The preclinical gap in pancreatic cancer and radiotherapy.

Pancreatic ductal adenocarcinoma is an aggressive malignancy with limited treatment options. Chemotherapy offers little benefit and, although there is some evidence that radiotherapy may improve response, its use in the clinical management of pancreatic cancer remains controversial due to conflicting reports on its survival benefit. There has also been a lack of clinical trials that directly investigate the efficacy of radiotherapy in pancreatic cancer. The limited progress in the development of radiotherapeutic strategies in pancreatic cancer can be attributed, at least in part, to a dearth of preclinical research and our limited understanding of the effects of radiation on the pancreatic tumour microenvironment. In this Perspective, we discuss how insight into the immunosuppressive tumour microenvironment and the complex signalling between tumour and stromal cells following radiation is needed to develop effective radiosensitising strategies for pancreatic cancer. We also highlight that to have the best chance for successful clinical translation, more preclinical research is required in appropriately complex models.

The Development of Principles for Patient and Public Involvement (PPI) in Preclinical Spinal Cord Research: A Modified Delphi Study.

INTRODUCTION: There is currently limited guidance for researchers on Patient and Public Involvement (PPI) for preclinical spinal cord research, leading to uncertainty about design and implementation. This study aimed to develop evidence-informed principles to support preclinical spinal cord researchers to incorporate PPI into their research. METHODS: This study used a modified Delphi method with the aim of establishing consensus on a set of principles for PPI in spinal cord research. Thirty-eight stakeholders including researchers, clinicians and people living with spinal cord injury took part in the expert panel. Participants were asked to rate their agreement with a series of statements relating to PPI in preclinical spinal cord research over two rounds. As part of Round 2, they were also asked to rate statements as essential or desirable. RESULTS: Thirty-eight statements were included in Round 1, after which five statements were amended and two additional statements were added. After Round 2, consensus (> 75% agreement) was reached for a total of 27 principles, with 13 rated as essential and 14 rated as desirable. The principles with highest agreement related to diversity in representation among PPI contributors, clarity of the purpose of PPI and effective communication. CONCLUSION: This research developed a previously unavailable set of evidence-informed principles to inform PPI in preclinical spinal cord research. These principles provide guidance for researchers seeking to conduct PPI in preclinical spinal cord research and may also inform PPI in other preclinical disciplines. PATIENT AND PUBLIC INVOLVEMENT STATEMENT: This study was conducted as part of a project aiming to develop PPI in preclinical spinal cord injury research associated with an ongoing research collaboration funded by the Irish Rugby Football Union Charitable Trust (IRFU CT) and the Science Foundation Ireland Centre for Advanced Materials and BioEngineering Research (SFI AMBER), with research conducted by the Tissue Engineering Research Group (TERG) at the RCSI University of Medicine and Health Sciences. The project aims to develop an advanced biomaterials platform for spinal cord repair and includes a PPI Advisory Panel comprising researchers, clinicians and seriously injured rugby players to oversee the work of the project. PPI is included in this study through the involvement of members of the PPI Advisory Panel in the conceptualisation of this research, review of findings, identification of key points for discussion and preparation of the study manuscript as co-authors.

Strategies for Measuring Non-Evoked Pain in Preclinical Models of Neuropathic Pain: Systematic Review.

The development of new analgesics for neuropathic pain treatment is crucial. The failure of promising drugs in clinical trials may be related to the over-reliance on reflex-based responses (evoked pain) in preclinical drug testing, which may not fully represent clinical neuropathic pain, characterized by spontaneous non-evoked pain (NEP). Hence, strategies for assessing NEP in preclinical studies emerged. This systematic review identified 443 articles evaluating NEP in neuropathic pain models (mainly traumatic nerve injuries in male rodents). An exponential growth in NEP evaluation was observed, which was assessed using 48 different tests classified in 12 NEP-related outcomes: anxiety, exploration/locomotion, paw lifting, depression, conditioned place preference, gait, autotomy, wellbeing, facial grooming, cognitive impairment, facial pain expressions and vocalizations. Although most of these outcomes showed clear limitations, our analysis suggests that conditioning-associated outcomes, pain-related comorbidities, and gait evaluation may be the most effective strategies. Moreover, a minimal part of the studies evaluated standard analgesics. The greater emphasis on evaluating NEP aligning with clinical pain symptoms may enhance analgesic drug development, improving clinical translation.

