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Cancers Jul 2020Tumor cells can "hijack" chemokine networks to support tumor progression. In this context, the C-C chemokine ligand 5/C-C chemokine receptor type 5 (CCL5/CCR5) axis is... (Review)
Review
Tumor cells can "hijack" chemokine networks to support tumor progression. In this context, the C-C chemokine ligand 5/C-C chemokine receptor type 5 (CCL5/CCR5) axis is gaining increasing attention, since abnormal expression and activity of CCL5 and its receptor CCR5 have been found in hematological malignancies and solid tumors. Numerous preclinical in vitro and in vivo studies have shown a key role of the CCL5/CCR5 axis in cancer, and thus provided the rationale for clinical trials using the repurposed drug maraviroc, a CCR5 antagonist used to treat HIV/AIDS. This review summarizes current knowledge on the role of the CCL5/CCR5 axis in cancer. First, it describes the involvement of the CCL5/CCR5 axis in cancer progression, including autocrine and paracrine tumor growth, ECM (extracellular matrix) remodeling and migration, cancer stem cell expansion, DNA damage repair, metabolic reprogramming, and angiogenesis. Then, it focuses on individual hematological and solid tumors in which CCL5 and CCR5 have been studied preclinically. Finally, it discusses clinical trials of strategies to counteract the CCL5/CCR5 axis in different cancers using maraviroc or therapeutic monoclonal antibodies.
PubMed: 32630699
DOI: 10.3390/cancers12071765 -
The European Respiratory Journal Jun 2020Idiopathic pulmonary fibrosis (IPF) is a complex disease of unknown aetiology, which makes drug development challenging. Single administration of bleomycin directly to... (Review)
Review
Idiopathic pulmonary fibrosis (IPF) is a complex disease of unknown aetiology, which makes drug development challenging. Single administration of bleomycin directly to the lungs of mice is a widely used experimental model for studying pulmonary fibrogenesis and evaluating the effect of therapeutic antifibrotic strategies. The model works by inducing an early inflammatory phase, which transitions into fibrosis after 5-7 days. This initial inflammation makes therapeutic timing crucial. To accurately assess antifibrotic efficacy, the intervention should inhibit fibrosis without impacting early inflammation.Studies published between 2008 and 2019 using the bleomycin model to investigate pulmonary fibrosis were retrieved from PubMed, and study characteristics were analysed. Intervention-based studies were classified as either preventative (starting <7 days after bleomycin installation) or therapeutic (>7 days). In addition, studies were cross-referenced with current major clinical trials to assess the availability of preclinical rationale.A total of 976 publications were evaluated. 726 investigated potential therapies, of which 443 (61.0%) were solely preventative, 166 (22.9%) were solely therapeutic and 105 (14.5%) were both. Of the 443 preventative studies, only 70 (15.8%) characterised inflammation during the model's early inflammatory phase. In the reported 145 IPF clinical trials investigating 93 compounds/combinations, only 25 (26.9%) interventions had any preclinical data on bleomycin available on PubMed.Since 2008, we observed a shift (from <5% to 37.4%) in the number of studies evaluating drugs in the therapeutic setting in the bleomycin model. While this shift is encouraging, further characterisation of early inflammation and appropriate preclinical therapeutic testing are still needed. This will facilitate fruitful drug development in IPF, and more therapeutic strategies for patients with this devastating disease.
Topics: Animals; Bleomycin; Disease Models, Animal; Fibrosis; Humans; Idiopathic Pulmonary Fibrosis; Lung; Mice
PubMed: 32165401
DOI: 10.1183/13993003.01105-2019 -
World Journal of Gastroenterology Apr 2020Colorectal cancer (CRC) is the third most common diagnosed malignancy among both sexes in the United States as well as in the European Union. While the incidence and... (Review)
Review
Colorectal cancer (CRC) is the third most common diagnosed malignancy among both sexes in the United States as well as in the European Union. While the incidence and mortality rates in western, high developed countries are declining, reflecting the success of screening programs and improved treatment regimen, a rise of the overall global CRC burden can be observed due to lifestyle changes paralleling an increasing human development index. Despite a growing insight into the biology of CRC and many therapeutic improvements in the recent decades, preclinical models are still indispensable for the development of new treatment approaches. Since the development of carcinogen-induced rodent models for CRC more than 80 years ago, a plethora of animal models has been established to study colon cancer biology. Despite tenuous invasiveness and metastatic behavior, these models are useful for chemoprevention studies and to evaluate colitis-related carcinogenesis. Genetically engineered mouse models (GEMM) mirror the pathogenesis of sporadic as well as inherited CRC depending on the specific molecular pathways activated or inhibited. Although the vast majority of CRC GEMM lack invasiveness, metastasis and tumor heterogeneity, they still have proven useful for examination of the tumor microenvironment as well as systemic immune responses; thus, supporting development of new therapeutic avenues. Induction of metastatic disease by orthotopic injection of CRC cell lines is possible, but the so generated models lack genetic diversity and the number of suited cell lines is very limited. Patient-derived xenografts, in contrast, maintain the pathological and molecular characteristics of the individual patient's CRC after subcutaneous implantation into immunodeficient mice and are therefore most reliable for preclinical drug development - even in comparison to GEMM or cell line-based analyses. However, subcutaneous patient-derived xenograft models are less suitable for studying most aspects of the tumor microenvironment and anti-tumoral immune responses. The authors review the distinct mouse models of CRC with an emphasis on their clinical relevance and shed light on the latest developments in the field of preclinical CRC models.
