Advances In Therapeutic Approaches Research Articles

The effects of telomerase inhibition on prostate tumor‐initiating cells

Prostate cancer is the most common malignancy in men, and patients with metastatic disease have poor outcome even with the most advanced therapeutic approaches. Most cancer therapies target the bulk tumor cells, but may leave intact a small population of tumor-initiating cells (TICs), which are believed to be responsible for the subsequent relapse and metastasis. Using specific surface markers (CD44, integrin alpha(2)beta(1) and CD133), Hoechst 33342 dye exclusion, and holoclone formation, we isolated TICs from a panel of prostate cancer cell lines (DU145, C4-2 and LNCaP). We have found that prostate TICs have significant telomerase activity which is inhibited by imetelstat sodium (GRN163L), a new telomerase antagonist that is currently in Phase I/II clinical trials for several hematological and solid tumor malignancies. Prostate TICs telomeres were of similar average length to the telomeres of the main population of cells and significant telomere shortening was detected in prostate TICs as a result of imetelstat treatment. These findings suggest that telomerase inhibition therapy may be able to efficiently target the prostate TICs in addition to the bulk tumor cells, providing new opportunities for combination therapies.

Intratracheal Gene Transfer of Adrenomedullin Using Polyplex Nanomicelles Attenuates Monocrotaline-induced Pulmonary Hypertension in Rats

Pulmonary arterial hypertension (PAH) is a life-threatening disease characterized by progressive PAH and right ventricular failure. Despite recent advances in therapeutic approaches using prostanoids, endothelin antagonists, and so on, PAH remains a challenging condition. To develop a novel therapeutic approach, we have established a nonviral gene delivery system of poly(ethylene glycol) (PEG)-based block catiomers, which form a polyplex nanomicelle with a nanoscaled core-shell structure in the presence of DNA. The polyplex nanomicelle from PEG-b-poly{N-[N-(2-aminoethyl)-2-aminoethyl]aspartamide} (PEG-b-P[Asp(DET)]), having ethylenediamine units at the side chain, showed ~100-fold increase in luciferase transgene expression activity in mouse lung via intratracheal administration with a minimal toxicity compared with the polyplex from linear poly(ethylenimine) (LPEI). The transfection activity was highest on day 3 after administration and remained detectable until day 14. PEG-b-P[Asp(DET)] polyplex nanomicelles were formulated with a therapeutic plasmid bearing the human adrenomedullin (AM) gene and intratracheally administered to rats with monocrotaline-induced pulmonary hypertension. The right ventricular pressure significantly decreased 3 days after administration as confirmed by a notable increase of pulmonary human AM mRNA levels. Intratracheal administration of PEG-b-P[Asp-(DET)] polyplex nanomicelles showed remarkable therapeutic efficacy with PAH animal models without compromising biocompatibility.

Systolic Swing of the Pendulum

Heart failure (HF) is a dreadful condition, a common final pathway of varied heart diseases. The lifetime risk of developing HF is 20%.1 Once diagnosed, HF carries a substantial risk of mortality. More than 70% of men and women at the age ≤65 years die within 8 years of the diagnosis.1 It has been estimated that, in 2009, the total direct and indirect costs of HF in the United States alone will exceed $37 billion1 despite the advances in therapeutic approaches that took place in the past 30 years. Clearly, a lot of effort still needs to be directed to fighting the modifiable risk factors. Among these, hypertension (HT) has long been recognized as a crucial one, predating development of HF in 75% of cases. Thus, virtually all recent expert recommendations place prevention, early detection, and treatment of HT high on the priority list of actions with high potential to avert the constant trend toward increased incidence of HF. However, HT is a disorder with many faces. For instance, for most of the past 20 years it has been far from decided whether it is systolic blood pressure (SBP) or diastolic blood pressure (DBP) that carries most of the blood pressure-associated risk. Nineteen years ago, a seminal meta-analysis was published that, based on the collection of a large number of data, proved the relation between DBP and cardiovascular risk but disregarded SBP altogether.2 This was in line with the approach at that time, which based decisions regarding diagnosis and treatment of HT primarily on DBP. However, with time it became evident that SBP plays a great role. An analysis of data from the …

