Exploiting death receptor signaling pathways for tumor therapy

Apoptosis or programmed cell death is a key regulator of physiological growth control and regulation of tissue homeostasis. Tipping the balance between cell death and proliferation in favor of cell survival may result in tumor formation. Moreover, current cancer therapies, e.g. chemotherapy, gamma-irradiation, immunotherapy or suicide gene therapy, primarily exert their antitumor effect by triggering an evolutionary conserved apoptosis program in cancer cells. For example, death receptor signaling has been implied to contribute to the efficacy of cancer therapy. Thus, failure to undergo apoptosis in response to anticancer therapy because of defects in death receptor pathways may result in resistance. Further insights into the mechanisms regulating apoptosis in response to anticancer therapy and how cancer cells evade cell death may provide novel opportunities for targeted therapeutics. Thus, agents designed to selectively activate death receptor pathways may enhance the efficacy of conventional therapies and may even overcome some forms of cancer resistance.     

Gene therapy. Therapeutic approaches and implications

The present article is an overview of gene therapy with an emphasis on different approaches and its implications in the clinic. Genetic interventions have been applied to the diagnosis of and therapy for an array of human diseases. The initial concept of gene therapy was focused on the treatment of genetic diseases. Subsequently, the field of gene therapy has been expanded, with a major focus on cancer. Although the results of early gene therapy-based clinical trials have been encouraging, there is a need for gene delivery vectors that feature reduced immunogenicity and improved targeting ability. The results of phases I/II clinical trials have suggested the important role of gene therapy as a versatile and powerful treatment tool, especially for human cancers. One reasonable expectation is that performing gene therapy at an earlier stage in the disease process or for minimal residual disease may be more advantageous.     

Gene Therapy Strategies for Hepatocellular Carcinoma

Summary Hepatocellular carcinoma (HCC) is one of the most frequent cancers worldwide. Effective therapy to this cancer is currently lacking, creating an urgent need for new therapeutic strategies for HCC. Gene therapy approach that relies on the transduction of cells with genetic materials, such as apoptotic genes, suicide genes, genes coding for antiangiogenic factors or immunomodulatory molecules, small interfering RNA (siRNA), or oncolytic viral vectors, may provide a promising strategy. The aforementioned strategies have been largely evaluated in the animal models with HCC or liver metastasis. Due to the diversity of vectors and therapeutic genes, being used alone or in combination, gene therapy approach may generate great beneficial effects to control the growth of tumors within the liver.     

Novel treatment for neuronopathic lysosomal storage diseases--cell therapy/gene therapy

Most lysosomal storage diseases (LSD) exhibit neurological symptoms and there has been limited success in their treatment. Innovative treatments employing novel therapy or gene therapy may offer the prospect of improvement. Recent attempts to treat the neurological forms of LSD include neural stem cell therapy, mesenchymal stem cell therapy, hematopoietic stem cell therapy and gene therapy. Additional approaches have included substrate deprivation/chaperone therapy for the treatment of LSD. This article reviews these new technologies, discusses recent progress, and suggests their possible application.     

Estrogens and age-related memory decline in rodents: what have we learned and where do we go from here?

The question of whether ovarian hormone therapy can prevent or reduce age-related memory decline in menopausal women has been the subject of much recent debate. Although numerous studies have demonstrated a beneficial effect of estrogen and/or progestin therapy for certain types of memory in menopausal women, recent clinical trials suggest that such therapy actually increases the risk of cognitive decline and dementia. Because rodent models have been frequently used to examine the effects of age and/or ovarian hormone deficiency on mnemonic function, rodent models of age-related hormone and memory decline may be useful in helping to resolve this issue. This review will focus on evidence suggesting that estradiol modulates memory, particularly hippocampal-dependent memory, in young and aging female rats and mice. Various factors affecting the mnemonic response to estradiol in aging females will be highlighted to illustrate the complications inherent to studies of estrogen therapy in aging females. Avenues for future development of estradiol-based therapies will also be discussed, and it is argued that an approach to drug development based on identifying the molecular mechanisms underlying estrogenic modulation of memory may lead to promising future treatments for reducing age-related mnemonic decline.     

