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Developments in molecular genetics, immunology, molecular and cellular biology, and tumor biology have given rise to the field of cancer gene therapy. Several gene delivery vehicles have been developed and are being examined in clinical trials. Most cancer gene therapy strategies involve introduction of genes to augment existing therapies. An overview is provided on gene delivery vehicles, gene therapy strategies, and cancer gene therapy clinical trials.
Development of novel strategies is required for cancer treatment because most human tumors are refractory to current conventional therapy. During the past decade, a number of oncogenes and tumor suppressor genes have been cloned and the molecular mechanisms as to how mutations in such genes contribute to tumor development are going to be clarified. It is, therefore, a great challenge to develop novel strategies for tumor specific therapy based on molecular biology of cancer. p53 tumor suppressor gene is one of the most frequently mutated genes in a variety of human cancers. This review paper introduces several recent approaches related to the p53 as a molecular target of cancer treatment, including (i) p53 status and chemo-radiosensitivity, (ii) p53 gene therapy, (iii) E1B-deficient adenovirus and (iv) restoration of p53 function by synthetic polypeptides.
Development of an efficient method of gene introduction to target cells is the key issue in treating genetic and acquired diseases by in vivo gene therapy. Although various nonviral approaches have been developed, any method needs to be optimized in terms of the target disease and transgene product. The most important information required is (i) target cell-specificity of gene transfer, (ii) efficiency, (iii) duration of transgene expression, and (iv) the number of transfected cells following in vivo application of a vector. These characteristics are determined by the properties of the vector used, as well as the route of its administration, biodistribution, interaction with biological components and the nature of the target cells. Cell-specific gene transfer can be achieved by controlling the tissue disposition of plasmid DNA (pDNA), although the interaction of the pDNA complex with biological components might limit the specificity. Various approaches have been reported to increase the efficiency of transgene expression, from cationic lipids/polymers to physical stimuli, but some of those are ineffective under in vivo conditions. The duration of transgene expression is a complex function involving variables including the cell type, transfection method, and plasmid construct. Immune response often reduces the level and duration of transgene expression. In addition, the number of transfected cells is important, especially in cases in which the therapeutic protein localizes within the target cells. Successful clinical application of nonviral gene delivery methods rely on the development of such methods optimized for a particular target disease.
The success of hematopoietic stem cell gene therapy for X-linked severe combined immunodeficiency (X-SCID) was a major breakthrough in the field of gene therapy. However, two patients treated with this gene therapy developed leukemia at a later time, and retroviral vector-mediated gene transfer was considered to trigger leukemogenesis; i.e. insertional mutagenesis caused activation of LMO 2 gene, which was one step toward leukemia development. To cope with this serious problem, basic studies are required to improve the safety of retroviral vectors and to develop the method for site-specific integration of transgenes. In addition, we have to develop technologies such as selective amplifier genes (SAGs), the system for selective expansion of transduced cells, in order to obtain therapeutic efficacy of hematopoietic stem cell gene therapy in many other disorders. Moreover, clinical applications of AAV vector are promising from the standpoint of safety issue, because this vector is derived from non-pathogenic virus. AAV vector is appropriate for gene transfer into neurons, muscles, and hepatocytes. For example, gene therapy for Parkinson's disease is investigated using AAV vectors. Genetic manipulation is also one of the indispensable technologies in the field of regeneration medicine, and further promotion of basic research is important.
Development of straightwire appliances and improvement in archwire technology have simplified fixed appliance therapy in orthodontics. Although straightwire appliances are routinely used to treat most malocclusions, there are inherent limitations and it is necessary to look at the needs of each individual case rather than to simply proceed through a "cookbook" series of archwires to achieve a desired result. The Bioprogressive Therapy, although biomechanically complex, offers several advantages that can be integrated with the straightwire appliances to overcome the latter's shortcomings. This article illustrates the use of simplified Bioprogressive mechanics by means of utility arch in the treatment of a Class II deep bite malocclusion with high anchorage requirement.
Implications of the requirements related to the documentation and justification of the cost of physical therapy services are considered. These implications include 1) the cost components of physical therapy services, 2) the development of fee schedules, and 3) reimbursement requirements of third-party payers. The development of a fee schedule based on a sampling of the prevailing rates in two San Francisco Bay area counties is presented. The relationship between cost accounting, community standards, and the "prevailing rate" as defined by Medicare is documented. Public Law 92-603 and its ramifications for physical therapy fees and salaries are discussed.