Current status of liver diseases in Korea: Hepatocellular carcinoma

Primary liver cancer, most of which is hepatocellular carcinoma (HCC), is the third common leading cancer in Korea. During the last two decades, the incidence rate of primary liver cancer has shown a modest decrease, but its mortality rate has slightly increased. The incidence of HCC, according to age, peaks in the late sixth decade in men and in the early seventh decade in women. Hepatitis B virus (HBV) is the most important risk factor, which represents approximately 70% of all HCC, and hepatitis C virus (HCV) and alcohol are the next in order of major risk factors for the development of HCC in Korea. HBV-associated HCC occurs 10 years earlier than HCV-associated HCC due to a more prolonged exposure to HBV, which is vertically transmitted almost from HBsAg-positive mother in HBV-endemic area. National Cancer Control Institute, which was reorganized in 2005, is now working for several national projects such as National Cancer Registration Program, National R&D Program for Cancer Control and National Cancer Screening Program. International collaboration for the clinico-epidemiologic research would be needed to provide the specific measures for managing HCC in diverse etiologic situations. Finally, the mechanisms of hepatitis virus-associated hepatocellular carcinogenesis might be clarified to provide insights into the advanced therapeutic and preventive approaches for HCC in Korea, where the majority of HCC originate from chronic HBV and HCV infections.

Biological repair of the degenerated intervertebral disc by the injection of growth factors

The homeostasis of intervertebral disc (IVD) tissues is accomplished through a complex and precise coordination of a variety of substances, including cytokines, growth factors, enzymes and enzyme inhibitors. Recent biological therapeutic strategies for disc degeneration have included attempts to up-regulate the production of key matrix proteins or to down-regulate the catabolic events induced by pro-inflammatory cytokines. Several approaches to deliver these therapeutic biologic agents have been proposed and tested in a preclinical setting. One of the most advanced biological therapeutic approaches to regenerate or repair a degenerated disc is the injection of a recombinant growth factor. Abundant evidence for the efficacy of growth factor injection therapy for the treatment of IVD degeneration can be found in preclinical animal studies. Recent data obtained from animal studies on changes in cytokine expression following growth factor injection illustrate the great potential for patients with chronic discogenic low back pain. The first clinical trial for growth factor injection has been initiated and the results of that study may prove the usefulness of growth factor injection for treating the symptoms of patients with degenerative disc diseases. The focus of this review article is the effects of an in vivo injection of growth factors on the biological repair of the degenerated intervertebral disc in animal models. The effects of growth factor injection on the symptoms of patients with low back pain, the therapeutic target of growth factor injection and the limitations of the efficacy of growth factor therapy are also reviewed. Further quantitative studies on the effect of growth factor injection on pain generation and the long term effects on the endplate and cell survival after an injection using large animals are needed. An international academic-industrial consortium addressing these aims, such as was achieved for osteoarthritis (The Osteoarthritis Initiative), may further the development of biological therapies for degenerative disc diseases.

