Reversing hepatocellular carcinoma progression by using networked biological therapies.
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The liver is distinguished from other tissues by (a) its detoxifying function, (b) its resistance to apoptosis, and (c) its regenerative response to damage. Hepatocellular carcinoma arises when chronic insults, such as hepatitis or iron overload, constitutively activate this regenerative program. Here, we propose that the proliferative response of the liver to damage underlies the resistance of hepatocellular carcinoma to cytotoxic therapy, and that hepatocellular carcinoma growth should therefore be more readily controlled by using a networked combination of noncytotoxic interventions to interrupt the damage-inducible regenerative pathway. To this end, hepatocellular carcinoma boasts a wealth of potential drug targets, including viral replication, the antiapoptotic immunosuppressant alpha-fetoprotein, hepatic iron overload, inflammatory signaling, extracellular proteases, and growth factors. By blocking these positive feedback loops in parallel, and so returning the host environment to a more normal state, epigenetic repression of tumor-suppressor gene function may be reversed and tumor dormancy restored. Noncytotoxic maneuvers that short circuit damage resistance loops may thus represent an indirect form of gene therapy meriting incorporation into hepatocellular carcinoma clinical trials. (+info)
Review article: steroid resistance in inflammatory bowel disease - mechanisms and therapeutic strategies.
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BACKGROUND: Steroid resistance in inflammatory bowel disease presents a difficult clinical challenge. The advent of biological therapies coupled with an increasing understanding of the pathogenesis of inflammatory bowel disease has provided new therapeutic options. METHODS: We review the available literature of the mechanisms behind steroid resistance. In addition, we outline some of the options available for treating those patients who fail to respond adequately to glucocorticoids. RESULTS: Approximately 30% of patients prescribed glucocorticoids will not achieve clinical remission. Many such patients are offered immunosuppressive or, recently, biological agents. However, these agents are ineffective in a large proportion of patients. Immunosuppressive agents only bring 40-60% of patients into remission, and biological agents typically induce remission in just 40% of patients. In this review, the possible explanations for glucocorticoid resistance are discussed. Recent evidence suggests that in many patients it is mediated by interleukin-2. Basiliximab, a biological agent that interrupts interleukin-2 signalling, has shown significant benefit in early clinical studies. CONCLUSIONS: Patients who fail to respond to steroid therapy should have alternative agents introduced in a timely fashion. Steroid refractory inflammatory bowel disease remains a difficult condition to treat, but new therapies and managements are emerging. (+info)
The use of therapeutic interchange for biologic therapies.
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Therapeutic interchange is the practice of switching or dispensing drugs that are chemically distinct but therapeutically similar in terms of their efficacy, safety, and tolerability profiles. The stated goal of therapeutic interchange is to achieve an improved or neutral outcome with the new agent while reducing overall treatment costs. Until recently, most interchange programs have been limited to switches within drug classes, such as angiotensin-converting enzyme (ACE) inhibitors, proton pump inhibitors (PPIs), HMG-CoA reductase inhibitors (statins), and selective serotonin reuptake inhibitors (SSRIs), and generally to drugs that use the same routes of administration. Therapeutic interchange now is being applied to some biologic agents, such as those used to treat psoriasis and rheumatoid arthritis (RA). In some cases, these agents differ in structure and mode of administration. Patients who require a biologic agent are often difficult to manage, and the comorbidities that are prevalent in these patients further complicate management and agent selection. Population-based outcomes among various agents may not appear notably different, but because there is no a priori means to determine the effects of a given biologic agent on any individual patient, therapeutic interchange is inadvisable once a patient receiving RA or psoriasis therapy has been stabilized. However, if a biologic agent has been designated as preferred on a formulary, it is reasonable to initiate treatment with that agent in a patient who is naive to biologic therapy if that agent is not contraindicated. Respectful, two-way communication between health care professionals and managed care organizations (MCOs) will help ensure that a patient receives the appropriate therapy at the right time. (+info)
Biologic therapies in juvenile idiopathic arthritis: why and for whom?