Virus-specific T cells for therapy--approaches, problems, solutions

Adoptive T cell therapy is the transfer of T cells to a patient in order to combat disease. This procedure is mainly being used but not limited to the treatment of viral infections and malignancies including virus-associated tumors. Depending on the clinical context, the T cell donor may be the same patient or another donor, usually a healthy person. Recent research is centered on the use of antigen-specific T cells, but T cells of uncharacterized specificity can be successfully used in some clinical conditions where target antigens are not known. Depending on underlying scientific hypotheses and preferred technologies, the therapeutic T cells may be anything from monoclonal to highly polyclonal; they may be specific for one epitope, several epitopes from one antigen, or various antigens; they may have been selected during the preparation process for their specificity, their functional capacity, their survival and proliferation in vitro, or the expression of surface markers associated with desirable functional properties. In this minireview, we give a brief overview on selected approaches, problems and solutions in adoptive T cell therapy. We focus on an area where T cell therapy has been particularly successful but is still calling for improvement: herpesviral disease in patients after transplantation.     

Congestive heart failure. New frontiers.

Congestive heart failure is a common syndrome with high mortality in its advanced stages. Current therapy includes the use of vasodilator drugs, which have been shown to prolong life. Despite current therapy, mortality remains high in patients with severe heart failure. Potent new inotropic vasodilators have improved ventricular performance but have not prolonged life in patients with end-stage heart failure. Serious arrhythmias are implicated in the sudden deaths of 30% to 40% of patients with severe heart failure, but the benefits of antiarrhythmic therapy have not been established. Upcoming trials will address this question. Ventricular remodeling and progressive dilatation after myocardial infarction commonly lead to congestive heart failure; early unloading of the ventricle with an angiotensin-converting enzyme inhibitor may attenuate these events. These findings support the concept that angiotensin-converting enzyme inhibitors may be useful in managing heart failure of all degrees of severity, including left ventricular dysfunction and end-stage heart failure. Part of the damage that may occur with acute myocardial infarction, particularly in this era of thrombolysis therapy, is reperfusion injury, which may be mediated by oxygen-derived free radicals. Better knowledge of the mechanisms and treatment of myocardial infarction, the leading cause of congestive heart failure, may help prevent or attenuate the development of this syndrome.     

Active and inactive gastroesophageal reflux diseases related to Helicobacter pylori therapy

We systematically reviewed the literature on gastroesophageal reflux disease (GERD) related to Helicobacter pylori therapy, and classified the GERD according to various aspects. Preexisting GERD is active GERD before H. pylori therapy, and a substantial proportion of the GERD patients improve after successful H. pylori therapy. If the GERD does not persist or recur after cessation of acid-suppressive therapy combined with H. pylori therapy, it may have been cured (cured GERD). If it recurs, it may have been masked by acid-suppressive therapy and unmasked with cessation of the therapy (pharmacologically masked and unmasked GERD). Newly developed GERD after successful H. pylori therapy is a kind of unmasked GERD arising after cure of infection (de novo unmasked GERD). The possible mechanism of the improvement of cured GERD is normalized hyperacidity associated with an improved cytokine-somatostatin-gastrin system followed by normalized G-cell activity and parietal cell mass. Preexisting GERD is not a reason to avoid eradication therapy. De novo unmasked GERD develops in a substantial proportion of patients with cured infection. The possible mechanism is increased acid exposure in the esophagus due to gastric acid increase, which is caused by a loss of neutralizing effect by ammonia, normalized cytokine-acid suppression and improvement of corpus atrophy. De novo unmasked GERD is important because GERD is recurrent and may induce adenocarcinoma of the esophagus. However, it is expected that cure of infection lowers gastric cancer incidence. Eradication therapy is recommended irrespective of the possibility that de novo unmasked GERD may have a slight increase of the risk of esophageal adenocarcinoma.     

