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PubMed2005

Advances in clinical trials for amyotrophic lateral sclerosis.

Because treatments are not yet powerful enough to reverse the symptoms of amyotrophic lateral sclerosis (ALS), randomized placebo-controlled trials remain the gold standard for testing new therapies. To date, only one drug, riluzole, has been shown to slow the course of ALS, albeit in a very modest way. Since the approval of riluzole almost 10 years ago, there have been a number of negative trials, and we still await the discovery of a medication with a truly meaningful effect. With each study, our sophistication in trial design grows, but hurdles remain, including how to use transgenic animal models optimally, which outcome measures most accurately reflect changes in the disease, and how to reduce the often high dropout rates in trials of ALS. This article is devoted to the recent evolution of clinical trials in ALS and discusses specific trials conducted during the past 5 years.

Amyotrophic Lateral Sclerosis↗
PubMed2006

Myocardial regeneration by embryonic stem cell transplantation: present and future trends.

Embryonic stem cells are a promising source for myocardial regeneration due to their pluripotency and plasticity. In theory, embryonic stem cells are capable of self-renewal in an unlimited fashion, and can differentiate into any cell type required for cell-based therapy, including cardiac myocytes. In recent years, embryonic stem cells have been transplanted for cardiac regeneration in animal models, and the results are encouraging. However, there are still many hurdles to be overcome for the clinical application of embryonic stem cells.

Animals↗
PubMed2004

Detailed clinical models for sharable, executable guidelines.

The goal of shareable, executable clinical guidelines is both worthwhile and challenging. One of the largest hurdles is that of representing the necessary clinical information in a precise and shareable manner. Standard terminologies and common information models, such as the HL7 RIM, are necessary, they are not sufficient. In addition, common detailed clinical models are needed to give precise semantics and to make the task of mapping between models manageable. We discuss the experience of the SAGE project related to detailed clinical models.

Decision Support Systems, Clinical↗
PubMed2006

Hematopoietic stem cell gene transfer in a tumor-prone mouse model uncovers low genotoxicity of lentiviral vector integration.

Insertional mutagenesis represents a major hurdle to gene therapy and necessitates sensitive preclinical genotoxicity assays. Cdkn2a-/- mice are susceptible to a broad range of cancer-triggering genetic lesions. We exploited hematopoietic stem cells from these tumor-prone mice to assess the oncogenicity of prototypical retroviral and lentiviral vectors. We transduced hematopoietic stem cells in matched clinically relevant conditions, and compared integration site selection and tumor development in transplanted mice. Retroviral vectors triggered dose-dependent acceleration of tumor onset contingent on long terminal repeat activity. Insertions at oncogenes and cell-cycle genes were enriched in early-onset tumors, indicating cooperation in tumorigenesis. In contrast, tumorigenesis was unaffected by lentiviral vectors and did not enrich for specific integrants, despite the higher integration load and robust expression of lentiviral vectors in all hematopoietic lineages. Our results validate a much-needed platform to assess vector safety and provide direct evidence that prototypical lentiviral vectors have low oncogenic potential, highlighting a major rationale for application to gene therapy.

Animals↗
PubMed1999

Use of genetic models in respiratory neurobiology and sleep.

In this review, two issues are highlighted: 1) the difficulties that can form major hurdles in trying to understand a disease or a fundamental biologic process at the genetic and molecular level and 2) the potential opportunities that genetic models such as the Drosophila or c-elegans can provide in answering clinically or biologically relevant questions. This review also lists in some detail the areas in which these models have been helpful and successes have been scored. For such models to be used, however, requires the "dissection" of a biologic or a disease process into a tractable phenotype that can be assayed in a genetic model and have relevant and interpretable conclusions. The hope is that questions pertaining to sleep, arousal, respiratory neurobiology, and their disorders can be formulated in such a way to be addressed in models that can lend themselves to very exciting discoveries.

Animals↗
PubMed2006

Outcomes research collaborations between third-party payers, academia, and pharmaceutical manufacturers: What can we learn from clinical research?

