Showing papers in "Discovery Medicine in 2010"

The role of p53 in apoptosis.

Abstract: The dynamic and multiple functions of p53, together with its involvement in the most common non-infectious diseases, underscore the need to elucidate the complexity of the p53 regulatory networks. Pathological conditions such as cancer, neurodegeneration, ischemia, cholestasis, and atherosclerosis are all strongly associated with deregulated levels of apoptosis in which p53 dysfunction has a prominent role. We will highlight recent developments of p53-induced apoptosis in human diseases, with a focus on modulation of liver cell apoptosis. In addition, we will discuss controversies arising from widespread p53 activation as a therapeutic approach to cancer. Recent studies have provided relevant and unprecedented information about mechanistic antiapoptotic functions of the endogenous bile acid, ursodeoxycholic acid (UDCA), suggesting that the finely tuned, complex control of p53 by Mdm-2 (mouse double minute-2, an oncoprotein) is a key step in UDCA modulation of p53-triggered apoptosis. We will also review recent therapeutic strategies and clinical applications of targeted agents, their safety, and efficacy, with particular emphasis on potential benefits of UDCA.

Does emotional stress cause type 2 diabetes mellitus? A review from the European Depression in Diabetes (EDID) Research Consortium.

Abstract: According to the World Health Organization, approximately 220 million people worldwide have type 2 diabetes mellitus. Patients with type 2 diabetes not only have a chronic disease to cope with, they are also at increased risk for coronary heart disease, peripheral vascular disease, retinopathy, nephropathy, and neuropathy. The exact causes of type 2 diabetes are still not clear. Since the 17th century, it has been suggested that emotional stress plays a role in the etiology of type 2 diabetes mellitus. So far, review studies have mainly focused on depression as a risk factor for the development of type 2 diabetes mellitus. Yet, chronic emotional stress is an established risk factor for the development of depression. The present review provides an overview of mainly prospective epidemiological studies that have investigated the associations between different forms of emotional stress and the development of type 2 diabetes mellitus. Results of longitudinal studies suggest that not only depression but also general emotional stress and anxiety, sleeping problems, anger, and hostility are associated with an increased risk for the development of type 2 diabetes. Conflicting results were found regarding childhood neglect, life events, and work stress. It is important to emphasize that publication-bias may have occurred, resulting from "fishing-expeditions," where authors search their data for significant associations. Publication bias may also be caused by the tendency of reviewers and Editors to reject manuscripts with negative results for publication. It is therefore essential that research groups, who aim to conduct a new epidemiological cohort study, prospectively describe and publish the design of their study. Future research should focus on identifying mechanisms linking different forms of stress and incident type 2 diabetes.

Noroviruses: The leading cause of gastroenteritis worldwide.

Abstract: Noroviruses are the leading cause of foodborne disease outbreaks worldwide, and may soon eclipse rotaviruses as the most common cause of severe pediatric gastroenteritis, as the use of rotavirus vaccines becomes more widespread Genetic mutations and recombinations contribute to the broad heterogeneity of noroviruses and the emergence of new epidemic strains Although typically a self-limited disease, norovirus gastroenteritis can cause significant morbidity and mortality among children, the elderly, and the immunocompromised The lack of a cell culture or small animal model has hindered norovirus research and the development of novel therapeutic and preventative interventions However, vaccines based on norovirus capsid protein virus-like particles are promising and may one day become widely available through transgenic expression in plants

Prostate specific membrane antigen- a target for imaging and therapy with radionuclides.

Abstract: Prostate cancer continues to represent a major health problem, and yet there is no effective treatment available for advanced metastatic disease. Thus, there is an urgent need for the development of more effective treatment modalities that could improve the outcome. Because prostate specific membrane antigen (PSMA), a transmembrane protein, is expressed by virtually all prostate cancers, and its expression is further increased in poorly differentiated, metastatic, and hormone-refractory carcinomas, it is a very attractive target. Molecules targeting PSMA can be labelled with radionuclides to become both diagnostic and/or therapeutic agents. The use of PSMA binding agents, labelled with diagnostic and therapeutic radio-isotopes, opens up the potential for a new era of personalized management of metastatic prostate cancer.

The next generation of antibody-drug conjugates comes of age.

