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PubMed2003

Research into molecular and genetic mechanisms underlying prostate carcinogenesis would be greatly advanced by in vitro prostate cell models.

Prostate cancer is the most commonly diagnosed malignancy in the United States, as well as in the Western world, and the second leading cause of male cancer death in the United States. Despite its high incidence, the molecular and genetic events involved in prostate cancer progression remain poorly understood. A hurdle in understanding the molecular genetic changes in prostate cancer has been the difficulty in establishing premalignant lesions and primary prostate tumors as in vitro cell cultures. Primary epithelial cells grow for a finite life span and then senesce. Immortalization is defined by continuous growth of otherwise senescing cells and is believed to represent an early stage in tumor progression. In order to examine these early stages, we and others have developed in vitro models of prostate epithelial cell immortalization. Because prostate cancer is a multistep, progressive disease with a typical onset later in life and with an usually high number of latent cases that do not develop into clinically manifest cancer, the steps in the progression to malignancy are of particular interest. To understand the many factors that are suspected to contribute to the development of this malignancy, there is a need for an in vitro multistep human prostate epithelial culture system. These models have been extremely important in identifying genetic and molecular changes involved in prostate cancer progression. Recently, novel human cell culture models for the study of prostate cancer have been developed. Successful establishment of primary prostate cancer cell lines from patients' familial and sporadic prostate cancer has been accomplished using telomerase, the gene that prevents cellular senescence. The novel models will be useful for identification and characterization of prostate cancer genes and will provide the new means for testing for chemoprevention and chemotherapeutic agents.

Cell Line, Tumor↗
PubMed1997

HLA-derived peptides as novel immunosuppressives.

Over the past decade the use of synthetic peptides corresponding to linear sequences of HLA molecules has progressed from a concept to a reality. These peptides are currently being evaluated in clinical trials. In animal models these peptides, given over 1 week with cyclosporin alone, induced long-term immunological tolerance (Figure 3). They may similarly induce tolerance in humans. The next major hurdle for such tolerogenic drugs, however, is to prove efficacy in clinical circumstances. Many of the drugs used to treat transplant patients today (steroids, cyclosporin, azathioprine, mycophenolate mofetil) may actually inhibit the 'active' processes of induction and maintenance of immunological tolerance. Demonstration that new drugs induce tolerance will require efficacy studies in other immune-mediated diseases in which monotherapy is feasible (such as psoriasis), before further advances can be made in the induction of transplant tolerance. In addition, rapid assays of rejection must be developed in order to reverse tolerance induction failures without graft damage or loss. Lastly, it will require heroic physicians, surgeons, and patients to make immunological tolerance a reproducible clinical reality.

Graft Survival↗
PubMedDate not supplied

Knowing a winning business idea when you see one.

Identifying which business ideas have real commercial potential is fraught with uncertainty, and even the most admired companies have stumbled. It's not as if they don't know what the challenges of innovation are. A new product has to offer customers exceptional utility at an attractive price, and the company must be able to deliver it at a tidy profit. But the uncertainties surrounding innovation are so great that even the most insightful managers have a hard time evaluating the commercial readiness of new business ideas. In this article, W. Chan Kim and Renée Mauborgne introduce three tools that managers can use to help strip away some of that uncertainty. The first tool, "the buyer utility map," indicates how likely it is that customers will be attracted to a new business idea. The second, "the price corridor of the mass," identifies what price will unlock the greatest number of customers. And the third tool, "the business model guide," offers a framework for figuring out whether and how a company can profitably deliver the new idea at the targeted price. Applying the tools, though, is not the end of the story. Many innovations have to overcome adoption hurdles--strong resistance from stakeholders inside and outside the company. Often overlooked in the planning process, adoption hurdles can make or break the commercial viability of even the most powerful new ideas. The authors conclude by discussing how managers can head off negative reactions from stakeholders.

Diffusion of Innovation↗
PubMed2003

Biological, pharmaceutical, and analytical considerations with respect to the transport media used in the absorption screening system, Caco-2.