Research collaborations between academic researchers, regulatory agencies, and pharmaceutical manufacturers have made the drug development process more efficient and have frequently supported the successful documentation of quality, safety, and efficacy of pharmaceuticals (the so-called three hurdles). Over recent years issues of drug cost, access, and utilization have moved to center stage, giving rise to a "fourth hurdle approval" process by third-party payers. This requires new forms of collaborative research among new players. This contribution highlights the need for a "triangular" relationship in the field of outcomes research between scientists in academia, third-party payer institutions, and pharmaceutical manufacturers. We discuss, and illustrate by case studies, how successful models of collaboration from the drug development process might be relevant to research activities related to the fourth hurdle. Case studies which may provide useful models for collaborative outcomes research include the "International Conference on Harmonization" process, the voluntary consultation procedures established by drug regulatory agencies, and the Quebec experience in database sharing.

Biomedical Research↗
PubMed1995

Hospital in the home units. Early issues for GP involvement.

This paper reviews the early challenges for Hospital in the Home units which choose to utilise general practitioner skills. A model is described. Issues surrounding GP selection, remuneration, responsibility, leadership, and other hurdles are described. Since alternatives to GP involvement exist, GPs should be prepared to seize this important opportunity.

Home Care Services, Hospital-Based↗
PubMed2003

Optimizing admissions to an intensive care unit.

This paper presents a model for optimizing admissions to an intensive care unit (ICU) where the objective is to maximize the expected incremental number of lives saved from operating the ICU. The probability distribution of the number of occupied ICU beds is modeled using queueing theory. Three different admissions policies are considered: first come first served (FCFS), first come firstserved for all referrals whose expected incremental survival benefits gained from ICU admission exceed some hurdle (FCFS-H), and first come first served for all referrals whose expected incremental survival benefits exceed a bed specific hurdle (BSH) that depends upon the number of occupied beds (FCFS-BSH). The model is applied to data describing patients referred to the ICU at Jerusalem's Hebrew University-Hadassah Hospital. After statistically estimating the distribution of expected incremental survival benefits among those referred to the ICU, we show that if only those referrals where ICU admission would improve the probability of survival by at least 19.4 percentage points were admitted, an additional 18 statistical lives would be saved annually compared to the FCFS policy, a relative life saving improvement of 17.9%. Implementing the more complex optimal bed specific hurdle policy would save an additional 1.4 statistical lives annually beyond what can be achieved with FCFS-H, a marginal improvement of only 1.2%.

Decision Support Techniques↗
PubMed2026

A Deep Model Framework for Morphological Trait Imputation Across Taxonomic Groups.

Incomplete morphological trait data pose major hurdles for trait-based analyses, particularly when missing values, multicollinearity, and sparse sampling constrain inference. These issues limit our ability to quantify trait variation and explore broad patterns of functional differentiation across taxa. Here, we introduce FS-DeepRBFNet, which overcomes these pitfalls through integrating correlation-based feature selection with a dual-layer adaptive radial basis function (RBF) network. This end-to-end approach effectively reduces noise and captures both linear allometric trends and nonlinear morphological relationships. We tested the framework on a large species-level morphological trait dataset of Chinese birds and further validated its cross-taxon transferability using the Amphibian Database (Caudata). FS-DeepRBFNet consistently outperformed conventional methods such as KNN, Random Forest, and XGBoost, demonstrating superior predictive accuracy across multiple traits. Beyond improvements, the model revealed biologically interpretable trait associations and stable cross-taxon generalization. These results demonstrate that FS-DeepRBFNet provides a robust and biologically grounded solution for morphological trait prediction, enabling reliable imputation for comparative phylogenetics, functional ecology, and biodiversity forecasting in data-limited situations.

cross‐taxon transferability↗
PubMed2006

Production and characterization of murine models of classic and intermediate maple syrup urine disease.

BACKGROUND: Maple Syrup Urine Disease (MSUD) is an inborn error of metabolism caused by a deficiency of branched-chain keto acid dehydrogenase. MSUD has several clinical phenotypes depending on the degree of enzyme deficiency. Current treatments are not satisfactory and require new approaches to combat this disease. A major hurdle in developing new treatments has been the lack of a suitable animal model. METHODS: To create a murine model of classic MSUD, we used gene targeting and embryonic stem cell technologies to create a mouse line that lacked a functional E2 subunit gene of branched-chain keto acid dehydrogenase. To create a murine model of intermediate MSUD, we used transgenic technology to express a human E2 cDNA on the knockout background. Mice of both models were characterized at the molecular, biochemical, and whole animal levels. RESULTS: By disrupting the E2 subunit gene of branched-chain keto acid dehydrogenase, we created a gene knockout mouse model of classic MSUD. The homozygous knockout mice lacked branched-chain keto acid dehydrogenase activity, E2 immunoreactivity, and had a 3-fold increase in circulating branched-chain amino acids. These metabolic derangements resulted in neonatal lethality. Transgenic expression of a human E2 cDNA in the liver of the E2 knockout animals produced a model of intermediate MSUD. Branched-chain keto acid dehydrogenase activity was 5-6% of normal and was sufficient to allow survival, but was insufficient to normalize circulating branched-chain amino acids levels, which were intermediate between wildtype and the classic MSUD mouse model. CONCLUSION: These mice represent important animal models that closely approximate the phenotype of humans with the classic and intermediate forms of MSUD. These animals provide useful models to further characterize the pathogenesis of MSUD, as well as models to test novel therapeutic strategies, such as gene and cellular therapies, to treat this devastating metabolic disease.