THE TREATMENT OF METASTATIC BREAST CANCER IN BONE

The author report clinical experience with 212 cases of mammary cancer metastatic to bone, in 186 of which radiotherapy was given, and in 26 steroid hormone therapy.At least 70 per cent of patients with bone metastasis from breast cancer were relieved of pain by adequate roentgen therapy, the relief lasting for most of the survival time in many instances.About 25 per cent of patients had recalcification or reossification of bony lesions with roentgen therapy; while dramatic, this is not always an indication that relief of pain will continue or that survival time will be lengthened.If and when adequate radiotherapy has not been effective or cannot be administered (for example, in a patient with extremely widespread metastasis, or one residing at a considerable distance from radiotherapeutic service) steroid hormone therapy in adequate dosage is frequently beneficial. From 40 per cent to 75 per cent of patients with bone metastases from breast cancer are relieved of pain by steroid hormone therapy. In about 15 per cent of cases recalcification of the lesion occurs.Effective roentgen therapy may usually be given in a relatively brief period of time (one to two weeks). Effective steroid hormone therapy usually requires from 12 to 24 weeks.Complications of steroid hormone therapy are numerous. Some patients are made considerably worse by such therapy. These complications may only be controlled by reduction or discontinuation of the hormones. For this reason, it is recommended that irradiation always be used as the initial method of palliation.     

Refractory heart failure

Any patient with so-called "refractory" heart failure should be looked upon as suboptimally handled. The patient should be studied for possible development of new disturbances, either inside or outside the vascular system, which, at the same time, have a bearing upon the heart failure.The entire therapeutic program should be reviewed to be sure that all aspects of therapy have been evaluated satisfactorily and established optimally. If diuretics, especially mercurial diuretics, have been given, the possible complications of such therapy, particularly in terms of electrolyte imbalance, should be considered. It is only through a general survey of the patient for an evaluation of these factors that they may be found and therapy instituted to minimize or eliminate them.     

Cancer immunogene therapy: A review

Although immunotherapy has long held out promise as a specific, potent approach to cancer therapy, clinical applications have been unrewarding to date. However, advances in gene transfer technology and basic immunology have opened new avenues to stimulate antitumor immune responses including immunogene therapy. Many different approaches to immunogene therapy have been identified. These include transferring genes encoding proinflammatory proteins to tumor cells, suppressing immunosuppressive gene expression, and transferring proinflammatory genes and/or tumor antigen genes to professional antigen-presenting cells. In some cases, genes are transferred to tumor or antigen-presenting cells in situ. In others, gene transfer is performed ex vivo as part of preparing an anticancer vaccine. We discuss the underlying approach, relative success, and clinical application of various cancer immunogene therapy strategies, paying particular attention to immunogene therapy vaccines. Large numbers of preclinical studies have been reported, but only scattered clinical trial results have appeared in the literature. Although very successful preclinically, the ideal cancer immunogene therapy approach remains to be determined and will likely vary with tumor type. Clinical impact may be improved in the future as treatment protocols are refined.     

Advances in the Management of Post-Radical Prostatectomy Erectile Dysfunction: Treatment Strategies When PDE-5 Inhibitors Don't Work

Phosphodiesterase type-5 (PDE-5) inhibitors have revolutionized the treatment of post-radical prostatectomy erectile dysfunction. For those patients who undergo a non-nerve-sparing radical prostatectomy or whose condition fails to respond to PDE-5 inhibitors, alternative treatment with intracavernous injection therapy, transurethral alprostadil, vacuum erection devices, and recently described combination therapy is available. The goals of therapy are to provide the patient with a means of obtaining an erection so that the patient and his partner may resume sexual relations as soon as possible following radical prostatectomy. There is evidence that early institution of treatment may promote improvement in the return of spontaneous erections in patients who have undergone nerve preservation. In patients who undergo non-nerve-sparing procedures, therapy may improve penile rigidity. Intracavernous injection therapy, transurethral alprostadil, and vacuum devices are highly effective in the management of post-prostatectomy erectile dysfunction. High dropout rates, which are not related to adverse effects, have been described with all 3 modalities. Pre- and postoperative counseling may improve patient and partner satisfaction.     

