis in prostate
cancers. Novel downstream target genes activated by Wnt/beta-catenin
signaling are emerging from expression profiling in genetically
defined classes of Wilms tumors, and similar analyses are
expected to reveal additional downstream genes of this pathway
specific to prostate cancers. The identities of these genes
will likely suggest new targeted therapies for urological
malignancies.
[Back to top]
Opportunities to Improve the Prevention and Treatment
of Cervical Cancer
Richard B.S. Roden, Archana Monie and T.-C. Wu
Human papillomavirus (HPV) is a causal agent for ~5.3% of
cancers worldwide, including cervical cancer, and subsets
of genital and head and neck cancer. Persistent HPV infection
is a necessary, but not sufficient, cause of cervical cancer.
Of the >100 HPV genotypes, only about a dozen, termed “high-risk”,
are associated with cancer. HPV-16 is present in ~50% of all
cervical cancers and HPV-16, HPV-18, HPV-31 and HPV-45 together
account for ~80%. Most high-risk HPV infections are subclinical,
and are cleared by the host’s immune system. The remainder
produces low or high-grade squamous intraepithelial lesions
(SILs), also called cervical intraepithelial neoplasia (CIN),
which also may regress spontaneously. However persistent high
grade SIL represents the precursor lesion of cervical cancer
and carcinogenic progression is associated with integration
of the viral DNA, loss of E2 and upregulation of viral oncogene
expression, and chromosomal rearrangements like 3q gain. Cytologic
screening of the cervix for SIL and intervention has reduced
the incidence of cervical cancer in the US by an estimated
80% and HPV viral DNA and other molecular tests may improve
screening further. The licensure of a preventive HPV vaccine
ushers in a new era, but issues remain, including: protection
restricted to a few oncogenic HPV types, access in low resource
settings and impact on current cytologic screening protocols.
Importantly, preventive HPV vaccination does not help with
current HPV infection or disease. Here we examine the potential
of second-generation preventive HPV vaccines and therapeutic
HPV vaccination to address these outstanding issues.
[Back to top]
Molecular Pathogenesis of Pancreatic Cancer: Advances
and Challenges
Thilo Welsch, Jörg Kleeff and Helmut Friess
Pancreatic ductal adenocarcinoma (PDAC) is still a devastating
and incurable disease with a median survival of 3-6 months
and a 5-year survival rate of 1-4% when all stages are considered.
Although crucial advances in our understanding of the molecular
pathogenesis of the disease have been made, the exceptional
aggressiveness of PDAC remains largely unexplained. Some key
results will probably direct future PDAC research activities.
For example, recent identification of pancreatic tumor stem
cells has stimulated the debate over the cell of origin. Further,
powerful new genetically engineered mouse models support the
concept that stepwise progression of epithelial precursor
lesions leads to invasive PDAC as a result of accumulating
mutations in K-ras, INK4A/ARF, TP53 and
DPC4; these models accentuate the initiating function
of the K-ras mutation. Established PDAC exhibits
all the classic hallmarks of cancer, including self-sufficiency
in growth signals, insensitivity to anti-growth signals, evasion
of apoptosis, limitless replicative potential, sustained angiogenesis,
tissue invasion, and metastasis. This review provides an overview
of the molecular machinery that PDAC utilizes to acquire these
tumorigenic capacities. Moreover, recent advances have identified
essential elements of key pathways partly recapitulating developmental
signals, and of the tumor microenvironment that promotes tumor
growth through the complex interplay of its different cellular
components.
In spite of progress in molecular research, there is still
a dichotomy between the encouraging results obtained with
targeted interference of numerous oncogenic pathways in
vitro and a lack of significant improvement in clinical
detection and survival. Thus our primary challenge remains
to translate the solid knowledge of genetic and epigenetic
alterations in PDAC into clinical tools which can be used
for early diagnosis and effective therapy.
[Back to top]
Toll-Like Receptors, New Horizons in Sepsis
Saulo F. Saturnino and Marcus V. Andrade
Sepsis and septic shock, its more severe form, have shown
alarming increases in incidence and a persistently high mortality
rate, despite technological advancement allowing adequate
support of vital functions in intensive care units. Progress
in understanding of physiopathology has directed the therapeutic
approach, until recently limited to sustaining failing organ
systems and combating infectious agents, towards the alterations
provoked by an unbalanced systemic inflammatory response and
its deleterious effects on cellular function.
Less than 10 years ago, the discovery of Toll-Like Receptor
proteins, which allow the detection of pathogen molecular
patterns, initiate and modulate the immune response, opened
up new and exciting possibilities in approaches to sepsis.
The elucidation of the transduction pathways triggered by
Toll-Like Receptors activation signals exposes promising therapeutic
targets. Currently, mechanisms associated within the context
of Toll-Like Receptor signalization are identified in the
tolerance phenomena described in the past. The description
of genetic polymorphisms associated with Toll-Like Receptors,
and the different patterns of response to infectious insults
have defined high-risk subgroups of imbalanced immune response
with greater specificity. A better understanding of the molecular
structures involved in the process and the negative-regulation
of some of them have opened up possibilities in antagonizing
and modulating the response to the inflammatory activation
mediated by Toll-Like Receptors.
Having understood how the immune system recognizes pathogens
and organizes the inflammatory response upon the discovery
of Toll-Like Receptors and their signaling pathways, we gained
an insight into the possibilities of specific treatment instead
of supportive measures for sepsis.
|