TU‐D‐351‐01: Image‐Guided Therapies: From Fundamentals to New Frontiers

Concurrent advances in medical imaging, therapeutics, and understanding the biological basis of disease progression and treatment response point convincingly to a transformative approach to medical interventions in the decades ahead. Such interventions are marked by a dramatic increase in the utilization of image information from multiple modalities and demand accurate coregistration of structural and functional information across a broad range of spatial and temporal scales. The scope of advanced therapeutic approaches enabled by such advances is broad, ranging from high‐precision image‐guided radiation therapy and surgery to minimally invasive target ablation, cell‐based therapies, and other forms of novel therapeutics. Moreover, the information acquired during the course of information will drive patterns of therapy delivery that are increasingly adaptive and patient‐specific. This symposium focuses on the scientific principles of imaging, guidance, treatment delivery, and feedback / adaptation in the context of advanced medical interventions and looks ahead to new technologies being developed for novel image‐guided therapies. Four expert speakers have been invited to present on topics central to such advancement: Dr. Siewerdsen will discuss principles of imaging performance, imaging task, and new imaging technologies; Dr. West will address principles of geometry, registration, and uncertainty (e.g., target registration error) in relation to real‐time tracking and navigation; Dr. Sherar will discuss a broad spectrum of technologies for therapeutic delivery, including physical, molecular, chemical, and cellular means by which a therapeutic insult can be delivered to disease under image guidance; finally, Dr. Yan will describe principles of feedback and control in the development of adapative therapies. Together, these topics present a “closed‐loop” in issues of imaging, navigation, therapy delivery, and adaptation that are central to the advancement of image‐guided interventions.

HTLV-1 and apoptosis: role in cellular transformation and recent advances in therapeutic approaches

A universal cellular defense mechanism against viral invasion is the elimination of infected cells through apoptotic cell death. To counteract host defenses many viruses have evolved complex apoptosis evasion strategies. The oncogenic human retrovirus HTLV-1 is the etiological agent of adult-T-cell leukemia/lymphoma (ATLL) and the neurodegenerative disease known as HTLV-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The poor prognosis in HTLV-1-induced ATLL is linked to the resistance of neoplastic T cells against conventional therapies and the immuno-compromised state of patients. Nevertheless, several studies have shown that the apoptotic pathway is largely intact and can be reactivated in ATLL tumor cells to induce specific killing. A better understanding of the molecular mechanisms employed by HTLV-1 to counteract cellular death pathways remains an important challenge for future therapies and the treatment of HTLV-1-associated diseases.

Excitotoxicity and new antiglutamatergic strategies in Parkinson's disease and Alzheimer's disease

N-methyl-D-aspartate (NMDA) receptors play central roles in a number of physiological processes, including long-term potentiation in the hippocampus, synaptogenesis and synaptic plasticity. Excessive NMDA receptor activation has been implicated in the pathophysiology of chronic neurodegenerative diseases, such as Parkinson's disease (PD) and Alzheimer's disease (AD). With the discovery of the heterogeneity of NMDA receptors through molecular biological approaches, new targets have been identified for new-generation NMDA receptor antagonists. This short article focuses on the evidence for the involvement of NMDA receptor subtypes in neurodegenerative disorders and reviews the scarce advances in therapeutic approaches with “selective” NMDA subunit antagonists in PD and AD.

Infectious Complications of Chronic Lymphocytic Leukemia

Infectious complications continue to be one of the major causes of morbidity and mortality in patients with chronic lymphocytic leukemia (CLL). The pathogenesis of infections in these patients is multifactorial. Hypogammaglobulinemia is an important predisposing factor for infection in patients with early-stage disease and for those treated with conventional alkylating agents. However, the proportion of patients treated with purine analogs and monoclonal antibodies such as rituximab and alemtuzumab is increasing. As a result of this therapy, these patients often experience profound and sustained T-cell immunodeficiency. Consequently, the spectrum of organisms causing infections in these patients is changing from common bacterial organisms to less common opportunistic pathogens such as Pneumocystis, Listeria, mycobacteria, herpesviruses, and Candida. This review focuses on the pathogenesis and risk factors for infections in patients with CLL, the spectrum of infectious organisms associated with the newer agents, and the management of these infections with an emphasis on prophylaxis and vaccination strategies.