Topics: Animals; Colorectal Neoplasms; Disease Models, Animal; Female; Male; Mice
PubMed: 32308343
DOI: 10.3748/wjg.v26.i13.1394 -
Pain Jul 2021This narrative review represents an output from the International Association for the Study of Pain's global task force on the use of cannabis, cannabinoids, and... (Meta-Analysis)
Meta-Analysis
This narrative review represents an output from the International Association for the Study of Pain's global task force on the use of cannabis, cannabinoids, and cannabis-based medicines for pain management, informed by our companion systematic review and meta-analysis of preclinical studies in this area. Our aims in this review are (1) to describe the value of studying cannabinoids and endogenous cannabinoid (endocannabinoid) system modulators in preclinical/animal models of pain; (2) to discuss both pain-related efficacy and additional pain-relevant effects (adverse and beneficial) of cannabinoids and endocannabinoid system modulators as they pertain to animal models of pathological or injury-related persistent pain; and (3) to identify important directions for future research. In service of these goals, this review (1) provides an overview of the endocannabinoid system and the pharmacology of cannabinoids and endocannabinoid system modulators, with specific relevance to animal models of pathological or injury-related persistent pain; (2) describes pharmacokinetics of cannabinoids in rodents and humans; and (3) highlights differences and discrepancies between preclinical and clinical studies in this area. Preclinical (rodent) models have advanced our understanding of the underlying sites and mechanisms of action of cannabinoids and the endocannabinoid system in suppressing nociceptive signaling and behaviors. We conclude that substantial evidence from animal models supports the contention that cannabinoids and endocannabinoid system modulators hold considerable promise for analgesic drug development, although the challenge of translating this knowledge into clinically useful medicines is not to be underestimated.
Topics: Animals; Cannabinoid Receptor Modulators; Cannabinoids; Cannabis; Endocannabinoids; Pain; Pain Management; Receptors, Cannabinoid
PubMed: 33729211
DOI: 10.1097/j.pain.0000000000002268 -
BMC Neuroscience Jun 2023When it comes to studying neural plasticity and psychedelics, the numerous and diverse neuroscientific fields converging on the topic provide unique insight into a...
When it comes to studying neural plasticity and psychedelics, the numerous and diverse neuroscientific fields converging on the topic provide unique insight into a complex picture. This editorial will describe the major ways in which the known effects of psychedelics on plasticity are being studied. We lay out strengths of different techniques and the major gaps and room for future research, particularly in the translation of pre-clinical studies to human research.
Topics: Humans; Hallucinogens; Neuronal Plasticity; Biomedical Research; Animals
PubMed: 37391744
DOI: 10.1186/s12868-023-00809-0 -
Regenerative Medicine Apr 2018This study aimed to evaluate the safety and therapeutic potential of autologous human adipose-derived mesenchymal stem cells (haMSCs) in patients with osteoarthritis. (Randomized Controlled Trial)
Randomized Controlled Trial
AIM
This study aimed to evaluate the safety and therapeutic potential of autologous human adipose-derived mesenchymal stem cells (haMSCs) in patients with osteoarthritis.
MATERIALS & METHODS
Safety and efficacy of haMSCs were preclinically assessed in vitro and in BALB/c-nu nude mice. 18 patients were enrolled and divided into three dose groups: the low-dose, mid-dose and high-dose group (1 × 10, 2 × 10 and 5 × 10 cells, respectively), provided three injections and followed up for 96 weeks.
RESULTS & CONCLUSION
The preclinical study established the safety and efficacy of haMSCs. Intra-articular injections of haMSCs were safe and improved pain, function and cartilage volume of the knee joint, rendering them a promising novel treatment for knee osteoarthritis. The dosage of 5 × 10 haMSCs exhibited the highest improvement (ClinicalTrials.gov Identifier: NCT01809769).
