-
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 -
Annals of Clinical and Translational... Nov 2023Numerous potential amyotrophic lateral sclerosis (ALS)-relevant pathways have been hypothesized and studied preclinically, with subsequent translation to clinical trial.... (Review)
Review
Numerous potential amyotrophic lateral sclerosis (ALS)-relevant pathways have been hypothesized and studied preclinically, with subsequent translation to clinical trial. However, few successes have been observed with only modest effects. Along with an improved but incomplete understanding of ALS as a neurodegenerative disease is the evolution of more sophisticated and diverse in vitro and in vivo preclinical modeling platforms, as well as clinical trial designs. We highlight proposed pathological pathways that have been major therapeutic targets for investigational compounds. It is likely that the failures of so many of these therapeutic compounds may not have occurred because of lack of efficacy but rather because of a lack of preclinical modeling that would help define an appropriate disease pathway, as well as a failure to establish target engagement. These challenges are compounded by shortcomings in clinical trial design, including lack of biomarkers that could predict clinical success and studies that are underpowered. Although research investments have provided abundant insights into new ALS-relevant pathways, most have not yet been developed more fully to result in clinical study. In this review, we detail some of the important, well-established pathways, the therapeutics targeting them, and the subsequent clinical design. With an understanding of some of the shortcomings in translational efforts over the last three decades of ALS investigation, we propose that scientists and clinicians may choose to revisit some of these therapeutic pathways reviewed here with an eye toward improving preclinical modeling, biomarker development, and the investment in more sophisticated clinical trial designs.
Topics: Humans; Amyotrophic Lateral Sclerosis; Neurodegenerative Diseases; Biomarkers
PubMed: 37641443
DOI: 10.1002/acn3.51887 -
Neuronal Signaling Jul 2023Stress exposure is associated with psychiatric conditions, such as depression, anxiety, and post-traumatic stress disorder (PTSD). It is also a vulnerability factor to... (Review)
Review
Stress exposure is associated with psychiatric conditions, such as depression, anxiety, and post-traumatic stress disorder (PTSD). It is also a vulnerability factor to developing or reinstating substance use disorder. Stress causes several changes in the neuro-immune-endocrine axis, potentially resulting in prolonged dysfunction and diseases. Changes in several transmitters, including serotonin, dopamine, glutamate, gamma-aminobutyric acid (GABA), glucocorticoids, and cytokines, are associated with psychiatric disorders or behavioral alterations in preclinical studies. Complex and interacting mechanisms make it very difficult to understand the physiopathology of psychiatry conditions; therefore, studying regulatory mechanisms that impact these alterations is a good approach. In the last decades, the impact of stress on biology through epigenetic markers, which directly impact gene expression, is under intense investigation; these mechanisms are associated with behavioral alterations in animal models after stress or drug exposure, for example. The endocannabinoid (eCB) system modulates stress response, reward circuits, and other physiological functions, including hypothalamus-pituitary-adrenal axis activation and immune response. eCBs, for example, act retrogradely at presynaptic neurons, limiting the release of neurotransmitters, a mechanism implicated in the antidepressant and anxiolytic effects after stress. Epigenetic mechanisms can impact the expression of eCB system molecules, which in turn can regulate epigenetic mechanisms. This review will present evidence of how the eCB system and epigenetic mechanisms interact and the consequences of this interaction in modulating behavioral changes after stress exposure in preclinical studies or psychiatric conditions. Moreover, evidence that correlates the involvement of the eCB system and epigenetic mechanisms in drug abuse contexts will be discussed.
PubMed: 37520658
DOI: 10.1042/NS20220034 -
Pharmaceutics Nov 2021The blood-brain barrier (BBB) precisely controls brain microenvironment and neural activity by regulating substance transport into and out of the brain. However, it... (Review)
Review
The blood-brain barrier (BBB) precisely controls brain microenvironment and neural activity by regulating substance transport into and out of the brain. However, it severely hinders drug entry into the brain, and the efficiency of various systemic therapies against brain diseases. Modulation of the BBB via opening tight junctions, inhibiting active efflux and/or enhancing transcytosis, possesses the potential to increase BBB permeability and improve intracranial drug concentrations and systemic therapeutic efficiency. Various strategies of BBB modulation have been reported and investigated preclinically and/or clinically. This review describes conventional and emerging BBB modulation strategies and related mechanisms, and safety issues according to BBB structures and functions, to try to give more promising directions for designing more reasonable preclinical and clinical studies.