During the evaluation and selection of drug candidates, the Caco-2 cell culture system is commonly used for the determination of intestinal transport characteristics and to anticipate permeability limited drug absorption. Although classic HBSS-like buffered salt solutions are commonly used to perform Caco-2 transport experiments, different shortcomings (e.g., adsorption and low solubility) have been associated with the use of plain aqueous buffers. As transport experiments performed with unoptimized conditions may compromize the value of the Caco-2 model as a permeation screening tool, many efforts have been made to optimize the experimental conditions of Caco-2 transport assays. In this minireview, the hurdles associated with the use of saline aqueous buffers in Caco-2 transport experiments are summarized and the different options, which have been proposed to overcome these issues, are reviewed and discussed. Biologically, pharmaceutically, as well as analytically relevant media affecting the outcome of the transport experiments are described. Unfortunately, up to now, no systematic studies comparing the different experimental conditions have been performed, jeopardizing the possibility to define a (single) optimal solution to overcome the different issues associated with the use of saline aqueous buffers. Based on the reported options it can be proposed to use DMSO (<or=1%) in standard screening procedures for the ranking of compounds based on their apical to basolateral transport. If compounds are not soluble in DMSO 1%, dimethylacetamide (3%) or N-1-methyl-pyrrolidone (2.5%) are good alternatives. However, these options do not imitate the in vivo situation. If one wants to take into account the physiological relevance of the media, the use of a biologically relevant apical medium (e.g., FASSIF) in combination with an analytically friendly, sink condition creating basolateral solvent (e.g., containing a micelle forming agent) can be suggested.

Absorption↗
PubMed1997

Current challenges of gene therapy for prostate cancer.

Gene therapy for prostate cancer faces hurdles similar to those being encountered for other cancers and nonmalignant processes. The greatest obstacle is the identification of efficient delivery systems, since numerous animal models and cell culture systems have shown potential efficacy when most cells express the introduced genetic material. Early prostate cancers are easily accessible to gene vector introduction, and the predictable metastatic patterns of this cancer may offer additional advantages for gene therapy. This article reviews gene vectors and gene products, as well as ongoing trials of gene therapy that have recently begun in prostate cancer.

Animals↗
PubMed2006

Translation in the health professions: converting science into action.

The systematic translation of evidence-based research findings, tools, and information into practice is critical to improving the quality of our nation's health. However, despite several decades of advances in developing medical knowledge based on high-quality empirical evidence, widespread implementation of these findings into practice in diverse applied settings has not been achieved. This article reviews definitions and conceptual models that describe the translation of research from basic discovery to real-world applications, summarizes the various issues involved in the process of translation, discusses multiple barriers, and provides recommendations to surmount these hurdles. Areas of further research in this arena are suggested. Finally, the article concludes that translational research is an important area to continue to pursue requiring long-term collaborative commitment among researchers and practitioners.

Biomedical Research↗
PubMed2003

Technical and regulatory hurdles for DNA vaccines.

DNA vaccines have been widely used in laboratory animals and non-human primates over the last decade to induce antibody and cellular immune responses. This approach has shown some promise, in models of infectious diseases of both bacterial and viral origin as well as in tumour models. Clinical trials have shown that DNA vaccines appear safe and well tolerated, but need to be made much more potent to be candidates for preventive immunisation of humans. This review describes recent work to improve the delivery of plasmid DNA vaccines and also to increase the immunogenicity of antigens expressed from the DNA vaccine plasmids, including various formulations and molecular adjuvants. Because DNA vaccines are relatively new and represent a novel vaccine technology, certain safety issues, such as the potential for induction of autoimmune disease and integration into the host genome, must be examined carefully. If potency can be improved and safety established, plasmid DNA vaccines offer advantages in speed, simplicity, and breadth of immune response that may be useful for the immunisation of humans against infectious diseases and cancers.

Adjuvants, Immunologic↗
PubMed2001

Random sampling or 'random' model in skin flux measurements? [Commentary on "Investigation of the mechanism of flux across human skin in vitro by quantitative structure-permeability relationships"].

