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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 -
Clinical Cancer Research : An Official... Aug 2023Patients with unresectable/metastatic chondrosarcoma have poor prognoses; conventional chondrosarcoma is associated with a median progression-free survival (PFS) of <4...
PURPOSE
Patients with unresectable/metastatic chondrosarcoma have poor prognoses; conventional chondrosarcoma is associated with a median progression-free survival (PFS) of <4 months after first-line chemotherapy. No standard targeted therapies are available. We present the preclinical characterization of INBRX-109, a third-generation death receptor 5 (DR5) agonist, and clinical findings from a phase I trial of INBRX-109 in unresectable/metastatic chondrosarcoma (NCT03715933).
PATIENTS AND METHODS
INBRX-109 was first characterized preclinically as a DR5 agonist, with binding specificity and hepatotoxicity evaluated in vitro and antitumor activity evaluated both in vitro and in vivo. INBRX-109 (3 mg/kg every 3 weeks) was then evaluated in a phase I study of solid tumors, which included a cohort with any subtype of chondrosarcoma and a cohort with IDH1/IDH2-mutant conventional chondrosarcoma. The primary endpoint was safety. Efficacy was an exploratory endpoint, with measures including objective response, disease control rate, and PFS.
RESULTS
In preclinical studies, INBRX-109 led to antitumor activity in vitro and in patient-derived xenograft models, with minimal hepatotoxicity. In the phase I study, INBRX-109 was well tolerated and demonstrated antitumor activity in unresectable/metastatic chondrosarcoma. INBRX-109 led to a disease control rate of 87.1% [27/31; durable clinical benefit, 40.7% (11/27)], including two partial responses, and median PFS of 7.6 months. Most treatment-related adverse events, including liver-related events, were low grade (grade ≥3 events in chondrosarcoma cohorts, 5.7%).
CONCLUSIONS
INBRX-109 demonstrated encouraging antitumor activity with a favorable safety profile in patients with unresectable/metastatic chondrosarcoma. A randomized, placebo-controlled, phase II trial (ChonDRAgon, NCT04950075) will further evaluate INBRX-109 in conventional chondrosarcoma.
Topics: Humans; Antibodies, Monoclonal; Bone Neoplasms; Chemical and Drug Induced Liver Injury; Chondrosarcoma; Receptors, TNF-Related Apoptosis-Inducing Ligand
PubMed: 37265425
DOI: 10.1158/1078-0432.CCR-23-0974 -
Frontiers in Molecular Neuroscience 2023Multiple molecular pathways and cellular processes have been implicated in the neurobiology of autism and other neurodevelopmental conditions. There is a current focus... (Review)
Review
Multiple molecular pathways and cellular processes have been implicated in the neurobiology of autism and other neurodevelopmental conditions. There is a current focus on synaptic gene conditions, or synaptopathies, which refer to clinical conditions associated with rare genetic variants disrupting genes involved in synaptic biology. Synaptopathies are commonly associated with autism and developmental delay and may be associated with a range of other neuropsychiatric outcomes. Altered synaptic biology is suggested by both preclinical and clinical studies in autism based on evidence of differences in early brain structural development and altered glutamatergic and GABAergic neurotransmission potentially perturbing excitatory and inhibitory balance. This review focusses on the NRXN-NLGN-SHANK pathway, which is implicated in the synaptic assembly, trans-synaptic signalling, and synaptic functioning. We provide an overview of the insights from preclinical molecular studies of the pathway. Concentrating on NRXN1 deletion and SHANK3 mutations, we discuss emerging understanding of cellular processes and electrophysiology from induced pluripotent stem cells (iPSC) models derived from individuals with synaptopathies, neuroimaging and behavioural findings in animal models of Nrxn1 and Shank3 synaptic gene conditions, and key findings regarding autism features, brain and behavioural phenotypes from human clinical studies of synaptopathies. The identification of molecular-based biomarkers from preclinical models aims to advance the development of targeted therapeutic treatments. However, it remains challenging to translate preclinical animal models and iPSC studies to interpret human brain development and autism features. We discuss the existing challenges in preclinical and clinical synaptopathy research, and potential solutions to align methodologies across preclinical and clinical research. Bridging the translational gap between preclinical and clinical studies will be necessary to understand biological mechanisms, to identify targeted therapies, and ultimately to progress towards personalised approaches for complex neurodevelopmental conditions such as autism.