PubMed: 34959306
DOI: 10.3390/pharmaceutics13122024 -
Evidence-based Complementary and... 2022is a plant native to America, with applications in folk medicine for a wide range of diseases, such as bronchial infections, lung disorders, nervous system disorders... (Review)
Review
is a plant native to America, with applications in folk medicine for a wide range of diseases, such as bronchial infections, lung disorders, nervous system disorders (depression, anxiety), and inflammatory processes, among others. However, investigations about this species and its biological actions are still scarce. This literature review was carried out using articles published in the past 30 years on the PubMed, SciELO, and Web of Science platforms, with the focus on the method of extraction, chemical composition, and clinical and preclinical studies on the pharmacological properties of . We noticed that the main constituents of are guaiol, pinocamphone, -pinene, and 1,8-cineole. Additionally, preclinical studies reveal that extracts present antidepressant, anti-inflammatory, antinociceptive, antibacterial, antifungal, and virucidal effects. The results also demonstrate that there is a greater interest on the part of researchers from 2012 onwards in studying extracts with potential for possible new drugs.
PubMed: 35096101
DOI: 10.1155/2022/1119435 -
Heliyon Dec 2022In vivo imaging in preclinical and clinical settings can enhance knowledge of the host-microbiome interactions. Imaging techniques are a crucial node between findings at... (Review)
Review
In vivo imaging in preclinical and clinical settings can enhance knowledge of the host-microbiome interactions. Imaging techniques are a crucial node between findings at the molecular level and clinical implementation in diagnostics and therapeutics. The purpose of this study was to review existing knowledge on the microbiota in the field of imaging and provide guidance for future research, emphasizing the critical role that molecular imaging plays in increasing understanding of the host-microbe interaction. Preclinical microbiota animal models lay the foundation for the clinical translatability of novel microbiota-based therapeutics. Adopting animal models in which factors such as host genetic landscape, microbiota profile, and diet can be controlled enables investigating how the microbiota contributes to immunological dysregulation and inflammatory disorders. Current preclinical imaging of gut microbiota relies on models where the bacteria can be isolated, labelled, and re-administered. , optical imaging, ultrasound and magnetic resonance imaging define the bacteria's biodistribution in preclinical models, whereas nuclear imaging investigates bacterial metabolic activity. For the clinical investigation of microbe-host interactions, molecular nuclear imaging is increasingly becoming a promising approach. Future microbiota research should develop selective imaging probes to investigate microbiota profiles and individual strains of specific microbes. Preclinical knowledge can be translated into the molecular imaging field with great opportunities for studying the microbiome.
PubMed: 36593827
DOI: 10.1016/j.heliyon.2022.e12511 -
Frontiers in Neural Circuits 2018MRI has been extensively used in neurodegenerative disorders, such as Alzheimer's disease (AD), frontal-temporal dementia (FTD), mild cognitive impairment (MCI),... (Review)
Review
MRI has been extensively used in neurodegenerative disorders, such as Alzheimer's disease (AD), frontal-temporal dementia (FTD), mild cognitive impairment (MCI), Parkinson's disease (PD), Huntington's disease (HD) and amyotrophic lateral sclerosis (ALS). MRI is important for monitoring the neurodegenerative components in other diseases such as epilepsy, stroke and multiple sclerosis (MS). Manganese enhanced MRI (MEMRI) has been used in many preclinical studies to image anatomy and cytoarchitecture, to obtain functional information in areas of the brain and to study neuronal connections. This is due to Mn ability to enter excitable cells through voltage gated calcium channels and be actively transported in an anterograde manner along axons and across synapses. The broad range of information obtained from MEMRI has led to the use of Mn in many animal models of neurodegeneration which has supplied important insight into brain degeneration in preclinical studies. Here we provide a brief review of MEMRI use in neurodegenerative diseases and in diseases with neurodegenerative components in animal studies and discuss the potential translation of MEMRI to clinical use in the future.