Transdermal therapy receives increasing attention as an attractive alternative to traditional drug delivery. Unfortunately the exact algorithm of transdermal permeation that could guide medicinal chemists towards delivery optimization at an early stage of the drug design process still remains to be decoded. This paper discusses some major hurdles on the way to full understanding of Quantitative Structure-Activity Relationships (QSAR) of skin permeation. From the statistical perspective, a recently published combined data set is found to be inappropriate with respect to the distribution of major molecular descriptors, and therefore should be approached cautiously as a source for QSAR model training and in modelling of occupational and environmental skin exposures.

Cell Membrane Permeability↗
PubMed2003

The quest for resilience.

In less turbulent times, executives had the luxury of assuming that business models were more or less immortal. Companies always had to work to get better, but they seldom had to get different--not at their core, not in their essence. Today, getting different is the imperative. It's the challenge facing Coca-Cola as it struggles to raise its "share of throat" in noncarbonated beverages. It's the task that bedevils McDonald's as it tries to restart its growth in a burger-weary world. It's the hurdle for Sun Microsystems as it searches for ways to protect its high-margin server business from the Linux onslaught. Continued success no longer hinges on momentum. Rather, it rides on resilience-on the ability to dynamically reinvent business models and strategies as circumstances change. Strategic resilience is not about responding to a onetime crisis or rebounding from a setback. It's about continually anticipating and adjusting to deep, secular trends that can permanently impair the earning power of a core business. It's about having the capacity to change even before the case for change becomes obvious. To thrive in turbulent times, companies must become as efficient at renewal as they are at producing today's products and services. To achieve strategic resilience, companies will have to overcome the cognitive challenge of eliminating denial, nostalgia, and arrogance; the strategic challenge of learning how to create a wealth of small tactical experiments; the political challenge of reallocating financial and human resources to where they can earn the best returns; and the ideological challenge of learning that strategic renewal is as important as optimization.

Commerce↗
PubMedDate not supplied

Transplantation of cardiac-committed mouse embryonic stem cells to infarcted sheep myocardium: a preclinical study.

BACKGROUND: Heart failure develops after myocardial infarction and is a major cause of morbidity and mortality. The ability to direct differentiation of embryonic stem cells (ESC) towards a cardiomyogenic phenotype makes them an attractive therapeutic option for cardiac repair, but species-specific and individual-specific immunological imprinting remains a hurdle. Our aim was to ascertain whether the purported immune privilege of ESC allows for their cross-species engraftment in a clinically relevant large-animal model. METHODS: We studied engraftment and differentiation of cardiac-committed mouse ESC in 18 sheep in which a myocardial infarction had been induced; nine controls received medium and nine sheep (five of which were immunosuppressed) received ESC. The gain in myocardial function was measured by echocardiography 1 month after cell transplantation. FINDINGS: Cardiac-committed murine ESC engrafted in infarcted myocardium of immunosuppressed and immunocompetent sheep, and differentiated into mature cardiomyocytes that expressed connexins. Colonisation of the scar area by ESC was accompanied by a functional benefit of the damaged myocardium. Left-ventricular ejection fraction deteriorated in the control group by a median of 9.9% (range -20 to 0.3) relative to baseline (p=0.011) whereas in the treated group it improved by 6.6% (-5.7 to 50.8; comparison between groups p=0.002). INTERPRETATION: These findings obtained in a clinically relevant large-animal model of heart failure strengthen the potential therapeutic use of ESC to regenerate the severely dysfunctional myocardium and bring additional evidence for an immune privilege of these cells.

Animals↗
PubMed1989

The UK demand for cigarettes 1954-1986, a double-hurdle approach.

The double-hurdle perspective suggests that it is crucial to distinguish between per capita and per smoker consumption when estimating the demand for cigarettes. This paper presents a two equation model which identifies consumption and participation as two separate decisions. The model is estimated with annual data on U.K. cigarette expenditure and participation rates, highlighting the differing influence of prices, income and health scares on the participation rate and on smokers' demand for cigarettes.

Data Collection↗
PubMedDate not supplied

Reducing the numbers of the uninsured: policy implications from state-level data analysis.