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With greater understanding of pathophysiological, genetic and environmental influences on juvenile arthritis, there is an opportunity to develop new targets for therapy and greater control of disease. Early, aggressive control of arthritis is essential in order to prevent long-term disability. For those children that are resistant to standard therapy, new and exciting alternative medications are emerging. However, continued research is needed to gain a greater understanding of immunological and genetic profiles of the disease. Pharmaco-vigilance is essential to establish efficacy and side effect profiles. Physiotherapy, occupational therapy, nursing issues, and psychology remain integral to the management of JIA, along with liaison with ophthalmology, orthopaedic and dental colleagues. This article reviews the current biologic treatment options available for children with arthritis and the evidence base that supports their use. (+info)
A review of biologic treatments for psoriasis with emphasis on infliximab.
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Moderate-to-severe psoriasis is known to affect millions of people around the globe. This chronic disease substantially impacts patients by impairing their quality of life, causing psychosocial distress, and creating an ongoing financial burden. The biologics are the newest and most effective therapeutic weapon in the treatment of moderate-to-severe psoriasis and psoriatic arthritis that can significantly alter the course of the disease in a relatively short period of time. There is a need to review the recommended treatment guidelines for moderate- to-severe psoriasis and psoriatic arthritis as the perception and demands of patients are constantly changing. Real world experience with this class of drugs is expanding and more new biologics are becoming available. (+info)
Emerging biological therapies in primary Sjogren's syndrome.
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Sjogren's syndrome (SS) is a systemic autoimmune disease that mainly affects the exocrine glands and usually presents as persistent dryness of the mouth and eyes. SS primarily affects white perimenopausal women, with an incidence of 4-5 cases per 100 000. Recent studies have analysed new therapeutic approaches, focusing mainly on the use of biological agents. B-cell targeted therapies seem to be the most promising agents in primary SS, especially rituximab, which has been used in more than 50 reported cases. Other promising B-cell targeted therapies include epratuzumab and belimumab, while T-cell targeted agents (efalizumab, abatacept, alefacept) should currently be considered as possible future options. In the near future, biological agents will play key roles in the treatment of severe involvement, broadening the therapeutic options in primary SS and offering a more optimistic point of view of the treatment of this disease, which, at present, is often considered to lack adequate specific therapy. However, the possible risks and benefits of using these agents should be carefully balanced, and a reasonable assessment of the risk of serious adverse events versus the benefits of treatment should be made. The use of biological agents targeting molecules and receptors involved in the aetiopathogenesis of primary SS opens a new era in the therapeutic management of patients with primary SS. (+info)
Calcium signals induce liver stem cells to acquire a cardiac phenotype.
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Heart failure is a major cause of premature death and disability in the United States. Stem cell therapy has attracted great interest for the treatment of myocardial infarction and heart failure. Some tissue-specific adult-derived stem cells demonstrate plasticity in that they are multipotent, react to inductive signals provided by a new micro-environment, and acquire the phenotype of cells endogenous to the new micro-environment. The mechanism through which this phenotype is acquired is unknown. We have demonstrated that a liver-derived clonal stem cell line, WB F344, differentiate into cardiomyocytes in vivo and in vitro. Using a coculture model of neonatal heart cells and WB F344 cells, we have found that cytosolic communication between the two cell types results in calcium-induced transcription of cardiac transcription factors and appears to usher in the cardiac phenotype. Functional gap junctions and IP3 receptors appear to be required for this process. We propose that the observed low frequency of stem cell differentiation into cardiomyocytes when transplanted into the injured heart is due, in part, to their inability to establish functioning intercellular communications with healthy cardiomyocytes and receive instructive signals needed to activate a cardiac gene program. (+info)
Propionibacterium acnes acts as an adjuvant in in vitro immunization of human peripheral blood mononuclear cells.
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We have established an in vitro immunization protocol whereby human peripheral blood mononuclear cells (PBMCs) are initially treated with L-leucyl-L-leucine methyl ester (LLME) and subsequently sensitized with antigen in the presence of interleukin (IL)-2, IL-4, and adjuvant. This protocol resulted in the production of antigen-specific antibodies. PBMCs are potentiated to react with exogenous antigens upon treatment with LLME. We are using this system to investigate the immunomodulatory activity of additives. In the present study, we aimed to evaluate the immunomodulatory activity of Propionibacterium acnes (P. acnes), which is known to exhibit various immunomodulatory effects in murine models, using this in vitro immunization protocol. P. acnes was found to augment the production of antigen-specific antibodies by PBMC, possibly through increased production of inflammatory cytokines and/or increased T-B cell interaction. P. acnes hence appears to act as an adjuvant in the antibody response in in vitro immunization. (+info)