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Cells Aug 2023This study investigates the feasibility of establishing urine-derived tumor organoids from bladder cancer (BC) patients as an alternative to tissue-derived organoids. BC...
This study investigates the feasibility of establishing urine-derived tumor organoids from bladder cancer (BC) patients as an alternative to tissue-derived organoids. BC is one of the most common cancers worldwide and current diagnostic methods involve invasive procedures. Here, we investigated the potential of using urine samples, which contain exfoliated tumor cells, to generate urine-derived BC organoids (uBCOs). Urine samples from 29 BC patients were collected and cells were isolated and cultured in a three-dimensional matrix. The establishment and primary expansion of uBCOs were successful in 83% of the specimens investigated. The culturing efficiency of uBCOs was comparable to cancer tissue-derived organoids. Immunohistochemistry and immunofluorescence to characterize the uBCOs exhibited similar expressions of BC markers compared to the parental tumor. These findings suggest that urine-derived BC organoids hold promise as a non-invasive tool for studying BC and evaluating therapeutic responses. This approach could potentially minimize the need for invasive procedures and provide a platform for personalized drug screening. Further research in this area may lead to improved diagnostic and treatment strategies for BC patients.
Topics: Humans; Body Fluids; Urinary Bladder Neoplasms; Organoids; Drug Evaluation, Preclinical
PubMed: 37681920
DOI: 10.3390/cells12172188 -
NPJ Precision Oncology Jul 2023Preclinical genetically engineered mouse models (GEMMs) of lung adenocarcinoma are invaluable for investigating molecular drivers of tumor formation, progression, and...
Preclinical genetically engineered mouse models (GEMMs) of lung adenocarcinoma are invaluable for investigating molecular drivers of tumor formation, progression, and therapeutic resistance. However, histological analysis of these GEMMs requires significant time and training to ensure accuracy and consistency. To achieve a more objective and standardized analysis, we used machine learning to create GLASS-AI, a histological image analysis tool that the broader cancer research community can utilize to grade, segment, and analyze tumors in preclinical models of lung adenocarcinoma. GLASS-AI demonstrates strong agreement with expert human raters while uncovering a significant degree of unreported intratumor heterogeneity. Integrating immunohistochemical staining with high-resolution grade analysis by GLASS-AI identified dysregulation of Mapk/Erk signaling in high-grade lung adenocarcinomas and locally advanced tumor regions. Our work demonstrates the benefit of employing GLASS-AI in preclinical lung adenocarcinoma models and the power of integrating machine learning and molecular biology techniques for studying the molecular pathways that underlie cancer progression.
PubMed: 37464050
DOI: 10.1038/s41698-023-00419-3 -
Neuromodulation : Journal of the... Oct 2023Falls in extrapyramidal disorders, particularly Parkinson's disease (PD), multisystem atrophy (MSA), and progressive supranuclear palsy (PSP), are key milestones... (Review)
Review
BACKGROUND
Falls in extrapyramidal disorders, particularly Parkinson's disease (PD), multisystem atrophy (MSA), and progressive supranuclear palsy (PSP), are key milestones affecting patients' quality of life, incurring increased morbidity/mortality and high healthcare costs. Unfortunately, gait and balance in parkinsonisms respond poorly to currently available treatments. A serendipitous observation of improved gait and balance in patients with PD receiving spinal cord stimulation (SCS) for back pain kindled an interest in using SCS to treat gait disorders in parkinsonisms.
OBJECTIVES
We reviewed preclinical and clinical studies of SCS to treat gait dysfunction in parkinsonisms, covering its putative mechanisms and efficacies.
MATERIALS AND METHODS
Preclinical studies in animal models of PD and clinical studies in patients with PD, PSP, and MSA who received SCS for gait disorders were included. The main outcome assessed was clinical improvement in gait, together with outcome measures used and possible mechanism of actions.
RESULTS
We identified 500 references, and 45 met the selection criteria and have been included in this study for analysis. Despite positive results in animal models, the outcomes in human studies are inconsistent.