The objective of the study described in this article was to identify a model that best predicts state uninsurance rates and quantifies the contribution of socio-economic factors to enable targeted state programs to reduce uninsurance. Linear regression analysis was carried out using state uninsurance rate as the dependent variable and state-level data on demographic, employment, income, and health care environment data (independent variables). For 2000 data, the model R is 0.77, indicating that 77% of the variation in uninsurance rates is explained by the percentage of immigrant population, the workforce in very small businesses, the Black population, the state's median income, and the Medicare-aged population (model R = 0.77 for 1999 and 0.68 for 1998 data). A 1% increase in immigrant population is associated with 0.18% increase in uninsurance rate. A 1% increase in workforce employed in very small businesses associates with 0.79% increase in uninsurance. The findings indicate substantial potential for reducing uninsurance through targeted state policies. Policy recommendations are made to alleviate the insurance hurdles faced by immigrant and small business employee populations.

Emigration and Immigration↗
PubMed2000

Ancient Pygmalion joins contemporary management: a meta-analysis of the result.

To determine the existence and relative magnitude of the Pygmalion effect among adults within management contexts, a meta-analysis of 17 relevant studies (58 effect sizes; N = 2,874) was conducted to provide an estimate of the population mean effect size and variation from Pygmalion interventions. Performance measures in these studies included exam scores, performance appraisals, and physical output. Results indicate that Pygmalion effects can be fairly strong within some management contexts (average d = 1.13) but may vary widely depending on moderating variables. Specifically, results were stronger in the military, with men, and when involving persons for whom low expectations were initially held. Findings also highlight the need for more research in ongoing work contexts (vs. training) and in for-profit organizations (vs. the military). Suggestions are given to help overcome possible hurdles in conducting research in these areas.

Adult↗
PubMed2002

Immunological hurdles in the path to gene therapy for Duchenne muscular dystrophy.

Patients with Duchenne muscular dystrophy (DMD), an X-linked lethal muscle-wasting disease, have abnormal expression of the protein dystrophin within their muscle fibres. In the mdx mouse model of this condition, both germline and neonatal somatic gene transfers of dystrophin cDNAs have demonstrated the potential of gene therapy in treating DMD. However, in many DMD patients, there appears to be no dystrophin expression when muscle biopsies are immunostained or western blots are performed. This raises the possibility that the expression of dystrophin following gene transfer might trigger a destructive immune response against this 'neoantigen'. Immune responses can also be generated against the gene transfer vector used to transfect the dystrophic muscle, and the combined immune response could further damage the already inflamed muscle. These problems are now beginning to be investigated in immunocompetent mdx mice. Although much work remains to be done, there are promising indications that these immune responses might not prove as much of a concern as originally envisaged.

Dystrophin↗
PubMed2005

Rapid dual-tracer PTSM+ATSM PET imaging of tumour blood flow and hypoxia: a simulation study.

Blood flow and hypoxia are interrelated aspects of physiology that affect cancer treatment and response. Cu-PTSM and Cu-ATSM are related PET tracers for blood flow and hypoxia, and the ability to rapidly image both tracers in a single scan would bring several advantages over conventional single-tracer techniques. Using dynamic imaging with staggered injections, overlapping signals for multiple PET tracers may be recovered utilizing information from kinetics and radioactive decay. In this work, rapid dual-tracer PTSM+ATSM PET was simulated and tested as a function of injection delay, order and relative dose for several copper isotopes, and the results were compared relative to separate single-tracer data. Time-activity curves representing a broad range of tumour blood flow and hypoxia levels were simulated, and parallel dual-tracer compartment modelling was used to recover the signals for each tracer. The main results were tested further using a torso phantom simulation of PET tumour imaging. Using scans as short as 30 minutes, the dual-tracer method provided measures of blood flow and hypoxia similar to single-tracer imaging. The best performance was obtained by injecting PTSM first and using a somewhat higher dose for ATSM. Comparable results for different copper isotopes suggest that tracer kinetics with staggered injections play a more important role than radioactive decay in the signal separation process. Rapid PTSM+ATSM PET has excellent potential for characterizing both tumour blood flow and hypoxia in a single, fast scan, provided that technological hurdles related to algorithm development and routine use can be overcome.

Algorithms↗
PubMed2006

Allergenicity assessment of apple cultivars: hurdles in quantifying labile fruit allergens.