Topics: Animals; Brain; Contrast Media; Humans; Magnetic Resonance Imaging; Manganese Compounds; Neurodegenerative Diseases
PubMed: 30666190
DOI: 10.3389/fncir.2018.00114 -
Global Advances in Health and Medicine Nov 2015Preclinical models for studying the effects of the human biofield have great potential to advance our understanding of human biofield modalities, which include external... (Review)
Review
Preclinical models for studying the effects of the human biofield have great potential to advance our understanding of human biofield modalities, which include external qigong, Johrei, Reiki, therapeutic touch, healing touch, polarity therapy, pranic healing, and other practices. A short history of Western biofield studies using preclinical models is presented and demonstrates numerous and consistent examples of human biofields significantly affecting biological systems both in vitro and in vivo. Methodological issues arising from these studies and practical solutions in experimental design are presented. Important questions still left unanswered with preclinical models include variable reproducibility, dosing, intentionality of the practitioner, best preclinical systems, and mechanisms. Input from the biofield practitioners in the experimental design is critical to improving experimental outcomes; however, the development of standard criteria for uniformity of practice and for inclusion of multiple practitioners is needed. Research in human biofield studies involving preclinical models promises a better understanding of the mechanisms underlying the efficacy of biofield therapies and will be important in guiding clinical protocols and integrating treatments with conventional medical therapies.
PubMed: 26665042
DOI: 10.7453/gahmj.2015.013.suppl -
EJNMMI Radiopharmacy and Chemistry Oct 2019Auger electrons (AEs) are very low energy electrons that are emitted by radionuclides that decay by electron capture (e.g. In, Ga, Tc, Pt, I and I). This energy is... (Review)
Review
BACKGROUND
Auger electrons (AEs) are very low energy electrons that are emitted by radionuclides that decay by electron capture (e.g. In, Ga, Tc, Pt, I and I). This energy is deposited over nanometre-micrometre distances, resulting in high linear energy transfer (LET) that is potent for causing lethal damage in cancer cells. Thus, AE-emitting radiotherapeutic agents have great potential for treatment of cancer. In this review, we describe the radiobiological properties of AEs, their radiation dosimetry, radiolabelling methods, and preclinical and clinical studies that have been performed to investigate AEs for cancer treatment.
RESULTS
AEs are most lethal to cancer cells when emitted near the cell nucleus and especially when incorporated into DNA (e.g. I-IUdR). AEs cause DNA damage both directly and indirectly via water radiolysis. AEs can also kill targeted cancer cells by damaging the cell membrane, and kill non-targeted cells through a cross-dose or bystander effect. The radiation dosimetry of AEs considers both organ doses and cellular doses. The Medical Internal Radiation Dose (MIRD) schema may be applied. Radiolabelling methods for complexing AE-emitters to biomolecules (antibodies and peptides) and nanoparticles include radioiodination (I and I) or radiometal chelation (In, Ga, Tc). Cancer cells exposed in vitro to AE-emitting radiotherapeutic agents exhibit decreased clonogenic survival correlated at least in part with unrepaired DNA double-strand breaks (DSBs) detected by immunofluorescence for γH2AX, and chromosomal aberrations. Preclinical studies of AE-emitting radiotherapeutic agents have shown strong tumour growth inhibition in vivo in tumour xenograft mouse models. Minimal normal tissue toxicity was found due to the restricted toxicity of AEs mostly on tumour cells targeted by the radiotherapeutic agents. Clinical studies of AEs for cancer treatment have been limited but some encouraging results were obtained in early studies using In-DTPA-octreotide and I-IUdR, in which tumour remissions were achieved in several patients at administered amounts that caused low normal tissue toxicity, as well as promising improvements in the survival of glioblastoma patients with I-mAb 425, with minimal normal tissue toxicity.
CONCLUSIONS
Proof-of-principle for AE radiotherapy of cancer has been shown preclinically, and clinically in a limited number of studies. The recent introduction of many biologically-targeted therapies for cancer creates new opportunities to design novel AE-emitting agents for cancer treatment. Pierre Auger did not conceive of the application of AEs for targeted cancer treatment, but this is a tremendously exciting future that we and many other scientists in this field envision.
PubMed: 31659527
DOI: 10.1186/s41181-019-0075-2