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BioRxiv : the Preprint Server For... Jun 2023Methodological rigor is a major priority in preclinical cardiovascular research to ensure experimental reproducibility and high quality research. Lack of reproducibility...
BACKGROUND
Methodological rigor is a major priority in preclinical cardiovascular research to ensure experimental reproducibility and high quality research. Lack of reproducibility results in diminished translation of preclinical discoveries into medical practice and wastes resources. In addition, lack of reproducibility fosters uncertainty in the public's acceptance of reported research results.
METHODS
We evaluate the reporting of rigorous methodological practices in preclinical cardiovascular research studies published in leading scientific journals by screening articles for the inclusion of the following key study design elements (SDEs): considering sex as a biological variable, randomization, blinding, and sample size power estimation. We have specifically chosen to screen for these SDEs across articles pertaining to preclinical cardiovascular research studies published between 2011 and 2021. Our study replicates and extends a study published in 2017 by Ramirez et al. We hypothesized that there would be higher SDE inclusion across preclinical studies over time, that preclinical studies that also include human and animal substudies within the same study will exhibit greater SDE inclusion than animal-only preclinical studies, and that there will be a difference in SDE usage between large and small animal models.
RESULTS
Overall, inclusion of SDEs was low. 15.2% of animal only studies included both sexes as a biological variable, 30.4% included randomization, 32.1% included blinding, and 8.2% included sample size estimation. Incorporation of SDE in preclinical studies did not significantly increase over the ten year time period in the articles we assessed. Although the inclusion of sex as a biological variable increased over the 10 year time frame, that change was not significant (p=0.411, corrected p=8.22). These trends were consistent across journals. Reporting of randomization and sample size estimation differs significantly between animal and human substudies (corrected p=3.690e-06 and corrected p=7.252e-08, respectively.) Large animal studies had a significantly greater percentage of blinding reported when compared to small animal studies (corrected p=0.01.) Additionally, overall, large animal studies tended to have higher SDE usage.
CONCLUSIONS
In summary, evidence of methodological rigor varies substantially depending on the study type and model organisms used. Over the time period of 2011-2021, the reporting of SDEs within preclinical cardiovascular studies has not improved and suggests extensive evaluation of other SDEs used in cardiovascular research. Limited incorporation of SDEs within research hinders experimental reproducibility that is critical to future research.
PubMed: 37425725
DOI: 10.1101/2023.06.27.546731 -
Biomedicine & Pharmacotherapy =... Nov 2020Stroke seriously threatens human health because of its characteristics of high morbidity, disability, recurrence, and mortality, thus representing a heavy financial and... (Review)
Review
Stroke seriously threatens human health because of its characteristics of high morbidity, disability, recurrence, and mortality, thus representing a heavy financial and mental burden to affected families and society. Many preclinical effective drugs end in clinical-translation failure. Animal models are an important approach for studying diseases and drug effects, and play a central role in biomedical research. Some details about animal models of cerebral ischemia have not been published, such as left-/right-sided lesions or permanent cerebral ischemia/cerebral ischemia-reperfusion. In this review, ischemia in the left- and right-hemisphere in patients with clinical stroke and preclinical studies were compared for the first time, as were the mechanisms of permanent cerebral ischemia and cerebral ischemia-reperfusion in different phases of the disease. The results showed that stroke in the left hemisphere was more common in clinical patients, and that most patients with stroke failed to achieve successful recanalization. Significant differences were detected between permanent cerebral ischemia and cerebral ischemia-reperfusion models in the early, subacute, and recovery phases. Therefore, it is recommended that, with the exception of the determined experimental purpose or drug mechanism, left-sided permanent cerebral ischemia animal models should be prioritized, as they would be more in line with the clinical scenario and would promote clinical translation. In addition, other details regarding the preoperative management, surgical procedures, and postoperative care of these animals are provided, to help establish a precise, effective, and reproducible model of cerebral ischemia model and establish a reference for researchers in this field.
Topics: Animals; Brain Ischemia; Cerebrovascular Circulation; Disease Models, Animal; Hemodynamics; Humans; Oxidative Stress
PubMed: 32937247
DOI: 10.1016/j.biopha.2020.110686 -
Therapeutic Advances in Respiratory... 2023Drug development for idiopathic pulmonary fibrosis (IPF) has been challenging due to poorly understood disease etiology, unpredictable disease progression, highly... (Review)
Review
Drug development for idiopathic pulmonary fibrosis (IPF) has been challenging due to poorly understood disease etiology, unpredictable disease progression, highly heterogeneous patient populations, and a lack of robust pharmacodynamic biomarkers. Moreover, because lung biopsy is invasive and dangerous, making the extent of fibrosis as a direct longitudinal measurement of IPF disease progression unfeasible, most clinical trials studying IPF can only assess progression of fibrosis indirectly through surrogate measures. This review discusses current state-of-art practices, identifies knowledge gaps, and brainstorms development opportunities for preclinical to clinical translation, clinical populations, pharmacodynamic endpoints, and dose optimization strategies. This article highlights clinical pharmacology perspectives in leveraging real-world data as well as modeling and simulation, special population considerations, and patient-centric approaches for designing future studies.