Challenges in the Therapy of Chromoblastomycosis

Chromoblastomycosis (CBM) is an implantation mycosis mainly occurring in tropical and subtropical zones worldwide. If not diagnosed at early stages, patients with CBM require long-term therapy with systemic antifungals flanked by various physical treatment regimens. As in other neglected endemic mycoses, comparative clinical trials have not been performed for this disease; nowadays, therapy is mainly based on a few open trials and on expert opinions. Itraconazole, either as monotherapy or associated with other drugs, or with physical methods, is widely used. Recently, photodynamic therapy has been employed successfully in combination with antifungals in patients presenting with CBM. In the present paper, the most used therapeutic options against CBM are reviewed as well as the several factors that may have impact on the patient’s outcome.     

CALIFORNIA MEDICAL ASSOCIATION

Any patient with so-called “refractory” heart failure should be looked upon as suboptimally handled. The patient should be studied for possible development of new disturbances, either inside or outside the vascular system, which, at the same time, have a bearing upon the heart failure.The entire therapeutic program should be reviewed to be sure that all aspects of therapy have been evaluated satisfactorily and established optimally. If diuretics, especially mercurial diuretics, have been given, the possible complications of such therapy, particularly in terms of electrolyte imbalance, should be considered. It is only through a general survey of the patient for an evaluation of these factors that they may be found and therapy instituted to minimize or eliminate them.     

Treatment of nonvalvular atrial fibrillation.

Nonvalvular atrial fibrillation is an increasingly common condition. It may cause disabling symptoms and is an important risk factor for stroke. The goals of treatment include the relief and prevention of rate- and rhythm-related symptoms and the prevention of stroke and systemic emboli. Three principal treatments should be considered: pharmacologic rate control, cardioversion and antiarrhythmic therapy to restore and maintain sinus rhythm, and prophylactic anticoagulation or antiplatelet therapy to reduce the risk of stroke. The risks and benefits of each of these therapies have been reviewed. Symptoms, if present, can often be managed safely with rate-directed therapy alone. Until issues regarding safety and long-term efficacy are resolved, cardioversion and antiarrhythmic therapy should be limited to those patients whose symptoms cannot otherwise be controlled. The benefits of warfarin anticoagulation for the primary and secondary prevention of stroke in nonvalvular atrial fibrillation have been demonstrated convincingly by several randomized clinical trials. These benefits must be weighed against the real risk of major hemorrhage. For patients at low risk of stroke, the use of aspirin may be an acceptable alternative to warfarin sodium therapy.     

Keratitis

Corneal inflammation or keratitis is a significant cause of ocular morbidity around the world. Fortunately, the majority of the cases are successfully managed with medical therapy, but the failure of therapy does occur, leading to devastating consequences of either losing the vision or the eye. This review attempts to provide current information on most, though not all, aspects of keratitis.Corneal inflammation may be ulcerative or nonulcerative and may arise because of infectious or noninfectious causes. The nonulcerative corneal inflammation may be confined to the epithelial layer or to the stroma of the cornea or may affect both. For clarity, this section has been divided into nonulcerative superficial keratitis and nonulcerative stromal keratitis. While the former usually includes hypersensitivity responses to microbial toxins and unknown agents, the latter can be either infectious or noninfectious.In the pathogenesis of ulcerative keratitis, microorganisms such as bacteria, fungi, parasites (Acanthamoeba), or viruses play an important role. Approximately, 12.2% of all corneal transplantations are done for active infectious keratitis. Available world literature pertaining to the incidence of microbial keratitis has been provided special place in this review. On the other hand, noninfectious ulcerative keratitis can be related to a variety of systemic or local causes, predominantly of autoimmune origin.     