PubMed: 37441676
DOI: 10.3389/fnmol.2023.1191323 -
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 -
Cell Mar 2024In response to the 2022 outbreak of mpox driven by unprecedented human-to-human monkeypox virus (MPXV) transmission, we designed BNT166, aiming to create a highly...
In response to the 2022 outbreak of mpox driven by unprecedented human-to-human monkeypox virus (MPXV) transmission, we designed BNT166, aiming to create a highly immunogenic, safe, accessible, and scalable next-generation vaccine against MPXV and related orthopoxviruses. To address the multiple viral forms and increase the breadth of immune response, two candidate multivalent mRNA vaccines were evaluated pre-clinically: a quadrivalent vaccine (BNT166a; encoding the MPXV antigens A35, B6, M1, H3) and a trivalent vaccine (BNT166c; without H3). Both candidates induced robust T cell responses and IgG antibodies in mice, including neutralizing antibodies to both MPXV and vaccinia virus. In challenge studies, BNT166a and BNT166c provided complete protection from vaccinia, clade I, and clade IIb MPXV. Furthermore, immunization with BNT166a was 100% effective at preventing death and at suppressing lesions in a lethal clade I MPXV challenge in cynomolgus macaques. These findings support the clinical evaluation of BNT166, now underway (NCT05988203).
Topics: Animals; Humans; Mice; Macaca fascicularis; Monkeypox virus; Mpox (monkeypox); Smallpox Vaccine; Vaccines, Combined; Vaccinia virus
PubMed: 38366591
DOI: 10.1016/j.cell.2024.01.017 -
Pharmaceuticals (Basel, Switzerland) Nov 2023Cancer remains a major cause of cancer-related death worldwide. Over 70% of epithelial malignancies are sporadic and are related to lifestyle. Epidemiological studies... (Review)
Review
Cancer remains a major cause of cancer-related death worldwide. Over 70% of epithelial malignancies are sporadic and are related to lifestyle. Epidemiological studies suggest an inverse correlation between cancer incidence and fruit and vegetable intake. Numerous preclinical studies using in vitro (cell lines) and in vivo animal models of oncogenesis have reported the chemopreventive effects of dietary phytochemical agents through alterations in different biomarkers and signaling pathways. However, there is contrasting evidence from preclinical studies and clinical trials. To date, the most studied compounds include curcumin, resveratrol, isoflavones, green tea extract (epigallocatechin gallate), black raspberry powder (anthocyanins and ellagitannins), bilberry extract (anthocyanins), ginger extract (gingerol derivatives), and pomegranate extract (ellagitannins and ellagic acid). Overall, the clinical evidence of the preventive effects of dietary phytochemicals against cancer development is still weak, and the amount of these phytochemicals needed to exert chemopreventive effects largely exceeds the common dietary doses. Therefore, we propose a combination treatment of natural compounds that are used clinically for another purpose in order to obtain excess inhibitory efficacy via low-dose administration and discuss the possible reasons behind the gap between preclinical research and clinical trials.
PubMed: 38004456
DOI: 10.3390/ph16111591 -
Behavioural Brain Research Oct 2023SARS-CoV-2 infection produces a wide range of symptoms. Some of the structural changes caused by the virus in the nervous system are found in the medial temporal lobe,... (Review)
Review
SARS-CoV-2 infection produces a wide range of symptoms. Some of the structural changes caused by the virus in the nervous system are found in the medial temporal lobe, and several neuropsychological sequelae of COVID-19 are related to the function of the hippocampus. The main objective of the systematic review is to update and further analyze the existing evidence of hippocampal and related cortices' structural and functional alterations due to SARS-CoV-2 infection. Both clinical and preclinical studies that used different methodologies to explore the effects of this disease at different stages and grades of severity were considered, besides exploring related cognitive and emotional symptomatology. A total of 24 studies were identified by searching in SCOPUS, Web Of Science (WOS), PubMed, and PsycInfo databases up to October 3rd, 2022. Thirteen studies were performed in clinical human samples, 9 included preclinical animal models, 3 were performed post-mortem, and 1 included both post-mortem and preclinical samples. Alterations in the hippocampus were detected in the acute stage and after several months of infection. Clinical studies revealed alterations in hippocampal connectivity and metabolism. Memory alterations correlated with altered metabolic profiles or changes in grey matter volumes. Hippocampal human postmortem and animal studies observed alterations in neurogenesis, dendrites, and immune response, besides high apoptosis and neuroinflammation. Preclinical studies reported the viral load in the hippocampus. Olfactory dysfunction was associated with alterations in brain functionality. Several clinical studies revealed cognitive complaints, neuropsychological alterations, and depressive and anxious symptomatology.