Abstract: Monoclonal antibodies (mAbs) and derivatives are currently the fastest growing class of therapeutic molecules. More than 30 G-type immunoglobulins (IgG) and related agents have been approved over the past 25 years mainly for cancers and inflammatory diseases. In oncology, mAbs are often combined with cytotoxic drugs to enhance their therapeutic efficacy. Alternatively, small anti-neoplastic molecules can be chemically conjugated to mAbs, used both as carriers (increased half-life) and as targeting agents (selectivity). Potential benefits of antibody-drug conjugates (ADCs), strategies, and development challenges are discussed in this review. Several examples of ADCs are presented with emphasis on three major molecules currently in late clinical development as well as next generation thio-mAbs conjugates with improved therapeutic index.

The functional neuroanatomy of pleasure and happiness.

Abstract: Over fifty years ago the discovery that rats would work to electrically stimulate their brains suggested the intriguing possibility that bliss could be achieved through the use of ‘pleasure electrodes’ implanted deep within the brain. Subsequent research has failed to bring about this brave new world of boundless pleasure, but more recent findings have started to throw new light on the intriguing links between brain mechanisms of pleasure and happiness. We discuss these findings of the underlying neural mechanisms and functional neuroanatomy of pleasure in the brain. In particular we address how they may come to shed light on our understanding of the brain basis of happiness. Beyond sensory pleasures, we examine how higher pleasures may be related to the brain’s default networks, especially in orchestrating cognitive aspects of the meaningfulness important to happiness. We also address how understanding of the hedonic brain might help alleviate the suffering caused by the lack of pleasure, anhedonia, which is a central feature of affective disorders such as depression and chronic pain.

mTOR signaling: a central pathway to pathogenesis in systemic lupus erythematosus?

Abstract: Systemic lupus erythematosus (SLE) is a common autoimmune disease with unclear etiology. Treatments for it often provide inadequate control of disease activity or are limited by side effects. Recent studies have shown that rapamycin can be an effective treatment in both murine lupus models and human SLE. We demonstrated that rapamycin could directly alter molecular abnormalities in SLE T cells related to calcium signaling but not mitochondrial function. However, in light of increased knowledge of the role of mammalian target of rapamycin (mTOR) signaling throughout the immune system, several other potential sites of rapamycin action have been revealed. Specifically, mTOR regulates the production of interferon-α and the maintenance of immune tolerance at the level of the regulatory T cell and the dendritic cell, and can promote Th2 versus Th1 immune responses. Thus mTOR offers a window into diverse facets of lupus pathogenesis as well as a unifying narrative in our understanding of the therapeutic efficacy of rapamycin in SLE.

Histone deacetylase inhibitors in the treatment of lymphoma.

Abstract: Histone deacetylases (HDACs) play an important role in the regulation of gene expression. In addition to histones, HDACs can modulate the function of many other proteins involved in the regulation of cell survival and proliferation, angiogenesis, inflammation, and immunity. Deregulated HDACs have been shown to be commonly associated with many types of cancer, and are considered promising targets for cancer therapy. Several HDAC inhibitors are in clinical trials as monotherapies or in combination with other anticancer agents, but only two such inhibitors -- vorinostat (suberoylanilide hydroxamic acid) and romidepsin (depsipeptide) -- have been approved by the US Food and Drug Administration for treating relapsed cutaneous T-cell lymphoma. Other HDAC inhibitors, such as belinostat (PXD101), mocetinostat (MGCD0103), entinostat (SNDX-275), and panobinostat (LBH589), are currently in clinical development. This review focuses on the use of HDAC inhibitors in the treatment of relapsed lymphoma.

The immunogenicity of therapeutic proteins.

Abstract: Nearly all therapeutic proteins induce antibodies in patients. However this immunogenicity has been neglected in the use of these products, even though the antibodies may have severe consequences. During the last few years, progress has been made in understanding why patients do not tolerate these protein therapeutic products and also how to manage the problem of immunogenicity.

Bromodomain coactivators in cancer, obesity, type 2 diabetes, and inflammation.