Topics: Adipose Tissue; Adult; Aged; Animals; Autografts; Female; Heterografts; Humans; Male; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Mice; Mice, Inbred BALB C; Mice, Nude; Middle Aged; Osteoarthritis, Knee; Pilot Projects
PubMed: 29417902
DOI: 10.2217/rme-2017-0152 -
Trends in Pharmacological Sciences Nov 2017Psychedelic drugs, such as lysergic acid diethylamide (LSD), mescaline, and psilocybin, exert profound effects on brain and behavior. After decades of difficulties in... (Review)
Review
Psychedelic drugs, such as lysergic acid diethylamide (LSD), mescaline, and psilocybin, exert profound effects on brain and behavior. After decades of difficulties in studying these compounds, psychedelics are again being tested as potential treatments for intractable biomedical disorders. Preclinical research of psychedelics complements human neuroimaging studies and pilot clinical trials, suggesting these compounds as promising treatments for addiction, depression, anxiety, and other conditions. However, many questions regarding the mechanisms of action, safety, and efficacy of psychedelics remain. Here, we summarize recent preclinical and clinical data in this field, discuss their pharmacological mechanisms of action, and outline critical areas for future studies of psychedelic drugs, with the goal of maximizing the potential benefits of translational psychedelic biomedicine to patients.
Topics: Animals; Brain; Hallucinogens; Humans; Mind-Body Relations, Metaphysical; Psychophysiology
PubMed: 28947075
DOI: 10.1016/j.tips.2017.08.003 -
Methods in Molecular Biology (Clifton,... 2023Three-dimensional (3D) organoid culture is a laboratory technique used to grow and study miniature organs that mimic the structure and function of real organs in the...
Three-dimensional (3D) organoid culture is a laboratory technique used to grow and study miniature organs that mimic the structure and function of real organs in the human body. Organoids are created from stem cells or tissue samples and are grown in a 3D matrix that allows them to self-organize into a complex, three-dimensional structure. Organoids are valuable tools for studying human biology and disease, including cancer. Pancreatic ductal adenocarcinoma (PDAC) still has the worst survival rate of common malignancies, despite recent advances in cancer treatment. Preclinical studies have shown that impaired cell death pathways, including apoptosis, necroptosis, ferroptosis, pyroptosis, and alkaliptosis, promote PDAC development. Organoid models are now widely used in the study of pancreatic cancer biology, including cell death machinery. This chapter provides step-by-step protocols for generating human or mice PDAC organoids in a 3D Matrigel system.
Topics: Animals; Mice; Humans; Carcinoma, Pancreatic Ductal; Pancreatic Neoplasms; Pancreatic Ducts; Organoids
PubMed: 37578695
DOI: 10.1007/978-1-0716-3433-2_5 -
FASEB BioAdvances Apr 2022Activation of the sympathetic nervous system releases catecholamines that can interact with β-adrenergic receptors on tumor cells. Preclinical models have shown that... (Review)
Review
Activation of the sympathetic nervous system releases catecholamines that can interact with β-adrenergic receptors on tumor cells. Preclinical models have shown that the signaling processes initiated by activation of β-adrenergic receptors increase tumorigenesis, stimulate cell proliferation, and inhibit apoptosis. Indeed, preclinical studies have also shown that β-adrenergic blockade can decrease tumor burden. Researchers have been studying the effects of β-adrenergic receptor blockers on tumor cells and how they may slow the progression of melanoma, basal cell carcinoma, and squamous cell carcinoma. Moreover, clinical data have shown improved prognosis in patients with skin cancer who take β-blockers. This review discusses the mechanisms of β-adrenergic signaling in cancer and immune cells, details preclinical models of sympathetic blockade, and considers clinical evidence of the effects of β-adrenergic blockade in skin cancers.
PubMed: 35415461
DOI: 10.1096/fba.2021-00097 -
Nature Biomedical Engineering Apr 2024Predicting the toxicity of cancer immunotherapies preclinically is challenging because models of tumours and healthy organs do not typically fully recapitulate the...
Predicting the toxicity of cancer immunotherapies preclinically is challenging because models of tumours and healthy organs do not typically fully recapitulate the expression of relevant human antigens. Here we show that patient-derived intestinal organoids and tumouroids supplemented with immune cells can be used to study the on-target off-tumour toxicities of T-cell-engaging bispecific antibodies (TCBs), and to capture clinical toxicities not predicted by conventional tissue-based models as well as inter-patient variabilities in TCB responses. We analysed the mechanisms of T-cell-mediated damage of neoplastic and donor-matched healthy epithelia at a single-cell resolution using multiplexed immunofluorescence. We found that TCBs that target the epithelial cell-adhesion molecule led to apoptosis in healthy organoids in accordance with clinical observations, and that apoptosis is associated with T-cell activation, cytokine release and intra-epithelial T-cell infiltration. Conversely, tumour organoids were more resistant to damage, probably owing to a reduced efficiency of T-cell infiltration within the epithelium. Patient-derived intestinal organoids can aid the study of immune-epithelial interactions as well as the preclinical and clinical development of cancer immunotherapies.
Topics: Antibodies, Bispecific; Humans; Organoids; T-Lymphocytes; Apoptosis; Intestines; Immunotherapy; Epithelial Cell Adhesion Molecule; Neoplasms; Female; Intestinal Mucosa
PubMed: 38114742
DOI: 10.1038/s41551-023-01156-5