Effects of N-Methyl-d-Aspartate Receptor Antagonists on Gamma-Band Activity During Auditory Stimulation Compared With Electro/Magneto-encephalographic Data in Schizophrenia and Early-Stage Psychosis: A Systematic Review and Perspective.

BACKGROUND AND HYPOTHESIS: N-Methyl-d-aspartate receptor (NMDA-R) hypofunctioning has been hypothesized to be involved in circuit dysfunctions in schizophrenia (ScZ). Yet, it remains to be determined whether the physiological changes observed following NMDA-R antagonist administration are consistent with auditory gamma-band activity in ScZ which is dependent on NMDA-R activity. STUDY DESIGN: This systematic review investigated the effects of NMDA-R antagonists on auditory gamma-band activity in preclinical (n = 15) and human (n = 3) studies and compared these data to electro/magneto-encephalographic measurements in ScZ patients (n = 37) and 9 studies in early-stage psychosis. The following gamma-band parameters were examined: (1) evoked spectral power, (2) intertrial phase coherence (ITPC), (3) induced spectral power, and (4) baseline power. STUDY RESULTS: Animal and human pharmacological data reported a reduction, especially for evoked gamma-band power and ITPC, as well as an increase and biphasic effects of gamma-band activity following NMDA-R antagonist administration. In addition, NMDA-R antagonists increased baseline gamma-band activity in preclinical studies. Reductions in ITPC and evoked gamma-band power were broadly compatible with findings observed in ScZ and early-stage psychosis patients where the majority of studies observed decreased gamma-band spectral power and ITPC. In regard to baseline gamma-band power, there were inconsistent findings. Finally, a publication bias was observed in studies investigating auditory gamma-band activity in ScZ patients. CONCLUSIONS: Our systematic review indicates that NMDA-R antagonists may partially recreate reductions in gamma-band spectral power and ITPC during auditory stimulation in ScZ. These findings are discussed in the context of current theories involving alteration in E/I balance and the role of NMDA hypofunction in the pathophysiology of ScZ.

Transcutaneous auricular vagus nerve stimulation for epilepsy.

BACKGROUND: Several studies have suggested that transcutaneous vagus nerve stimulation (tVNS) may be effective for the treatment of epilepsy. However, auricular acupoint therapy (including auricular acupuncture and auricular point-sticking therapy), a method of stimulating the vagus nerve, has been poorly reviewed. This systematic review is the first to categorize auricular acupoint therapy as transcutaneous auricular vagus nerve stimulation (taVNS), aiming to assess the efficacy of taVNS in patients with epilepsy (PWE), and to analyse the results of animal experiments on the antiepileptic effects of taVNS. METHODS: We searched MEDLINE, EMBASE, Web of Science, Scopus, and various Chinese databases from their inception to June 10, 2023 and found nine clinical studies (including a total of 788 PWE) and eight preclinical studies. We performed a meta-analysis and systematic review of these articles to assess the efficacy of taVNS in PWE and the association between taVNS and electroencephalogram (EEG) changes. We also analysed the effects on epileptic behaviour, latency of the first seizure, and seizure frequency in epileptic animals. The PRISMA 2020 checklist provided by the EQUATOR Network was used in this study. RESULTS: taVNS had a higher response rate in PWE than the control treatment (OR = 2.94, 95 % CI = 1.94 - 4.46, P < 0.05). The analysis showed that the taVNS group showed wider EEG changes than the control group (OR = 2.17, 95 % CI 1.03 to 4.58, P < 0.05). The preclinical studies analysis revealed significant differences in epileptic behaviour (SMD = -4.78, 95 % CI -5.86 to -3.71, P < 0.05) and seizure frequency (SMD = -5.06, 95 % CI -5.96 to -4.15, P < 0.05) between the taVNS and control groups. No statistical difference was found in the latency of the first seizure between the two groups (SMD =13.54; 95 % CI 7.76 to 19.33, P < 0.05). CONCLUSION: Based on the available data, PWE may benefit from the use of taVNS. taVNS is an effective procedure for improving epileptic behaviour in animal models.

Insights into Nimbolide molecular crosstalk and its anticancer properties.