To examine the effects of erythropoietin on the anemia of chronic renal disease and on the rate of renal deterioration, we administered recombinant human erythropoietin to 17 patients with anemia and progressive renal failure who did not yet require dialysis (serum creatinine level, 353 to 972 mumol per liter [4.0 to 11.0 mg per deciliter]). The dose of erythropoietin (50 to 150 units per kilogram of body weight) was adjusted according to the hematocrit response. In all 17 patients the anemia responded to erythropoietin. The median hematocrit increased from 0.27 to 0.37. The rate of the response depended on the initial erythropoietin dose and was similar to that observed in patients who were on dialysis. Hypertension was present in 14 patients before therapy, developed during therapy in 2 of the normotensive patients, and worsened in 9 patients, who required additional antihypertensive medications. The rate of the decline in renal function, as measured by serial determination of the reciprocal of the serum creatinine level, did not change significantly as the hematocrit rose (P = 0.78 by the paired t-test) during erythropoietin therapy. All the patients reported improvements in appetite, activity level, and sense of well-being. We conclude that erythropoietin therapy is effective in correcting the anemia of patients with progressive renal failure without affecting renal function, although it may be associated with an increase in blood pressure.
Renal cell carcinoma is the most common tumor of the kidney. It has an unpredictable behavior and poor response to systemic therapy. Developing newer therapy for this disease is a priority considering the high recurrence rate and the small subset of patients who benefit from the use of cytokines such as interferon-alpha or interleukin-2. Identifying molecular targets and targeting various biomarkers has revolutionized the therapeutic approach to advanced and metastatic renal cell carcinoma. Although some of the antiangiogenic agents and receptor tyrosine kinase inhibitors appear promising, further understanding of their mechanism of action and the patient population who would benefit most from such agents is still being explored. As numerous targeted agents are entering the clinical investigation arena in a relatively short period of time, newer challenges in renal cell carcinoma therapeutics are emerging. Some of the future challenges in using targeted antineoplastic agents in renal cell carcinoma will include evaluating their long-term safety and benefit, using the particular drug in the appropriate patient population after appropriate stratification and studying the combination of some of these drugs for synergy or additive effects.
1. Information abounds on teaching clients, partners and relatives about home i.v. therapy, but there is a lack of training for community nurses in this area. 2. Training for IV therapy has been difficult to develop in community settings, but must involve managers, specialists, and practitioners. 3. Community-led IV therapy training requires resources across acute and community sectors, with skills development through contract learning and focusing skills to specific practice contexts. 4. Training and experience in managing central venous access developed by community nurses are transferable to all clients and to other colleagues.
Development of adenovirus vectors as potential therapeutic agents for multiple applications of in vivo human gene therapy has resulted in numerous preclinical and clinical studies. However, lack of standardization of the methods for quantifying the physical concentration and functionally active fraction of virions in these studies has often made comparison between various studies difficult or impossible. This study was therefore carried out to define the variables for quantification of the concentration of adenovirus vectors. The methods for evaluation of total virion concentration included electron microscopy and optical absorbance. The methods for evaluation of the concentration of functional virions included detection of gene transfer (transgene transfer and expression) and the plaque assay on 293 cells. Enumeration of total virion concentration by optical absorbance was found to be a precise procedure, but accuracy was dependent on physical disruption of the virion to eliminate artifacts from light scattering and also on a correct value for the extinction coefficient. Both biological assays for enumerating functional virions were highly dependent on the assay conditions and in particular the time of virion adsorption and adsorption volume. Under optimal conditions, the bioactivity of the vector, defined as the fraction of total virions which leads to detected target cell infection, was determined to be 0.10 in the plaque assay and 0.29 in the gene transfer assay. This difference is most likely due to the fact that detection by gene transfer requires only measurement of levels of transgene expression in the infected cell whereas plaque formation is dependent on a series of biological events of much greater complexity. These results show that the exact conditions for determination of infectious virion concentration and bioactivity of recombinant adenovirus vectors are critical and must be standardized for comparability. These observations may be very useful in comparison of data from different preclinical and clinical studies and may also have important implications for how adenovirus vectors can optimally be used in human gene therapy.
In industrialised countries, highly active antiretroviral therapy (HAART) has drastically reduced HIV mortality. Only few developing countries have introduced HAART on a large scale, leaving millions of HIV-infected individuals without life-saving therapy. Although HAART appears to be economically viable for middle income countries, it remains unaffordable for many of the poorest and worst affected nations. In response, significant discounts for antiretrovirals and debt relief have been granted. Apart from economic problems, other important issues need to be addressed before antiretroviral therapy can be optimally utilised, including the logistics of drug supply, HIV education for hospital staff and patients, and laboratory facilities that allow clinicians to assess the efficacy of HAART.
Developments in the analysis and pharmacokinetics of lithium, and the role of the pharmacist in the management of lithium therapy in affective disorders, are described. Research showing that lithium levels in the brain may be better predicted from erythrocyte lithium levels than plasma levels is reviewed. Also reviewed is lithium kinetics in affective disorders. The pharmacist (1) determines relevant aspects of the patient's condition, (2) develops an appropriate blood sampling schedule, (3) initiates and maintains a serial lithium erythrocyte and plasma patient profile, (4) evaluates erythrocyte and serum levels in relation to established criteria to provide a basis for differential diagnosis of the patient, and (5) individualizes lithium dosage and schedules. Four cases are used to illustrate this approach. It is suggested that outpatient mental health clinics would be likely settings for the further development of this clinical role.