Abstract: Double bromodomain proteins bind to acetylated lysines in histones, bringing associated histone modification and nucleosome remodeling activity to chromatin. The ability of bromodomain regulators to alter chromatin status and control gene expression has long been appreciated to be important in the development of certain human cancers. However, bromodomain proteins have now been found also to be critical, non-redundant players in diverse, non-malignant phenotypes, directing transcriptional programs that control adipogenesis, energy metabolism and inflammation. The fact that such different processes are functionally linked by the same molecular machinery suggests a common epigenetic basis to understand and interpret the origins of several important co-morbidities, such as asthma or cancer that occurs in obesity, and complex inflammatory diseases like cardiovascular disease, systemic lupus erythematosus, rheumatoid arthritis and insulin resistance that may be built on a common pro-inflammatory foundation.

Two decades of clinical gene therapy--success is finally mounting.

Abstract: Human gene therapy has made substantial progress since the initiation of the first clinical trials 20 years ago. Here, we summarized important applications of gene transfer protocols in the treatment of various human diseases using different viral vectors. Recent successful trials on the treatment of ocular diseases and inherited immune deficiencies are particularly encouraging and have raised hopes that human gene therapy as a standard treatment option will finally become a reality. While immune responses and insertional mutagenesis pose obstacles for this novel form of molecular medicine, continuous progress suggests that a wider range of diseases can be treated with gene therapy in the future.

Diabetic nephropathy -- a multifaceted target of new therapies.

Abstract: Diabetic nephropathy (DN) remains the most common cause for end stage renal disease (ESRD) as the burden of diabetes increases worldwide. Nearly one-third of patients with diabetes develop nephropathy making early diagnosis critical in preventing long term kidney loss. Microalbuminuria is the earliest clinical manifestation of DN and is associated with substantial risk for progressive kidney damage. Hyperglycemia activates various inflammatory pathways both directly and via gene transcription to induce oxidative stress, reactive oxygen species, fibrotic factors TGF-β, renin-angiotensin- aldosterone system (RAAS), and advanced glycation end-products, leading collectively to podocyte injury, malfunction, apoptosis, and protein deposition in extracellular matrix of the nephron with albumin leak. Furthermore elevated glucose may also induce epigenetic metabolic memory with continued complications leading to diabetic complications. In addition, other clinical factors including genetic predisposition, obesity, blood pressure, high lipids, and smoking add to the rate of progression in DN. Thus early diagnosis and normalizing glycemic control in addition to careful blood pressure, weight, lipid control, and smoking cessation remain important in decreasing DN progression particularly for those with higher genetic risk.With evolution in the understanding of mechanistic processes leading to DN, targeted therapies such as RAAS blockers, thiazolidinediones, statins, and fibric acid derivatives are being utilized. However the optimal treatment for DM continues to evolve as newer therapies including inhibitors of sodium glucose transport and preglycated proteins as well as antifibrotic agents are being actively investigated in decreasing DN progression.

Nuclear Mode of the EGFR Signaling Network: Biology, Prognostic Value, and Therapeutic Implications

Abstract: Epidermal growth factor receptor (EGFR) belongs to a large family of receptor tyrosine kinases that mediates many important physiological processes in both normal and cancerous cells EGFR is best known for its classical role as a plasma membrane-bound receptor that, upon binding to its ligands, recruits and phosphorylates downstream molecules which subsequently regulate protein functions, protein-protein interactions, and gene expression Built upon this traditional view of the EGFR pathway, a number of therapeutic agents have been developed aiming to target EGFR by blocking ligand-mediated receptor activation or by inhibiting its kinase activity Unfortunately, most of these interventions have yielded disappointing clinical results in the majority of cancer types evaluated, with the exception of non-small cell lung cancer that carries specific EGFR mutants Given the notion that these EGFR mutations are absent or very rare in other cancer types, extensive investigations have been directed at other potential mechanisms Some of these efforts have led to rationales for EGFR-based combination regimens; however, they also demonstrated limited clinical benefits In this review, we will focus on an emerging line of research that examines a novel mode of EGFR signaling that takes place in the cell nucleus Specifically, we will outline the findings from a number of reports that have together established nuclear EGFR to be a functionally diversified molecule that regulates the biology of normal and malignantly transformed cells In light of the fact that the impact of nuclear EGFR on anti-cancer therapy has recently developed into an area of intensive investigations, this review will also summarize the results of these investigations that suggest a potential role the nuclear EGFR may play in tumor response to radiation, chemotherapy, and EGFR-targeted therapy

Targeting ion channels for drug discovery.