CONCLUSIONS
The lack of blind and statistically powered studies, the heterogeneity in patient selection and study outcomes, and the poor understanding of the underlying mechanisms of action of SCS are some of the limiting factors in the field. Addressing these limitations will allow us to draw more reliable conclusions on the effects of SCS on gait and balance in extrapyramidal disorders.
Topics: Humans; Parkinson Disease; Spinal Cord Stimulation; Quality of Life; Parkinsonian Disorders; Multiple System Atrophy; Gait
PubMed: 37452800
DOI: 10.1016/j.neurom.2023.06.003 -
Frontiers in Pharmacology 2023Preterm birth rates and maternal and neonatal mortality remain concerning global health issues, necessitating improved strategies for testing therapeutic compounds...
Preterm birth rates and maternal and neonatal mortality remain concerning global health issues, necessitating improved strategies for testing therapeutic compounds during pregnancy. Current 2D or 3D cell models and animal models often fail to provide data that can effectively translate into clinical trials, leading to pregnant women being excluded from drug development considerations and clinical studies. To address this limitation, we explored the utility of in silico simulation modeling and microfluidic-based organ-on-a-chip platforms to assess potential interventional agents. We developed a multi-organ feto-maternal interface on-chip (FMi-PLA-OOC) utilizing microfluidic channels to maintain intercellular interactions among seven different cell types (fetal membrane-decidua-placenta). This platform enabled the investigation of drug pharmacokinetics in vitro. Pravastatin, a model drug known for its efficacy in reducing oxidative stress and inflammation during pregnancy and currently in clinical trials, was used to test its transfer rate across both feto-maternal interfaces. The data obtained from FMi-PLA-OOC were compared with existing data from in vivo animal models and ex vivo placenta perfusion models. Additionally, we employed mechanistically based simulation software (Gastroplus®) to predict pravastatin pharmacokinetics in pregnant subjects based on validated nonpregnant drug data. Pravastatin transfer across the FMi-PLA-OOC and predicted pharmacokinetics in the in silico models were found to be similar, approximately 18%. In contrast, animal models showed supraphysiologic drug accumulation in the amniotic fluid, reaching approximately 33%. The results from this study suggest that the FMi-PLA-OOC and in silico models can serve as alternative methods for studying drug pharmacokinetics during pregnancy, providing valuable insights into drug transport and metabolism across the placenta and fetal membranes. These advanced platforms offer promising opportunities for safe, reliable, and faster testing of therapeutic compounds, potentially reducing the number of pregnant women referred to as "therapeutic orphans" due to the lack of consideration in drug development and clinical trials. By bridging the gap between preclinical studies and clinical trials, these approaches hold great promise in improving maternal and neonatal health outcomes.
PubMed: 37663251
DOI: 10.3389/fphar.2023.1241815 -
ACS Pharmacology & Translational Science Oct 2023COVID-19 (Coronavirus Disease 2019) is an infectious disease caused by SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) and has globally infected 768 million... (Review)
Review
COVID-19 (Coronavirus Disease 2019) is an infectious disease caused by SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) and has globally infected 768 million people and caused over 6 million deaths. COVID-19 primarily affects the respiratory system but increasing reports of neurologic symptoms associated with COVID-19 have been reported in the literature. The exact mechanism behind COVID-19 neurologic pathophysiology remains poorly understood due to difficulty quantifying clinical neurologic symptoms in humans and correlating them to findings in human post-mortem samples and animal models. Thus, robust preclinical experimental models for COVID-19 neurologic manifestations are urgently needed. Here, we review recent advances in , and other models and technologies for studying COVID-19 including primary cell cultures, pluripotent stem cell-derived neurons and organoids, rodents, nonhuman primates, 3D bioprinting, artificial intelligence, and multiomics. We specifically focus our discussion on the contribution, recent advancements, and limitations these preclinical models have on furthering our understanding of COVID-19's neuropathic physiology. We also discuss these models' roles in the screening and development of therapeutics, vaccines, antiviral drugs, and herbal medicine, and on future opportunities for COVID-19 neurologic research and clinical management.