3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)↗
PubMedDate not supplied

Animal models of Alport syndrome: advancing the prospects for effective human gene therapy.

Several animal models for Alport syndrome have been described. These are available for studies on the pathogenetic mechanisms of the disease, as well as for the development of new technologies for gene therapy in this progressive hereditary kidney disease. This review summarizes current knowledge on the molecular basis of Alport syndrome, and on the animal models which all remarkably well resemble the human disease. Recent work aimed at the development of gene therapy, including hurdles and progress are discussed.

Animals↗
PubMed2004

D-LogP: an alignment-free 3D description of local lipophilicity for QSAR studies.

The major hurdle to overcome in the development of 3D-QSAR models using steric, electrostatic, or lipophilic "fields" is related to both conformation selection and subsequent suitable overlay (alignment) of compounds. Therefore, it is of some interest to provide a conformationally sensitive lipophilicity descriptor that is alignment-independent. In this chapter we describe the derivation and parametrization of a new descriptor called 3D-LogP and demonstrate both its conformational sensitivity and its effectiveness in QSAR analysis. The 3D-LogP descriptor provides such a representation in the form of a rapidly computable description of the local lipophilicity at points on a user-defined molecular surface.

Computers↗
PubMed2003

Progress toward generating a ferret model of cystic fibrosis by somatic cell nuclear transfer.

Mammalian cloning by nuclear transfer from somatic cells has created new opportunities to generate animal models of genetic diseases in species other than mice. Although genetic mouse models play a critical role in basic and applied research for numerous diseases, often mouse models do not adequately reproduce the human disease phenotype. Cystic fibrosis (CF) is one such disease. Targeted ablation of the cystic fibrosis transmembrane conductance regulator (CFTR) gene in mice does not adequately replicate spontaneous bacterial infections observed in the human CF lung. Hence, several laboratories are pursuing alternative animal models of CF in larger species such as the pig, sheep, rabbits, and ferrets. Our laboratory has focused on developing the ferret as a CF animal model. Over the past few years, we have investigated several experimental parameters required for gene targeting and nuclear transfer (NT) cloning in the ferret using somatic cells. In this review, we will discuss our progress and the hurdles to NT cloning and gene-targeting that accompany efforts to generate animal models of genetic diseases in species such as the ferret.

Animals↗
PubMed2002

Chemokines in autoimmunity: from pathology to therapeutics.

Leukocyte recruitment, accumulation, and activation have been both a unifying and enigmatic feature of a variety of autoimmune pathologies. While these processes were not well-known for decades, recent scientific discoveries have underscored the importance of specific chemokines in the evolution of autoimmunity. This has been supported by in vivo data from clinical studies and animal model experiments. Although chemokines are an attractive target for drug development, there are hurdles that need to be cleared. Nonetheless, the quest to understand chemokine biology and develop effective therapies continues to capture the imagination of scientists in academia and pharma alike.

Animals↗
PubMed2003

Improving access to capital for health care infrastructure: the experience of the Southern Rural Access Program's revolving loan fund.

Lack of access to affordable capital is a formidable barrier that compromises rural health care infrastructure development in poor rural areas. Commercial lending institutions are often limited in their ability to respond to those needs due to traditional lending criteria: creditworthiness, equity, management ability, experiences, and cash flow or profits. In the Southern Rural Access Program, a development model more frequently used in other sectors has been successfully applied to health care to help clear these hurdles. This paper describes the 5 operational loan funds in Arkansas, Louisiana, Mississippi, South Carolina, and West Virginia receiving support from the Southern Rural Access Program. Two models of loan funds have evolved: those led by health agencies and those led by community development finance institutions whose mission is rural economic development. This paper outlines major distinctive features of these 2 approaches and describes major implementation challenges these loan funds face. Key accomplishments are high-lighted, including the ability to leverage additional resources from state, federal, philanthropic, and private sources through these funds. These loan fund programs provide models for other states interested in improving access to capital to help build the rural health care infrastructure while making health care more economically viable through integration with other community development initiatives.