Topics: Humans; Pharmacology, Clinical; Idiopathic Pulmonary Fibrosis; Biopsy; Fibrosis; Disease Progression
PubMed: 37392011
DOI: 10.1177/17534666231181537 -
Nanotheranostics 2022Novel targeted therapies are rapidly emerging for the treatment of cancer. With the advent of new immune targeting agents, understanding the changes in the tumor... (Review)
Review
Novel targeted therapies are rapidly emerging for the treatment of cancer. With the advent of new immune targeting agents, understanding the changes in the tumor microenvironment (TME) is critical. Given the complexity and several cellular mechanisms and factors that play a role in the TME, novel imaging methods to assess and evaluate the dynamic changes in the TME during treatment are needed. Several techniques are being developed for imaging TME including optical, fluorescence and photoacoustic methods. Positron emission tomography (PET) imaging can be used to track the dynamics of different molecular targets in the TME in live animals and in humans. Several novel PET imaging probes including radiolabeled antibodies, antibody fragments, and small molecules have been developed with many more that are under development preclinically and in early human studies. This review is a brief overview of some of the PET agents that are either in the preclinical developmental phase or undergoing early clinical studies.
Topics: Animals; Neoplasms; Positron-Emission Tomography; Tumor Microenvironment
PubMed: 35223381
DOI: 10.7150/ntno.66556 -
World Journal of Oncology Apr 2024Pigs are playing an increasingly vital role as translational biomedical models for studying human pathophysiology. The annotation of the pig genome was a huge step... (Review)
Review
Pigs are playing an increasingly vital role as translational biomedical models for studying human pathophysiology. The annotation of the pig genome was a huge step forward in translatability of pigs as a biomedical model for various human diseases. Similarities between humans and pigs in terms of anatomy, physiology, genetics, and immunology have allowed pigs to become a comprehensive preclinical model for human diseases. With a diverse range, from craniofacial and ophthalmology to reproduction, wound healing, musculoskeletal, and cancer, pigs have provided a seminal understanding of human pathophysiology. This review focuses on the current research using pigs as preclinical models for cancer research and highlights the strengths and opportunities for studying various human cancers.
PubMed: 38545477
DOI: 10.14740/wjon1763 -
Neoplasia (New York, N.Y.) Feb 2023Among children and adolescents in the United States (0 to 19 years old), brain and other central nervous system tumors are the second most common types of cancers,...
Among children and adolescents in the United States (0 to 19 years old), brain and other central nervous system tumors are the second most common types of cancers, surpassed in incidence only by leukemias. Despite significant progress in the diagnosis and treatment modalities, brain cancer remains the leading cause of death in the pediatric population. There is an obvious unfulfilled need to streamline the therapeutic strategies and improve survival for these patients. For that purpose, preclinical models play a pivotal role. Numerous models are currently used in pediatric brain tumor research, including genetically engineered mouse models, patient-derived xenografts and cell lines, and newer models that utilize novel technologies such as genome engineering and organoids. Furthermore, extensive studies by the Children's Brain Tumor Network (CBTN) researchers and others have revealed multiomic landscapes of variable pediatric brain tumors. Combined with such integrative data, these novel technologies have enabled numerous applicable models. Genome engineering, including CRISPR/Cas9, expanded the flexibility of modeling. Models generated through genome engineering enabled studying particular genetic alterations in clean isogenic backgrounds, facilitating the dissection of functional mechanisms of those mutations in tumor biology. Organoids have been applied to study tumor-to-tumor-microenvironment interactions and to address developmental aspects of tumorigenesis, which is essential in some pediatric brain tumors. Other modalities, such as humanized mouse models, could potentially be applied to pediatric brain tumors. In addition to current valuable models, such novel models are anticipated to expedite functional tumor biology study and establish effective therapeutics for pediatric brain tumors.
Topics: Animals; Mice; Humans; Child; Brain Neoplasms; Brain; Disease Models, Animal; Mutation; Tumor Microenvironment
PubMed: 36599191
DOI: 10.1016/j.neo.2022.100859 -
British Journal of Pharmacology Mar 2022Mammalian models including non-human primates, pigs and rodents have been used extensively to study the mechanisms of cardiovascular disease. However, there is an... (Review)
Review
Mammalian models including non-human primates, pigs and rodents have been used extensively to study the mechanisms of cardiovascular disease. However, there is an increasing desire for alternative model systems that provide excellent scientific value while replacing or reducing the use of mammals. Here, we review the use of zebrafish, Danio rerio, to study cardiovascular development and disease. The anatomy and physiology of zebrafish and mammalian cardiovascular systems are compared, and we describe the use of zebrafish models in studying the mechanisms of cardiac (e.g. congenital heart defects, cardiomyopathy, conduction disorders and regeneration) and vascular (endothelial dysfunction and atherosclerosis, lipid metabolism, vascular ageing, neurovascular physiology and stroke) pathologies. We also review the use of zebrafish for studying pharmacological responses to cardiovascular drugs and describe several features of zebrafish that make them a compelling model for in vivo screening of compounds for the treatment cardiovascular disease. LINKED ARTICLES: This article is part of a themed issue on Preclinical Models for Cardiovascular disease research (BJP 75th Anniversary). To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.5/issuetoc.