PubMed: 37854617
DOI: 10.1021/acsptsci.3c00127 -
Journal of the Endocrine Society Dec 2023We have recently proposed experimental design guidelines and areas of study for preclinical rodent models of gender-affirming hormone therapy in neuroscience. These...
We have recently proposed experimental design guidelines and areas of study for preclinical rodent models of gender-affirming hormone therapy in neuroscience. These guidelines also apply to any field subject to the influences of gonadal steroid hormones, including metabolism and growth, cancer, and physiology. This perspective briefly describes our suggestions for these fields. Studying the effects of exogenous steroid hormones will have translational benefits for the community. We also discuss the need for equitable practices for cisgender scientists who wish to implement these guidelines and engage with the community. It is necessary that community-informed practices are implemented in preclinical research to maximize the benefit to transgender, nonbinary, and/or gender diverse (TNG) healthcare, which is currently in jeopardy in the United States, Europe, and across the globe.
PubMed: 38090229
DOI: 10.1210/jendso/bvad144 -
Pharmacology & Therapeutics May 2024Mouse models of disease play a pivotal role at all stages of cancer drug development. Cell-line derived subcutaneous tumour models are predominant in early drug... (Review)
Review
Mouse models of disease play a pivotal role at all stages of cancer drug development. Cell-line derived subcutaneous tumour models are predominant in early drug discovery, but there is growing recognition of the importance of the more complex orthotopic and metastatic tumour models for understanding both target biology in the correct tissue context, and the impact of the tumour microenvironment and the immune system in responses to treatment. The aim of this review is to highlight the value that orthotopic and metastatic models bring to the study of tumour biology and drug development while pointing out those models that are most likely to be encountered in the literature. Important developments in orthotopic models, such as the increasing use of early passage patient material (PDXs, organoids) and humanised mouse models are discussed, as these approaches have the potential to increase the predictive value of preclinical studies, and ultimately improve the success rate of anticancer drugs in clinical trials.
Topics: Animals; Mice; Humans; Xenograft Model Antitumor Assays; Immune System; Antineoplastic Agents; Neoplasms; Disease Models, Animal; Tumor Microenvironment
PubMed: 38467308
DOI: 10.1016/j.pharmthera.2024.108631 -
Molecules (Basel, Switzerland) Jul 2023Psychostimulant use disorders (PSUD) affect a growing number of men and women and exert sizable public health and economic burdens on our global society. Notably, there... (Review)
Review
Psychostimulant use disorders (PSUD) affect a growing number of men and women and exert sizable public health and economic burdens on our global society. Notably, there are some sex differences in the onset of dependence, relapse rates, and treatment success with PSUD observed in preclinical and clinical studies. The subtle sex differences observed in the behavioral aspects of PSUD may be associated with differences in the neurochemistry of the dopaminergic system between sexes. Preclinically, psychostimulants have been shown to increase synaptic dopamine (DA) levels and may downregulate the dopamine transporter (DAT). This effect is greatest in females during the high estradiol phase of the estrous cycle. Interestingly, women have been shown to be more likely to begin drug use at younger ages and report higher levels of desire to use cocaine than males. Even though there is currently no FDA-approved medication, modafinil, a DAT inhibitor approved for use in the treatment of narcolepsy and sleep disorders, has shown promise in the treatment of PSUD among specific populations of affected individuals. In this review, we highlight the therapeutic potential of modafinil and other atypical DAT inhibitors focusing on the lack of sex differences in the actions of these agents.
Topics: Female; Humans; Male; Dopamine Uptake Inhibitors; Modafinil; Sex Characteristics; Benzhydryl Compounds; Central Nervous System Stimulants; Cocaine; Dopamine
PubMed: 37446929
DOI: 10.3390/molecules28135270 -
Journal of Psychopharmacology (Oxford,... Nov 2023Animal models are important in preclinical psychopharmacology to study mechanisms and potential treatments for psychiatric disorders. A working group of 14 volunteers,...