Nimbolide, one of the main ingredients constituent of Azadirachta indica (neem) leaf extract, has garnered attention for its potential as an anticancer agent. Its efficacy against various cancers and chemopreventive action has been demonstrated through numerous in vivo and in vitro studies. This updated review aims to comprehensively explore the chemopreventive and anticancer properties of nimbolide, emphasizing its molecular mechanisms of action and potential therapeutic applications in oncology. The review synthesizes evidence from various studies that examine nimbolide's roles in apoptosis induction, anti-proliferation, cell death, metastasis inhibition, angiogenesis suppression, and modulation of carcinogen-metabolizing enzymes. Nimbolide exhibits multifaceted anticancer activities, including the modulation of multiple cell signaling pathways related to inflammation, invasion, survival, growth, metastasis, and angiogenesis. However, its pharmacological development is still in the early stages, mainly due to limited pharmacokinetic and comprehensive long-term toxicological studies. Nimbolide shows promising anticancer and chemopreventive properties, but there is need for systematic preclinical pharmacokinetic and toxicological research. Such studies are essential for establishing safe dosage ranges for first-in-human clinical trials and further advancing nimbolide's development as a therapeutic agent against various cancers. The review highlights the potential of nimbolide in cancer treatment and underscores the importance of rigorous preclinical evaluation to realize its full therapeutic potential.

Evaluation of gender differences in the pharmacokinetics of oral zileuton nanocrystalline formulation using a rat model.

Zileuton is a leukotriene inhibitor used to treat asthma. As a BCS class II drug it exhibits challenges with solubility which likely impact its absorption. As patient gender significantly impacts the pharmacokinetics of many drugs, this study aimed to investigate potential gender-based pharmacokinetic differences after oral zileuton administration in rats. Male and female Sprague Dawley rats received single oral gavage doses of pure zileuton as an active pharmaceutical ingredient (30 mg/kg body weight (bw)), physical mixture (PM; at 30 mg/kg bw of the formulation contains zileuton, kollidon VA64 fine, dowfax2A1 and trehalose), and nanocrystalline formulation of zileuton (NfZ; at 30 mg/kg bw of the formulation). Plasma, tissue, and urine concentrations were quantified using high performance liquid chromatography (HPLC). Noncompartmental pharmacokinetic analysis showed higher zileuton levels in the plasma of female versus male rats across all evaluated forms of zileuton (API, PM, and NfZ). Female rats demonstrated higher peak plasma concentrations (Cmax) and increased area under the plasma concentration-time curve (AUC) relative to males, regardless of formulation. These findings reveal substantial gender disparities in the pharmacokinetics of zileuton in the rat model. This study emphasizes the critical need to evaluate gender differences during preclinical drug development to enable gender-based precision dosing strategies for equivalent efficacy/safety outcomes in male and female patients. Additional studies are warranted to investigate underlying mechanisms of such pharmacokinetic gender divergences.

Targeted remodeling of the human gut microbiome using Juemingzi (Senna seed extracts).

The genus Senna contains globally distributed plant species of which the leaves, roots, and seeds have multiple traditional medicinal and nutritional uses. Notable chemical compounds derived from Senna spp. include sennosides and emodin which have been tested for antimicrobial effects in addition to their known laxative functions. However, studies of the effects of the combined chemical components on intact human gut microbiome communities are lacking. This study evaluated the effects of Juemingzi (Senna sp.) extract on the human gut microbiome using SIFR® (Systemic Intestinal Fermentation Research) technology. After a 48-hour human fecal incubation, we measured total bacterial cell density and fermentation products including pH, gas production and concentrations of short chain fatty acids (SCFAs). The initial and post-incubation microbial community structure and functional potential were characterized using shotgun metagenomic sequencing. Juemingzi (Senna seed) extracts displayed strong, taxon-specific anti-microbial effects as indicated by significant reductions in cell density (40%) and intra-sample community diversity. Members of the Bacteroidota were nearly eliminated over the 48-hour incubation. While generally part of a healthy gut microbiome, specific species of Bacteroides can be pathogenic. The active persistence of the members of the Enterobacteriaceae and selected Actinomycetota despite the reduction in overall cell numbers was demonstrated by increased fermentative outputs including high concentrations of gas and acetate with correspondingly reduced pH. These large-scale shifts in microbial community structure indicate the need for further evaluation of dosages and potential administration with prebiotic or synbiotic supplements. Overall, the very specific effects of these extracts may offer the potential for targeted antimicrobial uses or as a tool in the targeted remodeling of the gut microbiome.