Abstract: Ion channels are important therapeutic targets which are modulated by a range of currently prescribed drugs. Most of these were developed empirically by traditional pharmacology without knowing their precise target, and the discovery of novel ion channel drugs by high-throughput molecular approaches has proven challenging. A key stumbling-block has been the development of biologically relevant assays with the capacity for randomly screening sizeable compound libraries. While various screening formats exist, e.g., using ion- or voltage-sensitive fluorescent dyes, these lack the precision, temporal resolution, and voltage control normally required for monitoring channel modulation. On the other hand, traditional electrophysiology is too slow, technically demanding, and labor intensive for primary screening. Recently, these limitations have been addressed by the development of automated electrophysiology instruments. While retaining much of the fidelity and precision of electrophysiology, these systems also address the main disadvantages by using automation to increase throughput and "de-skill" the process. Though the capacities currently attainable are not yet compatible with primary screening, these instruments are nevertheless having a significant impact on drug discovery. By providing high quality, information-rich assays for medium-throughput secondary screening, these instruments bridge significant gaps that, historically, have hampered the early ion channel drug discovery pipeline.

Adoptive immunotherapy for B-cell malignancies with autologous chimeric antigen receptor modified tumor targeted T cells.

Abstract: Chemotherapy-resistant B-cell hematologic malignancies may be cured with allogeneic hematopoietic stem cell transplantation (HSCT), demonstrating the potential susceptibility of these tumors to donor T-cell mediated immune responses. However, high rates of transplant-related morbidity and mortality limit this approach. For this reason, there is an urgent need for less-toxic forms of immune-based cellular therapy to treat these malignancies. Adoptive transfer of autologous T cells genetically modified to express chimeric antigen receptors (CARs) targeted to specific tumor-associated antigens represents an attractive means of overcoming the limitations of conventional HSCT. To this end, investigators have generated CARs targeted to various antigens expressed by B-cell malignancies, optimized the design of these CARs to enhance receptor mediated T cell signaling, and demonstrated significant anti-tumor efficacy of the resulting CAR modified T cells both in vitro and in vivo mouse tumor models. These encouraging preclinical data have justified the translation of this approach to the clinical setting with currently 12 open clinical trials and one completed clinical trial treating various B-cell malignancies utilizing CAR modified T cells targeted to either the CD19 or CD20 B-cell specific antigens.

The NF-kappaB signaling in cystic fibrosis lung disease: pathophysiology and therapeutic potential.

Abstract: Lung disease is the major cause of morbidity and mortality of cystic fibrosis (CF), an autosomal recessive disease caused by mutations in CF transmembrane-conductance regulator (CFTR) gene. In CF, elevated levels of interleukin-8 (IL-8) signaling mediated by the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB) result in chronic infection, neutrophilic inflammation, and progressive airway destruction. The most frequent mutation in the CFTR gene is the deletion of phenylalanine 508 (DeltaF508), which results in its endoplasmic reticulum associated degradation (ERAD) by the ubiquitin-proteasome system. The inability of DeltaF508-CFTR to reach cell surface leads to inherently high levels of NF-kappaB. Severity of CF lung disease depends on the levels of functional CFTR on cell surface that control its chloride transport and NF-kappaB mediated innate immune response functions. NF-kappaB mediated chronic inflammation is a prominent feature of CF lung disease and the mechanism(s) by which CFTR regulates these inflammatory signaling pathways is becoming apparent. Recent data suggest that CFTR localization to lipid-rafts is critical for regulating NF-kappaB mediated innate immune response and chronic CF lung disease. We anticipate that targeting the pathways, which facilitates CFTR's rescue to the cell surface and lipid-rafts, will not only restore CFTR channel function but also control NF-kappaB mediated chronic inflammation, although the level of correction may be a critical factor for therapeutic efficacy. We discuss here the mechanisms of NF-kappaB induction in CF, pathogenesis of CF lung disease, and novel therapeutic strategies that may help in reversing the chronic CF lung disease.

Control of HIV-1 replication in elite suppressors.