Animal models are important in preclinical psychopharmacology to study mechanisms and potential treatments for psychiatric disorders. A working group of 14 volunteers, comprising an international team of researchers from academia and industry, convened in 2021 to discuss how to improve the translational relevance and interpretation of findings from animal models that are used in preclinical psychopharmacology. The following paper distils the outcomes of the working group's discussions into 10 key considerations for the planning and reporting of behavioural studies in animal models relevant to psychiatric disorders. These form the iTRIPP guidelines (Improving Translational Relevance In Preclinical Psychopharmacology). These guidelines reflect the key considerations that the group thinks will likely have substantial impact in terms of improving the translational relevance of behavioural studies in animal models that are used to study psychiatric disorders and their treatment. They are relevant to the research community when drafting and reviewing manuscripts, presentations and grant applications. The iTRIPP guidelines are intended to complement general recommendations for planning and reporting animal studies that have been published elsewhere, by enabling researchers to fully consider the most appropriate animal model for the research purpose and to interpret their findings appropriately. This in turn will increase the clinical benefit of such research and is therefore important not only for the scientific community but also for patients and the lay public.
Topics: Animals; Humans; Psychopharmacology; Mental Disorders; Disease Models, Animal
PubMed: 37522187
DOI: 10.1177/02698811231182607 -
Journal of Cachexia, Sarcopenia and... Feb 2024Patients with chronic kidney disease (CKD) are often regarded as experiencing wasting of muscle mass and declining muscle strength and function, collectively termed... (Meta-Analysis)
Meta-Analysis Review
Patients with chronic kidney disease (CKD) are often regarded as experiencing wasting of muscle mass and declining muscle strength and function, collectively termed sarcopenia. The extent of skeletal muscle wasting in clinical and preclinical CKD populations is unclear. We evaluated skeletal muscle atrophy in preclinical and clinical models of CKD, with multiple sub-analyses for muscle mass assessment methods, CKD severity, sex and across the different preclinical models of CKD. We performed a systematic literature review of clinical and preclinical studies that measured muscle mass/size using the following databases: Ovid Medline, Embase and Scopus. A random effects meta-analysis was utilized to determine standard mean difference (SMD; Hedges' g) between healthy and CKD. Heterogeneity was evaluated using the I statistic. Preclinical study quality was assessed via the Systematic Review Centre for Laboratory Animal Experimentation and clinical studies quality was assessed via the Newcastle-Ottawa Scale. This study was registered in PROSPERO (CRD42020180737) prior to initiation of the search. A total of 111 studies were included in this analysis using the following subgroups: 106 studies in the primary CKD analysis, 18 studies that accounted for diabetes and 7 kidney transplant studies. Significant atrophy was demonstrated in 78% of the preclinical studies and 49% of the clinical studies. The random effects model demonstrated a medium overall SMD (SMD = 0.58, 95% CI = 0.52-0.64) when combining clinical and preclinical studies, a medium SMD for the clinical population (SMD = 0.48, 95% CI = 0.42-0.55; all stages) and a large SMD for preclinical CKD (SMD = 0.95, 95% CI = 0.76-1.14). Further sub-analyses were performed based upon assessment methods, disease status and animal model. Muscle atrophy was reported in 49% of the clinical studies, paired with small mean differences. Preclinical studies reported significant atrophy in 78% of studies, with large mean differences. Across multiple clinical sub-analyses such as severity of CKD, dialysis modality and diabetes, a medium mean difference was found. Sub-analyses in both clinical and preclinical studies found a large mean difference for males and medium for females suggesting sex-specific implications. Muscle atrophy differences varied based upon assessment method for clinical and preclinical studies. Limitations in study design prevented conclusions to be made about the extent of muscle loss with disease progression, or the impact of dialysis. Future work would benefit from the use of standardized measurement methods and consistent clinical staging to improve our understanding of atrophy changes in CKD progression, and analysis of biological sex differences.
Topics: Humans; Female; Male; Renal Insufficiency, Chronic; Muscular Atrophy; Renal Dialysis; Muscle, Skeletal; Diabetes Mellitus
PubMed: 38062879
DOI: 10.1002/jcsm.13400