Cell Markers and the Side Population Phenotype in Ocular Surface Epithelial Stem Cell Characterization and Isolation

The ocular surface is covered by two rapidly renewing and embryologically-related linings, the corneal and conjunctival epithelia. The long-term survival of these tissues is ultimately dependent on their respective resident stem cells. In the corneal epithelium, the stem cells and their early precursors are exclusively circumscribed to the narrow vascularized limbal rim that provides epithelial precursor cells to the critically transparent central cornea. Limbal damage causes an interruption of this essential cell supply and allows the invasion of the corneal surface by the conjunctival epithelium, an event that ultimately leads to corneal scarring. The limited supply of immunocompatible tissue is a major hindrance to efforts to develop effective procedures for ocular surface reconstruction. This review describes some of the current work and strategies being developed to achieve the isolation of the limbal stem cell and define its genetic, biochemical, and functional make-up. The study of isolated ocular surface stem cells will foster basic understanding of the environmental requisites for their survival and proliferation in a self-replicative mode, leading eventually to advances in therapeutic approaches.

Advances in therapeutic approaches to ulcerative colitis and crohn’s disease

Advances (from 2004 to 2006) in the use of conventional agents include the molecular mechanisms of action, which have implications for monitoring (azathioprine and thioguanosine triphosphate) and chemoprevention (mesalamine and peroxisome proliferator activated receptor gamma). Advances in biotherapy include new data on monoclonal antibodies (infliximab in ulcerative colitis, adalimumab, certolizumab pegol, fontolizumab, selective anti-adhesion molecules, and others), antisense oligonucleotides, the development of small molecules, and cell-gene therapy (including helminth ova, leukocytapheresis, stem cell transplantation, and probiotic intestinal mucosal delivery systems). However, management of inflammatory bowel disease is about more than drug therapy, dose, and timing. The goals remain induction of remission, limitation of side effects, modification of the pattern of disease, and avoidance of complications. With the cost and complexity of biotherapy, inflammatory bowel disease is emerging as a specific subspecialty.

The Potential for molecular therapeutic targets in Ewing’s sarcoma

Ewing's sarcoma is an uncompromising tumor of children and young adults. Before the introduction of chemotherapy for Ewing's sarcoma, nearly all patients succumbed to their disease, even with highly aggressive approaches to local control. The realization that most patients have micrometastatic disease at presentation, and the identification of active chemotherapeutic agents for this tumor, have resulted in significant improvements in patient survival. Modern therapy for Ewing's sarcoma combines high-dose chemotherapy for systemic control of disease, with advanced surgical and/or radiation therapeutic approaches for local control. Current therapy remains imperfect. Despite optimal management, the cure rate for localized disease is only approximately 70%, whereas the cure rate for metastatic disease at presentation is less than 30%. Patients who experience long-term disease-free survival are at risk for significant side effects of therapy, including infertility, limb dysfunction, and an increased risk for second malignancies. More effective and less toxic therapies are needed. This report presents an overview of dysregulated molecular pathways in Ewing's sarcoma and highlights the possibility that they may serve as therapeutic targets for the disease. Although a great deal of additional investigation is required before most of these approaches can be assessed in the clinic, we think that these potential new targets offer a great deal of hope for patients with Ewing's sarcoma.

Biological treatments for systemic lupus erythematosus

There have been many recent advances in therapeutic approaches to systemic lupus erythematosus (SLE). The roles of cyclophosphamide, hydroxychloroquine, methotrexate and hormonal treatments in the management of SLE have been investigated in recent randomised controlled trials (1). However, although these pharmacological agents have a role to play in some patients with lupus, broad based effects have led to problems with side effects and adverse reactions. For this reason, more specific therapies are urgently required. Such strategies currently under evaluation include altering the cytokine balance, reducing T cell activation and inducing tolerance, blocking T cell costimulatory molecules, reducing auto-antibody production from B cells, targetting specific genes and stem cell transplantation. These are known as ''biological'' treatments as their aim is to alter patho-physiological processes occurring in the diseased state. This review will focus on the biological therapies currently under investigation-with particular attention on the cytokine-directed therapies.

Approaches to prevention of a first stroke

Stroke is one of the leading causes of mortality and morbidity worldwide. Despite recent important advances in therapeutic approaches, only a very small proportion of patients receive treatment and treatment is still far from satisfactory. Several conditions and life-style factors have been identified as risk factors for stroke, and strategies aimed at modifying these are the best way to reduce the burden imposed by the disease. We review the available data on the effectiveness of modifying risk factors by means of life-style changes, drugs, and surgery in the primary prevention of stroke. Identification of new risk factors and of markers for individuals at high risk is essential for more efficacious prevention.