Abstract: HIV-1 infection usually results in high level of viral replication leading to a progressive decline of CD4+ T cells and eventually to full blown AIDS. Long term non-progressors (LTNPs) are patients who have stable CD4 counts for more than 5 years without antiretroviral therapy. Most of these patients have detectable levels of viremia and eventually will progress to AIDS. Elite controllers or suppressors (ES) represent a distinct subset of untreated patients who appear to be able to completely control viral replication. These patients maintain viral loads below the limit of detection of commercial assays for many years and generally do not show any clinical signs of disease progression. The mechanisms responsible for this remarkable control may lead to the design of effective HIV-1 vaccines.

Adult mesenchymal stem cells: an innovative therapeutic for lung diseases.

Abstract: Adult human mesenchymal stem cells (hMSCs) are the focus of a number of clinical applications. The advantage of hMSCs is that they are immuno-modulatory and versatile due to their secreted bioactive molecules that are anti-inflammatory and regenerative. These cells have the potential to orchestrate reparative processes in diseased or injured tissues. Much of the diversity and uniqueness of hMSCs is defined by their response to the milieu of injured tissue. hMSCs are sensitive to their site-specific microenvironment, and it is anticipated that they will deliver the bioactive agents in a site-specific manner quite different from the way pharmaceutical drugs work. This review highlights current concepts of such functions with a focus on the clinical utility of hMSCs in the treatment of lung diseases.

Neurorestorative treatments for traumatic brain injury.

Abstract: Traumatic brain injury (TBI) remains a major cause of death and permanent disability worldwide, especially in children and young adults. A total of 1.5 million people experience head trauma each year in the United States, with an annual economic cost exceeding $56 billion. Unfortunately, almost all Phase III TBI clinical trials have yet to yield a safe and effective neuroprotective treatment, raising questions regarding the use of neuroprotective strategies as the primary therapy for acute brain injuries. Recent preclinical data suggest that neurorestorative strategies that promote angiogenesis (formation of new blood vessels from pre-existing endothelial cells), axonal remodeling (axonal sprouting and pruning), neurogenesis (generation of new neurons) and synaptogenesis (formation of new synapses) provide promising opportunities for the treatment of TBI. This review discusses select cell-based and pharmacological therapies that activate and amplify these endogenous restorative brain plasticity processes to promote both repair and regeneration of injured brain tissue and functional recovery after TBI.

Prophylactic HPV Vaccines: Current Knowledge of Impact on Gynecologic Premalignancies

Abstract: Approaches for cervical cancer prevention are changing. Screening still remains the most effective method for cervical cancer prevention. Guidelines are moving to an older group of women to be screened less frequently with combinations of technologies that include biomarkers and cytology. HPV vaccination is an appropriate option for this older group of women as well, should the woman not wish to make her decision about vaccination until 21 years of age, the age of screening. Parents making decisions about HPV vaccination for their young adolescent daughters need to be fully informed that only continued screening prevents cervical cancer. HPV vaccination reduces the possibility of their daughter having an abnormal Pap test by 10% if the vaccines have not waned by the time the young adolescent becomes sexually active. HPV vaccine efficacy must last at least 15 years to contribute to the prevention of cervical cancers. At this time, protection against cervical intraepithelial neoplasia grade 2/3 (CIN 2/3) is 5 years for Gardasil and 8.4 years for Cervarix. The value of the current protection HPV vaccines offer will be viewed differently by different women. Physicians' ethical duties are to provide full explanation of the risks and benefits of adding HPV vaccination to the ongoing screening programs, and to support women in their personal choice for cervical cancer prevention.

Epigenetic regulation of aging.

Abstract: Aging is one of the most challenging and unresolved problems in biology owing to its highly complex nature. Public interest in aging has increased not only because all of us can expect to live to a ripe old age but also because we wish to avoid those age-related changes that lead to physical invalidity or other diseases (cancer, depression) and may ultimately cause social isolation. Aging is a process of genetic and epigenetic interactions at all biological levels, where epigenetics has an important function in determining the phenotypic differences that arise. Epigenetics also plays a key role in the development of diseases associated with aging and explains the relationship between an individual's genetic background, the environment, aging, and disease. DNA plasticity is mediated in part by the epigenetic changes that lead the role of a cell, and can be passed on to future generations. Epigenetics establishes the idea that our health can be affected not only by the interplay of our genes and environment but also by the inherited effects of our ancestors' genes and environment.