Strategies and techniques for preclinical therapeutic targeting of PI3K in oncology: where do we stand in 2024?

INTRODUCTION: The PI3K/AKT/mTOR signaling pathway is an important signaling pathway in eukaryotic cells that is activated in a variety of cancers and is also associated with treatment resistance. This signaling pathway is an important target for anticancer therapy and holds great promise for research. At the same time PI3K inhibitors have a general problem that they have unavoidable toxic side effects. AREAS COVERED: This review provides an explanation of the role of PI3K in the development and progression of cancer, including several important mutations, and a table listing the cancers caused by these mutations. We discuss the current landscape of PI3K inhibitors in preclinical and clinical trials, address the mechanisms of resistance to PI3K inhibition along with their associated toxic effects, and highlight significant advancements in preclinical research of this field. Furthermore, based on our study and comprehension of PI3K, we provide a recapitulation of the key lessons learned from the research process and propose potential measures for improvement that could prove valuable. EXPERT OPINION: The PI3K pathway is a biological pathway of great potential value. However, the reduction of its toxic side effects and combination therapies need to be further investigated.

Emerging roles of SIRT1 activator, SRT2104, in disease treatment.

Silent information regulator 1 (SIRT1) is a NAD+-dependent class III deacetylase that plays important roles in the pathogenesis of numerous diseases, positioning it as a prime candidate for therapeutic intervention. Among its modulators, SRT2104 emerges as the most specific small molecule activator of SIRT1, currently advancing into the clinical translation phase. The primary objective of this review is to evaluate the emerging roles of SRT2104, and to explore its potential as a therapeutic agent in various diseases. In the present review, we systematically summarized the findings from an extensive array of literature sources including the progress of its application in disease treatment and its potential molecular mechanisms by reviewing the literature published in databases such as PubMed, Web of Science, and the World Health Organization International Clinical Trials Registry Platform. We focuses on the strides made in employing SRT2104 for disease treatment, elucidating its potential molecular underpinnings based on preclinical and clinical research data. The findings reveal that SRT2104, as a potent SIRT1 activator, holds considerable therapeutic potential, particularly in modulating metabolic and longevity-related pathways. This review establishes SRT2104 as a leading SIRT1 activator with significant therapeutic promise.

Development of Novel Models of Aggressive Variants of Castration-resistant Prostate Cancer.

BACKGROUND: Genomic studies have identified new subsets of aggressive prostate cancer (PCa) with poor prognosis (eg, neuroendocrine prostate cancer [NEPC], PCa with DNA damage response [DDR] alterations, or PCa resistant to androgen receptor pathway inhibitors [ARPIs]). Development of novel therapies relies on the availability of relevant preclinical models. OBJECTIVE: To develop new preclinical models (patient-derived xenograft [PDX], PDX-derived organoid [PDXO], and patient-derived organoid [PDO]) representative of the most aggressive variants of PCa and to develop a new drug evaluation strategy. DESIGN, SETTING, AND PARTICIPANTS: NEPC (n = 5), DDR (n = 7), and microsatellite instability (MSI)-high (n = 1) PDXs were established from 51 patients with metastatic PCa; PDXOs (n = 16) and PDOs (n = 6) were developed to perform drug screening. Histopathology and treatment response were characterized. Molecular profiling was performed by whole-exome sequencing (WES; n = 13), RNA sequencing (RNA-seq; n = 13), and single-cell RNA-seq (n = 14). WES and RNA-seq data from patient tumors were compared with the models. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Relationships with outcome were analyzed using the multivariable chi-square test and the tumor growth inhibition test. RESULTS AND LIMITATIONS: Our PDXs captured both common and rare molecular phenotypes and their molecular drivers, including alterations of BRCA2, CDK12, MSI-high status, and NEPC. RNA-seq profiling demonstrated broad representation of PCa subtypes. Single-cell RNA-seq indicates that PDXs reproduce cellular and molecular intratumor heterogeneity. WES of matched patient tumors showed preservation of most genetic driver alterations. PDXOs and PDOs preserve drug sensitivity of the matched tissue and can be used to determine drug sensitivity. CONCLUSIONS: Our models reproduce the phenotypic and genomic features of both common and aggressive PCa variants and capture their molecular heterogeneity. Successfully developed aggressive-variant PCa preclinical models provide an important tool for predicting tumor response to anticancer therapy and studying resistance mechanisms. PATIENT SUMMARY: In this report, we looked at the outcomes of preclinical models from patients with metastatic prostate cancer enrolled in the MATCH-R trial (NCT02517892).