BACKGROUND: Assessment of allergenicity of foods is important for allergic consumers and regulators. Immunoassays to measure major food allergens are widely applied, often giving variable results. Using the major apple allergen Mal d 1 as a model, we aimed to establish at the molecular level why different immunoassays for assessing allergenicity of apple cultivars produce conflicting outcomes. METHODS: Mal d 1 was measured in 53 cultivars from Italy and 35 from The Netherlands, using four different immunoassays. Purified Mal d 1 standards were molecularly characterized by size-exclusion chromatography (SEC) and mass spectrometry (MS). RESULTS: Three immunoassays using an identical standard gave similar results. Minor differences in sample preparation already resulted in significant loss of allergenicity. The fourth assay, using a different Mal d 1 standard, gave 10- to 100-fold lower outcomes. By SEC, this standard was shown to be almost fully aggregated. This aggregation was accompanied by a decrease of the mass of the Mal d 1 molecule by approximately 1 kDa as analyzed by MS. The deviating immunoassay was shown to selectively recognize this aggregated form of Mal d 1, whereas the other three assays, including the one based on IgE antibody recognition, preferentially bound non-aggregated allergen. CONCLUSIONS: Variable and poorly controllable major allergen modification in both extracts and standards hamper accurate allergenicity assessments of fruits.

Allergens↗
PubMed2006

Current understanding of dystrophin-related muscular dystrophy and therapeutic challenges ahead.

OBJECTIVE: To review the recent research progress in dystrophin-related muscular dystrophy includes X-linked hereditary Duchenne and Becker muscular dystrophies (DMD and BMD). DATA SOURCES: Information included in this article was identified by searches of PUBMED and other online resources using the key terms DMD, dystrophin, mutations, animal models, pathophysiology, gene expression, stem cells, gene therapy, cell therapy, and pharmacological. Study selection Mainly original milestone articles and timely reviews written by major pioneer investigators of the field were selected. RESULTS: The key issues related to the genetic basis and pathophysiological factors of the diseases were critically addressed. The availabilities and advantages of various animal models for the diseases were described. Major molecular and cellular therapeutic approaches were also discussed, many of which have indeed exhibited some success in pre-clinical studies but at the same time encountered a number of technical hurdles, including the efficient and systemic delivery of a functional gene and myogenic precursor/stem cells to repair genetic defects. CONCLUSIONS: Further understanding of pathophysiological mechanisms at molecular levels and regenerative properties of myogenic precursor/stem cells will promote the development of multiple therapeutic strategies. The combined use of multiple strategies may represent the major challenge as well as the greatest hope for the therapy of these diseases in coming years.

Animals↗
PubMed1997

Lightweight fuzzy processes in clinical computing.

In spite of advances in computing hardware, many hospitals still have a hard time finding extra capacity in their production clinical information system to run artificial intelligence (AI) modules, for example: to support real-time drug-drug or drug-lab interactions; to track infection trends; to monitor compliance with case specific clinical guidelines; or to monitor/ control biomedical devices like an intelligent ventilator. Historically, adding AI functionality was not a major design concern when a typical clinical system is originally specified. AI technology is usually retrofitted 'on top of the old system' or 'run off line' in tandem with the old system to ensure that the routine work load would still get done (with as little impact from the AI side as possible). To compound the burden on system performance, most institutions have witnessed a long and increasing trend for intramural and extramural reporting, (e.g. the collection of data for a quality-control report in microbiology, or a meta-analysis of a suite of coronary artery bypass grafts techniques, etc.) and these place an ever-growing burden on typical the computer system's performance. We discuss a promising approach to adding extra AI processing power to a heavily-used system based on the notion 'lightweight fuzzy processing (LFP)', that is, fuzzy modules designed from the outset to impose a small computational load. A formal model for a useful subclass of fuzzy systems is defined below and is used as a framework for the automated generation of LFPs. By seeking to reduce the arithmetic complexity of the model (a hand-crafted process) and the data complexity of the model (an automated process), we show how LFPs can be generated for three sample datasets of clinical relevance.

Biopsy, Needle↗