Behavioral and cognitive effects of anti-epileptic drugs.

Abstract: Anti-epileptic drugs (AEDs) have a variety of mechanisms of action which are reflected through different anticonvulsant activities and behavioral effects. Two categories of AEDs are considered based on psychotropic profile. The first group is characterized by potentiation of gamma-aminobutyric acid (GABA) inhibitory neurotransmission, and comprises of agents such as vigabatrin, tiagabine, and gabapentin. These agents are noted to have sedating effects ranging from cognitive slowing to anti-manic effects. On the other hand, the second group is typified by attenuation of glutamate excitatory neurotransmission and has activating effects including anxiogenic and antidepressant actions. Lamotrigine and felbamate feature in this latter group. Mechanisms of action, chief clinical indications, as well as behavioral profile including comment on chief cognitive effects of the newer AEDs are reviewed in accordance with this dual categorization. In clinical practice, assessment of an individual patient alongside consideration of AED behavioral profile primes for appropriate prescription according to patient mood profile, also permitting exposure of AED-induced behavioral disturbance.

GM-CSF-secreting vaccines for solid tumors: moving forward.

Abstract: Cancer vaccines consisting of intact tumor cells genetically modified to secrete the cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF) have undergone extensive preclinical development. These vaccines induce the massive accumulation of dendritic cells at the injection site, which engulf, process, and present tumor antigens to activate tumor-specific T cells. Early phase clinical testing demonstrated promising evidence of safety and bioactivity, although initial Phase III clinical trials were unsuccessful. Together, the preclinical and clinical data argue for the continued clinical development of these vaccines, integrating them with standard and novel cancer therapeutics that enhance vaccine activity by overcoming immune tolerance and suppression, and or augmenting co-stimulatory pathways of T cell activation.

Laryngopharyngeal reflux and voice disorders: an overview on disease mechanisms, treatments, and research advances.

Abstract: Laryngopharyngeal reflux (LPR) is common. Nevertheless, controversy persists regarding its pathophysiology, diagnosis, and treatment. Research studies have been unconvincing, and contradictory in some cases. Standards of diagnosis remain controversial, and there is a paucity of incontrovertible data confirming efficacy of treatment. Because of the high prevalence of LPR and its potential serious consequences (including laryngeal carcinoma), it is important for physicians to be familiar with contemporary perspectives on this disorder, current standards of patient care, and the need for additional multidisciplinary research.

A look at the pathogenesis of asthma: the need for a change in direction.

Abstract: While asthma is an inflammatory disorder of the conducting airways, most frequently therapeutics directed specifically at components of these pathways have had limited or no success in the clinic. Part of the problem lies in over-reliance on simple animal models of antigen sensitization and challenge to select therapeutic candidates, and partly because allergic mechanisms have been studied out of context of the formed elements that make up the structure of the airways such as the epithelium and underlying vasculature and mesenchyme. This review covers recent experience with some new therapeutics that include biologics and concludes by presenting a new paradigm for the disease that embraces heterogeneity and greater consideration of the role played by functionally active structural components. Since asthma was originally described in terms of reversible airflow obstruction, this moves away from placing inflammation at the center of the disease more towards a parallel involvement of the epithelial mesenchymal trophic unit to provide the context within which the inflammatory response occurs.

Gene therapy and virotherapy: novel therapeutic approaches for brain tumors.

Abstract: Glioblastoma multiforme (GBM) is a deadly primary brain tumor in adults, with a median survival of ~12-18 months post-diagnosis. Despite recent advances in conventional therapeutic approaches, only modest improvements in median survival have been achieved; GBM usually recurs within 12 months post-resection, with poor prognosis. Thus, novel therapeutic strategies to target and kill GBM cells are desperately needed. Our group and others are pursuing virotherapy and gene therapy strategies for the treatment of GBM. In this review, we will discuss various virotherapy and gene therapy approaches for GBM currently under pre-clinical and clinical evaluation including direct or conditional cytotoxic, and/or immunostimulatory approaches. We also discuss cutting-edge technologies for drug/gene delivery and targeting brain tumors, including the use of stem cells as delivery platforms, the use of targeted immunotoxins, and the therapeutic potential of using GBM microvesicles to deliver therapeutic siRNAs or virotherapies. Finally, various animal models available to test novel GBM therapies are discussed.