Topics: Animals; Humans; COVID-19; SARS-CoV-2; Hippocampus; Temporal Lobe
PubMed: 37703951
DOI: 10.1016/j.bbr.2023.114662 -
Aging and Disease Oct 2023Sarcopenia is defined as the age-related loss of muscle mass and function that can lead to prolonged hospital stays and decreased independence. It is a significant... (Review)
Review
Sarcopenia is defined as the age-related loss of muscle mass and function that can lead to prolonged hospital stays and decreased independence. It is a significant health and financial burden for individuals, families, and society as a whole. The accumulation of damaged mitochondria in skeletal muscle contributes to the degeneration of muscles with age. Currently, the treatment of sarcopenia is limited to improving nutrition and physical activity. Studying effective methods to alleviate and treat sarcopenia to improve the quality of life and lifespan of older people is a growing area of interest in geriatric medicine. Therapies targeting mitochondria and restoring mitochondrial function are promising treatment strategies. This article provides an overview of stem cell transplantation for sarcopenia, including the mitochondrial delivery pathway and the protective role of stem cells. It also highlights recent advances in preclinical and clinical research on sarcopenia and presents a new treatment method involving stem cell-derived mitochondrial transplantation, outlining its advantages and challenges.
PubMed: 37196123
DOI: 10.14336/AD.2023.0210 -
International Wound Journal Dec 2023Diabetic foot ulcer (DFU), a common intractable chronic complication of diabetes mellitus (DM), has a prevalence of up to 25%, with more than 17% of the affected... (Review)
Review
Diabetic foot ulcer (DFU), a common intractable chronic complication of diabetes mellitus (DM), has a prevalence of up to 25%, with more than 17% of the affected patients at risk of amputation or even death. Vascular risk factors, including vascular stenosis or occlusion, dyslipidemia, impaired neurosensory and motor function, and skin infection caused by trauma, all increase the risk of DFU in patients with diabetes. Therefore, diabetic foot is not a single pathogenesis. Preclinical studies have contributed greatly to the pathogenesis determination and efficacy evaluation of DFU. Many therapeutic tools are currently being investigated using DFU animal models for effective clinical translation. However, preclinical animal models that completely mimic the pathogenesis of DFU remain unexplored. Therefore, in this review, the preparation methods and evaluation criteria of DFU animal models with three major pathological mechanisms: neuropathy, angiopathy and DFU infection were discussed in detail. And the advantages and disadvantages of various DFU animal models for clinical sign simulation. Furthermore, the current status of vitro models of DFU and some preclinical studies have been transformed into clinical treatment programs, such as medical dressings, growth factor therapy, 3D bioprinting and pre-vascularization, Traditional Chinese Medicine treatment. However, because of the complexity of the pathological mechanism of DFU, the clinical transformation of DFU model still faces many challenges. We need to further optimize the existing preclinical studies of DFU to provide an effective animal platform for the future study of pathophysiology and clinical treatment of DFU.
Topics: Humans; Diabetic Foot; Risk Factors; Diabetes Mellitus
PubMed: 37438679
DOI: 10.1111/iwj.14311 -
Frontiers in Psychiatry 2023The over-prescription of opioid analgesics is a growing problem in the field of addiction, which has reached epidemic-like proportions in North America. Over the past... (Review)
Review
The over-prescription of opioid analgesics is a growing problem in the field of addiction, which has reached epidemic-like proportions in North America. Over the past decade, oxycodone has gained attention as the leading opioid responsible for the North America opioid crisis. Oxycodone is the most incriminated drug in the early years of the epidemic of opioid use disorder in USA (roughly 1999-2016). The number of preclinical articles on oxycodone is rapidly increasing. Several publications have already compared oxycodone with other opioids, focusing mainly on their analgesic properties. The aim of this review is to focus on the genomic and epigenetic regulatory features of oxycodone compared with other opioid agonists. Our aim is to initiate a discussion of perceptible differences in the pharmacological response observed with these various opioids, particularly after repeated administration in preclinical models commonly used to study drug dependence potential.
PubMed: 38152360
DOI: 10.3389/fpsyt.2023.1229439