Capital Financing↗
PubMed2003

The use of animal models to investigate the pathogenesis of neuroinflammatory disorders of the central nervous system.

PURPOSE OF REVIEW: A major hurdle in the research of neuroinflammatory disorders of the central nervous system is the inaccessibility of the organ. Thus investigation is limited to end-stage disease and systemic changes that occur during disease progression, neither of which may reflect the pathological process in the central nervous system. These factors may explain the lack of effective therapies in multiple sclerosis, a common chronic inflammatory disease of the central nervous system. To overcome such limitations approaches using more relevant animal models have been developed to study pathological mechanisms as well as the design of rational therapeutic strategies. This review describes the animal models used to study pathological processes leading to inflammation within the central nervous system that may be operating in multiple sclerosis and the use of these models in the design of more rational therapeutic strategies. RECENT FINDINGS: The clinical heterogeneity of multiple sclerosis as well as the finding of different pathological patterns suggests that multiple sclerosis may be a spectrum of diseases that may represent different pathological processes. This and the renewed interest in the extent of axonal damage has led to the development of more relevant animal models, such as those in nonhuman primates, that both reflect the spectrum of multiple sclerosis and allow the development of species-specific therapeutic approaches. SUMMARY: While many animal models are available, the use of relevant animal models that mimic either the different forms of multiple sclerosis or the spectrum of multiple sclerosis is critical to examine those factors, for example genes or proteins, that are of pathogenic relevance and can be used as targets for therapy.

Animals↗
PubMed2003

Endoscopic therapy for gastroesophageal reflux disease: what have we learned and what needs to be done?

GERD is a common, morbid, and expensive-to-treat disease. Clinicians have a clearly defined "therapeutic bar" for the efficacy of GERD therapy established from extensive study of current pharmacologic and surgical therapies. Endoscopic therapies for GERD are promising technologies that probably will find clinical application in subsets of patients with GERD. Integration of these new endoscopic GERD therapies into routine clinical practice requires more information from carefully performed and analyzed trials. Issues that still need to be addressed include the efficacy of these devices compared with placebo, efficacy compared with other endoscopic techniques, and efficacy versus current therapies. Addressing these issues requires the performance of well-designed, blinded studies using sham techniques and measuring clinically relevant outcomes using validated instruments. Once efficacy has been established, durability of response needs to be clearly determined. Intensive postmarketing surveillance, device registries, and long-term clinical follow-up studies will be able to document durability. The effect of retreatment for relapses or suboptimal initial treatment response should also be determined. Safety can best be established with extensive postmarketing surveillance and device registries. The impact of formal training programs on decreasing the learning curve and improving outcomes, including safety, should also be studied. Finally, the cost-effectiveness of these devices has to be determined either by economic models or clinical trials measuring actual costs. Despite these seemingly large hurdles, one, if not more, of these technologies should meet these criteria and soon be used as an effective, durable, safe, and cost-effective treatment option for patients with GERD.

Clinical Trials as Topic↗
PubMed2025

From Worms to Tumors: Conserved Strategies of Cellular Arrest and Survival Governing Dormancy.

The recurrence of metastatic lesions months to years after the treatment of primary cancers remains a major contributor to cancer-related mortality, highlighting the need to better understand the mechanisms that govern dormancy and dormancy reawakening. A major hurdle is the lack of adequate in vitro and in vivo models to dissect the complex cascades that trigger tumor cell dissemination, adoption of the dormant state, or tumor cell outgrowth in the new metastatic microenvironmental niche. However, many organisms use dormancy to survive stressful environments or periods of nutrient deprivation. Of these, the dauer state of the free-living nematode Caenorhabditis elegans has unparalleled characterization. In this study, we discuss the remarkable physiologic, signaling, genomic, and metabolic similarities between dormant cancer cells and C. elegans dauers, arguing for the use of dauers as a facile model to help dissect dormancy and reawakening pathways in cancer cells.

Animals↗