THE DIAGNOSIS AND TREATMENT OF MENINGITIS

Treatment of meningitis is no longer a question of the administration of antimeningococcal serum and awaiting results. Today there is at hand an ever expanding armamentarium of drugs effective on various bacteria, rickettsia and some of the larger viruses. The skillful use of these singly or in combination offers an excellent prognosis in most forms of bacterial meningitis. Tuberculous meningitis continues to present a poor outlook, but this has been improved with more intensive therapy. More effective agents are needed in the treatment of this disease.“Shotgun” therapy may be indicated in critically ill patients prior to accurate bacteriological diagnosis; it is more important that therapy should include an effective agent or combination of agents than to attempt to determine in advance the most potent form of specific therapy. Partially treated purulent meningitis may be confused with aseptic meningitis. There is at present no effective therapeutic agent for the viral meningitides, but the prognosis is favorable in most of these diseases without specific therapy.     

TRAIL: a potential agent for cancer therapy

Induction of apoptosis in cancer cells with chemotherapy and radiation treatment is a major strategy in cancer therapy at present. Nevertheless, innate or acquired resistance has been an obstacle for conventional clinical therapy. TNF-related apoptosis inducing ligand (TRAIL/Apo-2L) is a typical member of the TNF ligand family that induces apoptosis through activating the death receptors. In recent years, considerable attention has been focused on the potential benefits of TRAIL in cancer therapy, as the majority of cancer cells are sensitive to TRAIL-induced apoptosis, while most normal cells are TRAIL-resistant. Furthermore, the use of TRAIL in combination with chemotherapeutic agents or irradiation strengthens its apoptotic effects. In this review, we will discuss the regulation mechanism of TRAIL-induced apoptosis and the molecular basis of the synergies created by its use in combination with chemotherapeutic agents and irradiation. We also analyze in detail that TRAIL may be cytotoxic, as this is a potential obstacle to its development for being used in cancer therapy.     

Combination Therapy for Invasive Fungal Infections

The purpose of this review is to summarize and evaluate relevant literature on combination antifungal therapy for invasive fungal infections (IFIs). Cryptococcal meningitis has the largest body and highest quality in support of combination therapy with amphotericin B and flucytosine. More recent data in treatment of invasive aspergillosis suggest combination therapy with voriconazole and echinocandins may be effective in select patients. Quality studies are needed to define combination therapy in rare mold infections. Multiple strategies have been employed to optimize treatment of the growing incidence of IFIs. With exceptions as noted above, justification for the use of combination antifungal therapy is most often based on uncontrolled and/or underpowered studies, in vitro data, and case reports.     

Evidence for early disease-modifying drugs in rheumatoid arthritis

Some research evidence supports early aggressive treatment of rheumatoid arthritis (RA) using combination therapy with two or more disease modifying anti-rheumatic drugs (DMARDs) plus steroids, or even DMARDs plus an anti-TNF. By contrast, conservatively delayed DMARD monotherapy, given after non-steroidal anti-inflammatory drugs have failed, has been criticised. However, recent long-term studies highlight the complexities in evaluating whether to abandon pyramidal treatment in favour of early DMARDs. Although patients given early DMARD therapy show short-term benefits, longer-term results show no prolonged clinical advantages from early DMARDs. By 5 years patients receiving early DMARDs had similar disease activity and comparable health assessment questionnaire scores to patients who received DMARDs later in their disease course. X-ray progression was persistent and virtually identical in both groups. These negative findings do not invalidate the case for early DMARD therapy, as it is gives sustained reductions in disease activity in the early years of treatment without excessive risks from adverse effects. However, early DMARDs alone do not adequately control RA in the longer term. This may require starting with very aggressive therapy or treating patients more aggressively after early DMARD therapy has been initiated.