Topics: Aging; Animals; Cardiovascular Agents; Cardiovascular Diseases; Humans; Mammals; Stroke; Swine; Zebrafish
PubMed: 33788282
DOI: 10.1111/bph.15473 -
Metabolites Sep 2023Cancer cachexia, a multifactorial metabolic syndrome developed during malignant tumor growth, is characterized by an accelerated loss of body weight accompanied by the... (Review)
Review
Cancer cachexia, a multifactorial metabolic syndrome developed during malignant tumor growth, is characterized by an accelerated loss of body weight accompanied by the depletion of skeletal muscle mass. This debilitating condition is associated with muscle degradation, impaired immune function, reduced functional capacity, compromised quality of life, and diminished survival in cancer patients. Despite the lack of the known capability of fully reversing or ameliorating this condition, ongoing research is shedding light on promising preclinical approaches that target the disrupted mechanisms in the pathophysiology of cancer cachexia. This comprehensive review delves into critical aspects of cancer cachexia, including its underlying pathophysiological mechanisms, preclinical models for studying the progression of cancer cachexia, methods for clinical assessment, relevant biomarkers, and potential therapeutic strategies. These discussions collectively aim to contribute to the evolving foundation for effective, multifaceted counteractive strategies against this challenging condition.
PubMed: 37755304
DOI: 10.3390/metabo13091024 -
Cells Jun 2023Identifying effective immunotherapies for solid tumors remains challenging despite the significant clinical responses observed in subsets of patients treated with immune... (Review)
Review
Identifying effective immunotherapies for solid tumors remains challenging despite the significant clinical responses observed in subsets of patients treated with immune checkpoint inhibitors. Interleukin-15 (IL-15) is a promising cytokine for the treatment of cancer as it stimulates NK and CD8 lymphocytes. However, unfavorable pharmacokinetics and safety concerns render recombinant IL-15 (rIL-15) a less attractive modality. These shortcomings were addressed by the clinical development of heterodimeric IL-15 agonists, including N803. In preclinical tumor models, N803 elicited significant Th1 immune activation and tumor suppressive effects, primarily mediated by NK and CD8 T lymphocytes. In addition, multiple clinical studies have demonstrated N803 to be safe for the treatment of cancer patients. The combination of N803 with the immune checkpoint inhibitor nivolumab demonstrated encouraging clinical responses in nivolumab-naïve and nivolumab-refractory patients with non-small cell lung cancer. In a recent Phase II/III clinical study, most Bacillus Calmette-Guerin (BCG)-refractory bladder cancer patients treated with N803 plus BCG experienced durable complete responses. Currently, N803 is being evaluated preclinically and clinically in combination with various agents, including chemotherapeutics, immune checkpoint inhibitors, vaccines, and other immuno-oncology agents. This report will review the mechanism(s) of action of N803 and how it relates to the preclinical and clinical studies of N803.
Topics: Humans; BCG Vaccine; Interleukin-15; Nivolumab; Carcinoma, Non-Small-Cell Lung; Immune Checkpoint Inhibitors; Lung Neoplasms; Urinary Bladder Neoplasms; Mycobacterium bovis; Immunotherapy
PubMed: 37371081
DOI: 10.3390/cells12121611 -
Annals of Joint Jan 2021The human elbow is a complex joint that is essential for activities of daily living requiring the upper extremities; however, this complexity generates significant...
The human elbow is a complex joint that is essential for activities of daily living requiring the upper extremities; however, this complexity generates significant challenges when considering its response to injury and management of treatment. The current understanding of elbow injury and pathologies lags behind that of other joints and musculoskeletal tissues. Most research on the elbow joint is mainly focused on the late-stage disease states when irreversible damage has occurred. Consequentially, the specific contribution and relative time course of different elbow tissues in disease progression, as well as optimized approaches for treating such conditions, remains largely unknown. Given the challenge of studying elbow pathologies in humans, preclinical models can serve as ideal alternatives. However, a limited number of preclinical models exist to investigate elbow injury and pathology. This review highlights significant clinical elbow diseases and the preclinical models currently available to recapitulate these diseases, while also providing recommendations for the development of future preclinical models. Overall, this review will serve as a guide for preclinical models studying injuries and pathologies of the elbow, with the long-term goal of developing novel intervention strategies to improve the treatment of elbow diseases in human patients.
PubMed: 35990575
DOI: 10.21037/aoj.2020.02.09