Current Molecular Medicine - Volume 7, Issue 5, 2007

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.

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.

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.

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.

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.

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.

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.

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.