Sex matters in preclinical research.

International Women's Day 2024 has a theme of inclusion. As publishers of preclinical research, we aim to show how inclusion of females in research advances scientific rigor and improves treatment reliability. Sexual reproduction is key to all life across the plant and animal kingdoms. Biological sex takes many forms that are morphologically differentiated during development: stamens versus pistils in plants; color and plumage in birds; fallopian tubes versus vas deferens in mammals; and differences in size, for instance, males are smaller in the fruit fly Drosophila melanogaster. Physical differences may be obvious, but many traits may be more obscure, including hormonal, physiological and metabolic factors. These traits have a big influence on disease and responses to treatment. Thus, we call for improved inclusion, analysis and reporting of sex as a biological variable in preclinical animal modeling research.

Preclinical Rodent Models for Human Bone Disease, Including a Focus on Cortical Bone.

Preclinical models (typically ovariectomized rats and genetically altered mice) have underpinned much of what we know about skeletal biology. They have been pivotal for developing therapies for osteoporosis and monogenic skeletal conditions, including osteogenesis imperfecta, achondroplasia, hypophosphatasia, and craniodysplasias. Further therapeutic advances, particularly to improve cortical strength, require improved understanding and more rigorous use and reporting. We describe here how trabecular and cortical bone structure develop, are maintained, and degenerate with aging in mice, rats, and humans, and how cortical bone structure is changed in some preclinical models of endocrine conditions (eg, postmenopausal osteoporosis, chronic kidney disease, hyperparathyroidism, diabetes). We provide examples of preclinical models used to identify and test current therapies for osteoporosis, and discuss common concerns raised when comparing rodent preclinical models to the human skeleton. We focus especially on cortical bone, because it differs between small and larger mammals in its organizational structure. We discuss mechanisms common to mouse and human controlling cortical bone strength and structure, including recent examples revealing genetic contributors to cortical porosity and osteocyte network configurations during growth, maturity, and aging. We conclude with guidelines for clear reporting on mouse models with a goal for better consistency in the use and interpretation of these models.

Why Do I Choose an Animal Model or an Alternative Method in Basic and Preclinical Biomedical Research? A Spectrum of Ethically Relevant Reasons and Their Evaluation.

BACKGROUND: Research model selection decisions in basic and preclinical biomedical research have not yet been the subject of an ethical investigation. Therefore, this paper aims, (1) to identify a spectrum of reasons for choosing between animal and alternative research models (e.g., based on in vitro or in silico models) and (2) provides an ethical analysis of the selected reasons. METHODS: In total, 13 researchers were interviewed; the interviews were analyzed qualitatively. The ethical analysis was based on the principlism approach and a value judgement model. RESULTS: This paper presents 66 reasons underlying the choice of researchers using animal (27 reasons) or alternative models (39). Most of the reasons were assigned to the work environment (29) and scientific standards (22). Other reasons were assigned to personal attitudes (11) and animal welfare (4). Qualitative relevant normative differences are presented in the ethical analysis. Even if few reasons can be rejected outright from an ethical point of view, there are good reasons to give some more weight than others. CONCLUSIONS: The spectrum of reasons and their ethical assessment provide a framework for reflection for researchers who may have to choose between animal models and (investing in) alternatives. This can help to reflect on and ethically justify decisions.

Secondary Ischemia Assessment in Murine and Rat Preclinical Subarachnoid Hemorrhage Models: A Systematic Review.