Cataracts and uveitis.

Abstract: Most uveitics enjoy good vision despite potentially sight-threatening complications including cataract development. In those patients who develop cataracts, successful surgery stems from educated patient selection, careful surgical technique, and aggressive preoperative and postoperative control of inflammation. While commonly accepted in the adult patient population, recent investigations reflect the increased tolerance for primary intraocular lens placement in the pediatric cohort. The role of absolute control of inflammation continues with greater focus on immunomodulatory therapies. However, these agents bear their own side effect and complication profiles. Cataract extraction with intraocular lens implantation in the setting of meticulous control of inflammation can optimize visual outcome in adults and children with uveitis.

The therapeutic potential of microRNA modulation.

Abstract: microRNAs are endogenous small non-coding RNAs that regulate gene expression by interfering with translation or stability of target transcripts. The importance and varied functions of microRNAs are illustrated by the diverse phenotypes, including disease, that arise when microRNAs are mutated or improperly expressed. The association of microRNA dysfunction with disease phenotypes has given rise to the idea that selective modulation of microRNAs could alter the course of disease. With the recent demonstration that inhibition of miR-122 reduces viral load in HCV-infected chimpanzees, microRNA modulators are no longer merely theoretical, but have become strong candidate therapeutics. Here we review the evidence for microRNA dysfunction in human disease, as well as recent examples of microRNA modulation that provided therapeutic benefit.

Advances in synthetic siRNA delivery.

Abstract: The application of RNA interference-based gene silencing technologies has the potential to treat a variety of illness. Preclinical studies and some early clinical trials have already demonstrated the utility of small interfering RNAs (siRNAs) as a potential novel therapy for the treatment of cancer, viral infections, as well as a wide range of additional diseases. To be effective, an siRNA must be taken up by specific cells, enter the cytoplasm, and be loaded onto the Argonaute protein, the catalytic core of the RNA induced silencing complex (RISC) to direct the cleavage of the homologous transcripts. To meet this need, a variety of novel siRNA delivery strategies have been developed. As our understanding of the molecular mechanisms underlying the RNAi pathway has increased so has the ability to rationally design effective silencing and delivery strategies. This review will examine the latest advances in non-viral delivery of siRNA, with special reference to targeted siRNA delivery to specific target tissues and cell types in vivo in preclinical animal models.

Churg-Strauss syndrome: evolving concepts.

Abstract: Churg-Strauss syndrome is a rare, small-sized vessel systemic necrotizing vasculitis that was first described in the early 1950s. Its most typical presentation consists of the appearance, in a patient with late-onset asthma, of vasculitic manifestations, like fever, cutaneous purpura and mononeuritis multiplex. In such a setting, the combination of blood eosinophilia and inflammatory syndrome is highly suggestive of the diagnosis, which can be further supported by the detection of antineutrophil cytoplasmic autoantibodies (ANCN), especially P-ANCA with anti-myeloperoxidase specificity, in almost 40% of the patients, and the presence of eosinophilic granulomas and/or necrotizing vasculitis in an affected-tissue biopsy. Although these disease hallmarks are now well-known, its pathophysiological mechanisms remain to be fully understood. Several gene polymorphisms and immune dysregulations are surely implicated, ranging from direct eosinophil toxicity to T- or even B-cell dysfunctions and, altogether, suggesting the existence of different disease stages and subsets according to the predominantly involved pathway. Only half the patients initially have severe life-threatening manifestations, like cardiac involvement, which require prompt aggressive treatments based on combined corticosteroids and immunosuppressants (mainly cyclophosphamide). Other less severe disease forms can usually be controlled with corticosteroids alone. Even though this current standardized therapy quite effectively and safely obtains remission, more than three-quarters of all the patients will remain corticosteroid-dependent, mostly because of residual asthma and/or eosinophilia. Hence, progress is needed in Churg-Strauss syndrome's therapeutic management, and better understanding of the complex disease mechanisms may aid such a quest.