The effect of an osteolytic tumor on the three-dimensional trabecular bone morphology in an animal model.

To investigate the application of micro-computed tomography (microCT) for the assessment of density differences and deterioration of three-dimensional architecture of trabecular bone in an experimental rat model for tumor-induced osteolytic defects. Walker carcinosarcoma 256 malignant breast cancer cells (W256) were surgically implanted into the medullary canal of the left femur of 15 4-month-old rats. Twenty-eight days after surgery all animals were killed and both femora from each rat were harvested. A total of 30 specimens (left and right femur) were scanned in a desktop microCT imaging system (microCT 20, Scanco Medical) to assess densitometric and architectural parameters. For each specimen a total of 200 micro-tomographic slices with a resolution of 30 microns in the distal metaphysis was taken. Bone mineral content (BMC) was analyzed for both cortical and trabecular bone (ctBMC), and for trabecular bone only (tBMC). Architectural indices (BV/TV, Tb.N, Tb.Th, Tb.Sp) according to standard definitions used in histomorphometry were calculated for trabecular bone. The quantitative analysis of density parameters revealed significantly (P < 0.001) lower values for ctBMC and tBMC in the tumor-bearing group (T) of 26% and 31%, respectively, compared with the contralateral control group. The quantitative analysis revealed significant (P < 0.001) changes in the architectural parameters in the tumor-bearing bones compared with the contralateral control group: BV/TV was 30% lower, Tb.N and BS/TV decreased by 24% and 21%, respectively, Tb.Th. decreased by 10% and Tb.Sp. increased by 94%. This study demonstrates that microCT is able to provide three-dimensional parameters of bone mass and trabecular structure in an animal model for tumor-induced bone loss. Recent advances in therapeutic approaches for skeletal diseases such as osteoporosis and metastatic bone diseasse rely on an understanding of the effects of the agents on the mechanical properties of bone. In order to quantify the structural changes of the affected bones the application of a non-destructive method is mandatory. The use of microCT seems to be a great advantage, since biomechanical tests and further histologic analysis can be done for the same specimens.

Primary stroke prevention.

Stroke is one of the leading causes of death and disability worldwide. Although important advances in therapeutic approaches have been made, treatment is still far from satisfactory. Thus, major efforts should be made on stroke prevention. We present evidence-based recommendations for primary stroke prevention. Changes to modifiable risk factors, the role of drugs and surgery are discussed. New markers may help identification of subjects at high risk.

Oral soft tissues in hereditary epidermolysis bullosa

Epidermolysis bullosa (EB) is associated with diverse oral manifestations, which can potentially involve both hard and soft tissues, depending on the specific EB subtype. This study determined the frequency and extent of oral soft tissue involvement in the inherited forms of EB. Examination of 216 affected persons revealed significant differences in the oral soft tissue involvement among the various types of EB. The frequency of oral involvement was greater in the dominant dystrophic (81.1%) and simplex (generalized, 58.6%; localized, 34.7%) types than previously reported. The marked frequency of oral blistering was similar in both major subtypes of junctional (Herlitz, 83.3%; non-Herlitz, 91.6%) and recessive dystrophic EB (generalized, 100%; localized, 92.3%). Obliteration of the oral vestibule, ankyloglossia, and microstomia were consistent findings in generalized recessive dystrophic EB. Oral milia were present in all major EB categories, most prevalently in the dystrophic forms, but were not seen in all the distinct EB subtypes. These findings indicate that although there are no pathognomonic intraoral soft tissue manifestations in the various forms of inherited EB, there are predictable patterns of involvement associated with specific subtypes of this disease. Understanding the oral involvement associated with EB may aid clinicians in the development of more advanced therapeutic approaches that are compatible with and directed at the unique characteristics of each EB subtype.