BACKGROUND: Delayed cerebral ischemia represents a significant contributor to death and disability following aneurysmal subarachnoid hemorrhage. Although preclinical models have shown promising results, clinical trials have consistently failed to replicate the success of therapeutic strategies. The lack of standardized experimental setups and outcome assessments, particularly regarding secondary vasospastic/ischemic events, may be partly responsible for the translational failure. The study aims to delineate the procedural characteristics and assessment modalities of secondary vasospastic and ischemic events, serving as surrogates for clinically relevant delayed cerebral ischemia, in recent rat and murine subarachnoid hemorrhage models. METHODS AND RESULTS: We conducted a systematic review of rat and murine in vivo subarachnoid hemorrhage studies (published: 2016-2020) using delayed cerebral ischemia/vasospasm as outcome parameters. Our analysis included 102 eligible studies. In murine studies (n=30), the endovascular perforation model was predominantly used, while rat studies primarily employed intracisternal blood injection to mimic subarachnoid hemorrhage. Particularly, the injection models exhibited considerable variation in injection volume, rate, and cerebrospinal fluid withdrawal. Peri-interventional monitoring was generally inadequately reported across all models, with body temperature and blood pressure being the most frequently documented parameters (62% and 34%, respectively). Vasospastic events were mainly assessed through microscopy of large cerebral arteries. In 90% of the rat and 86% of the murine studies, only male animals were used. CONCLUSIONS: Our study underscores the substantial heterogeneity in procedural characteristics and outcome assessments of experimental subarachnoid hemorrhage research. To address these challenges, drafting guidelines for standardization and ensuring rigorous control of methodological and experimental quality by funders and journals are essential. REGISTRATION: URL: https://www.crd.york.ac.uk/prospero/; Unique identifier: CRD42022337279.

Miniaturized screening and performance prediction of tailored subcutaneous extended-release formulations for preclinical in vivo studies.

Microencapsulation of active pharmaceutical ingredients (APIs) for preparation of long acting injectable (LAI) formulations is an auspicious technique to enable preclinical characterization of a broad variety of APIs, ideally independent of their physicochemical and pharmacokinetic (PK) characteristics. During early API discovery, tunable LAI formulations may enable pharmacological proof-of-concept for the given variety of candidates by tailoring the level of plasma exposure over the duration of various timespans. Although numerous reports on small scale preparation methods for LAIs utilizing copolymers of lactic and glycolic acid (PLGA) and polymers of lactic acid (PLA) highlight their potential, application in formulation screening and use in preclinical in vivo studies is yet very limited. Transfer from downscale formulation preparation to in vivo experiments is hampered in early preclinical API screening by the large number of API candidates with simultaneously very limited available amount in the lower sub-gram scale, lack of formulation stability and deficient tunability of sustained release. We hereby present a novel comprehensive platform tool for tailored extended-release formulations, aiming to support a variety of preclinical in vivo experiments with ranging required plasma exposure levels and timespans. A novel small-scale spray drying process was successfully implemented by using an air brush based instrument for preparation of PLGA and PLA based formulations. Using Design of Experiments (DoE), required API amount of 250 mg was demonstrated to suffice for identification of dominant polymer characteristics with largest impact on sustained release capability for an individual API. BI-3231, a hydrophilic and weakly acidic small compound with good water solubility and permeability, but low metabolic stability, was used as an exemplary model for one of the many candidates during API discovery. Furthermore, an in vitro to in vivo correlation (IVIVC) of API release rate was established in mice, which enabled the prediction of in vivo plasma concentration plateaus after single subcutaneous injection, using only in vitro dissolution profiles of screened formulations. By tailoring LAI formulations and their doses for acute and sub-chronic preclinical experiments, we exemplary demonstrate the practical use for BI-3231. Pharmacological proof-of-concept could be enabled whilst circumventing the need of multiple administration as result of extensive hepatic metabolism and simultaneously superseding numerous in vivo experiments for formulation tailoring.

Sensory nerve release of CGRP increases tumor growth in HNSCC by suppressing TILs.

BACKGROUND: Perineural invasion (PNI) and nerve density within the tumor microenvironment (TME) have long been associated with worse outcomes in head and neck squamous cell carcinoma (HNSCC). This prompted an investigation into how nerves within the tumor microenvironment affect the adaptive immune system and tumor growth. METHODS: We used RNA sequencing analysis of human tumor tissue from a recent HNSCC clinical trial, proteomics of human nerves from HNSCC patients, and syngeneic orthotopic murine models of HPV-unrelated HNSCC to investigate how sensory nerves modulate the adaptive immune system. FINDINGS: Calcitonin gene-related peptide (CGRP) directly inhibited CD8 T cell activity in vitro, and blocking sensory nerve function surgically, pharmacologically, or genetically increased CD8 and CD4 T cell activity in vivo. CONCLUSIONS: Our data support sensory nerves playing a role in accelerating tumor growth by directly acting on the adaptive immune system to decrease Th1 CD4 T cells and activated CD8 T cells in the TME. These data support further investigation into the role of sensory nerves in the TME of HNSCC and points toward the possible treatment efficacy of blocking sensory nerve function or specifically inhibiting CGRP release or activity within the TME to improve outcomes. FUNDING: 1R01DE028282-01, 1R01DE028529-01, 1P50CA261605-01 (to S.D.K.), 1R01CA284651-01 (to S.D.K.), and F31 DE029997 (to L.B.D.).