Occupational therapy programs form an essential component of the overall treatment program on medical psychiatry units for patients with depression, physical debilitation, and cognitive dysfunction. This article outlines theoretical and practical aspects of developing an occupational therapy program for medical-psychiatric inpatients. Emphasis is placed on accurate assessment of cognitive and physical functioning to facilitate stratification of patients into appropriate therapeutic activities that are commensurate with their level of functioning. The theoretical basis and orientation of occupational therapy is also discussed vis-à-vis its relevance to the treatment of patients with concurrent medical and psychiatric illness.
Development of a host immune response against gene products expressed by genetically modified cells could be a serious limitation for gene therapy. During examination of whether site-specific differences in antigen presentation could regulate the host immune response, we observed an absence of antibodies against hepatitis B virus surface antigen (HBsAg) when HBsAg producing transgenic hepatocytes were transplanted into the spleen. Intrasplenic transplantation resulted in translocation of a large number of cells into the portal vascular bed and liver sinusoids. In these recipients, HBsAg secreted by the transplanted hepatocytes circulated indefinitely in the blood. In contrast, subcutaneous or intraperitoneal transplantation of the transgenic hepatocytes induced an anti-HBs response, followed by clearance of serum HBsAg. Rechallenge with HBsAg in a highly immunogenic form failed to break the tolerance in intrasplenic hepatocyte recipients even though these animals responded to another antigen (keyhole limpet hemocyanin). Immunization with HBsAg in intraperitoneal recipients of HBsAg producing hepatocytes further elevated anti-HBs titers. Our results indicate that hepatocyte transplantation into the portal vascular bed via injection into the spleen can confer immune tolerance to secreted heterologous antigens. This finding should have important implications for human gene therapy as well as for analyzing the mechanisms of immune tolerance.
OBJECTIVE: The purpose of this study was to evaluate, from the participants' perspective, the effectiveness over time of 10 occupational therapy faculty development workshops conducted between 1994 and 1998. METHOD: Surveys were mailed to 179 occupational therapy faculty participants to gather demographic data and perceptions of the following aspects of the workshops: benefits over time of the instructional content, changes made in current teaching practices, progress as a faculty member, and future needs for faculty development. RESULTS: The response rate was 63% (n = 106). The majority (72%) of respondents had less than 5 years of teaching experience. Respondents were women in their early 40s with approximately 12 years of clinical experience and a master's degree. Respondents perceived the most effective aspect of the faculty development workshops as the opportunity to participate in a face-to-face environment in which they observed the skills of a master teacher demonstrating instructional principles. Further, respondents reported that the greatest changes in their current teaching practices occurred in their ability to design, implement, and evaluate a course of instruction, thus increasing their perceptions of progress as a faculty member. CONCLUSION: The 10 faculty development workshops conducted between 1994 and 1998 were judged effective by occupational therapy faculty members who perceived that their participation resulted in benefits over time to their current teaching practices.
Developments in anti-HIV medication have meant that people with HIV/AIDS are now living longer, with some authors arguing that HIV should now be defined as a manageable rather than terminal illness. However uncertainty about the long-term efficacy of such treatments remains. This research aimed to examine the psychosocial impact of the new treatments and to explore whether, and in what ways, they affect psychological wellbeing. Clients were also asked about their use of services and whether they thought services should be changing in response to new pharmacological treatments. A semi-structured interview schedule was developed to elicit the views of six service users. From multiple readings of the qualitative data generated, prominent themes were identified suggesting that participants had ambivalent feelings about taking antiretroviral combination therapy and that being well with HIV raised a number of difficult issues. Four main themes were revealed: (1) disruptions in daily living: antiretrovirals as intrusions to life, (2) the tablets as a visible marker for HIV infection, (3) tempered optimism and increasing horizons, (4) an uncertain and fragile future: life without benefits and services. The results were discussed in terms of limitations of the current study and suggestions for further research.
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Endometrial carcinoma is the most frequent genital malignoma in women. Considering the tumor-biological and prognostically very different subtypes of endometrial carcinoma, an individual therapeutic strategy plays a very important role. Besides the question of an individualized organ-preserving procedure for women who wish to have a baby, the reduction of morbidity by minimally invasive laparoscopic/vaginal surgery is discussed. While adjuvant gestagen therapy is not useful, platinum-containing chemotherapy seems to be effective in certain risk situations. The indication of lymphonodectomy with regard to staging as well as the effect of adjuvant radiation therapy for local control are undisputed. In view of a postulated curative effect, the results of the ongoing prospective studies will make things clearer.