Protocol for co-producing a framework and integrated resource platform for engaging patients in laboratory-based research.

BACKGROUND: Patient engagement in research is the meaningful and collaborative interaction between patients and researchers throughout the research process. Patient engagement can help to ensure patient-oriented values and perspectives are incorporated into the development, conduct, and dissemination of research. While patient engagement is increasingly prevalent in clinical research, it remains relatively unrealized in preclinical laboratory research. This may reflect the nature of preclinical research, in which routine interactions or engagement with patients may be less common. Our team of patient partners and researchers has previously identified few published examples of patient engagement in preclinical laboratory research, as well as a paucity of guidance on this topic. Here we propose the development of a process framework to facilitate patient engagement in preclinical laboratory research. METHODS: Our team, inclusive of researchers and patient partners, will develop a comprehensive, empirically-derived, and stakeholder-informed process framework for 'patient engagement in preclinical laboratory research.' First, our team will create a 'deliberative knowledge space' to conduct semi-structured discussions that will inform a draft framework for preclinical patient engagement. Over the course of several sessions, we will identify actions, activities, barriers, and enablers (e.g. considerations and motivations for patient engagement in preclinical laboratory research, define roles of key players). The resulting draft process framework will be further populated with examples and refined through an international consensus-building Delphi survey with patients, researchers, and other collaborator organizations. We will then conduct pilot field tests to evaluate the framework with preclinical laboratory research groups paired with patient partners. These results will be used to create a refined framework enriched with real-world examples and considerations. All resources developed will be made available through an online repository. DISCUSSION: Our proposed process framework will provide guidance, best practices, and standardized procedures to promote patient engagement in preclinical laboratory research. Supporting and facilitating patient engagement in this setting presents an exciting new opportunity to help realize the important impact that patients can make.

Engaging patients as partners or collaborators in clinical research is becoming more common, but it is still new in preclinical research. Preclinical researchers work in laboratories on cell and animal experiments. They traditionally don't have frequent interactions with patients compared to their clinical research colleagues. Integrating patient engagement in preclinical laboratory research may help ensure that patient perspectives and values are considered. To help preclinical laboratory research align with patient-centred priorities we propose the development of a practical framework. This framework will facilitate patient engagement in preclinical laboratory research. To achieve this, we will first hold in-depth discussions with patient partners, researchers, and other collaborators to understand views on patient engagement in preclinical laboratory research. Together, we will identify key considerations to draft a framework, including motivations for patient engagement in preclinical laboratory research, and defining the roles of those who need to be involved. We will refine the framework through an international survey where we will collect feedback from researchers, patient partners, and other collaborators to make further improvements. The framework will then be tested and refined by preclinical laboratory teams inclusive of patient partners. The finalized framework and other resources to facilitate patient engagement in preclinical laboratory research will be hosted in a 'one-stop-shop' of online resources. Ultimately, this framework will enable partnerships between patients and researchers and provide a roadmap for patient engagement in preclinical laboratory research. This presents an exciting new opportunity for patients and researchers to collaborate and potentially improve translation of laboratory-based research.

Making Sense of Psychedelics in the CNS.

For centuries, ancient lineages have consumed psychedelic compounds from natural sources. In the modern era, scientists have since harnessed the power of computational tools, cellular assays, and behavioral metrics to study how these compounds instigate changes on molecular, cellular, circuit-wide, and system levels. Here, we provide a brief history of psychedelics and their use in science, medicine, and culture. We then outline current techniques for studying psychedelics from a pharmacological perspective. Finally, we address known gaps in the field and potential avenues of further research to broaden our collective understanding of physiological changes induced by psychedelics, the limits of their therapeutic capabilities, and how researchers can improve and inform treatments that are rapidly becoming accessible worldwide.