Translational Research Strategies Research Articles

Top Three Healthcare Trends in Orthopaedics Affecting Musculoskeletal Care in the Elderly.

Several trends toward patient-centered multi-care models employing translational research strategies are currently emerging in orthopaedics. These align seamlessly with epigenetics discussions in pain, a clinical approach to pain management that prioritizes tailoring healthcare to individual needs, preferences, and circumstances. Recognizing the unique genetic and epigenetic factors influencing pain perception, healthcare providers can integrate personalized insights into their patient-centered approach, offering more targeted and effective pain management strategies tailored to each individual's experience. Custom 3D-printing technologies may also become increasingly relevant to more effectively and reliably treat painful degenerative structural abnormalities. They are expected to go hand-in-hand with the precision medicine redefinition of musculoskeletal care. More effective analysis of surgeons' clinical decision-making and patients' perception of high-value orthopaedic care is needed. Shared Decision Making (SDM) is critical to identifying the best solution for each patient and improving stakeholders' understanding of factors influencing the diverse prioritizing values of surgical or non-surgical treatments by payers, systems, and other providers. Identifying high-value orthopaedic surgeries via effective SDM in orthopedic surgery requires more than just presenting patients with information. The Rasch analysis of patient expectations can provide this nuanced approach that involves understanding patient values, addressing misconceptions, and aligning surgical recommendations with patient-specific goals. Optimizing orthopaedic treatment within the patient-centered framework can drive innovation in reimbursement policies that support the field more broadly. Research on separating high-value from low-value orthopaedic procedures may likely impact healthcare decision- makers' resource allocation.

Testing psychosocial interventions in context: Commentary on Beidas et al. (2023).

In their recent Viewpoint article, Beidas et al. (2023) argue that researchers should test psychosocial interventions in the contexts in which they are meant to be delivered and that they can accelerate the deployment of these interventions by advancing directly from pilot trials to effectiveness and implementation studies without conducting efficacy trials. In this commentary, we argue that this is a well-intended but problematic approach and that there is a more productive strategy for translational behavioral intervention research. The commentary discusses issues concerning intervention development, refinement, and optimization; pilot and efficacy testing of interventions; the contexts in which interventions are delivered; clinical practice guidelines; and quick versus programmatic answers to significant clinical research questions. Testing psychosocial interventions in the contexts in which they are meant to be delivered is a complex task for interventions that are designed to be used in a wide variety of contexts. Nevertheless, interventions can be tested in the contexts in which they are meant to be delivered without sacrificing programmatic intervention development or safety and efficacy testing. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Preclinical and translational pharmacology of afucosylated anti-CCR8 antibody for depletion of tumour-infiltrating regulatory T cells.

RO7502175 is an afucosylated antibody designed to eliminate C-C motif chemokine receptor 8 (CCR8)+ Treg cells in the tumour microenvironment through enhanced antibody-dependent cellular cytotoxicity (ADCC). We report findings from preclinical studies characterizing pharmacology, pharmacokinetics (PK)/pharmacodynamics (PD) and safety profile of RO7502175 and discuss the translational PK/PD approach used to inform first-in-human (FiH) dosing strategy and clinical development in solid tumour indications. RO7502175 demonstrated selective ADCC against human CCR8+ Treg cells from dissociated tumours in vitro. In cynomolgus monkeys, RO7502175 exhibited a biphasic concentration-time profile consistent with immunoglobulin G1 (IgG1) antibodies, reduced CCR8+ Treg cells in the blood, induced minimal and transient cytokine secretion, and was well tolerated with a no-observed-adverse-effect level (NOAEL) of 100 mg·kg-1. Moreover, RO7502175 caused minimal cytokine release from peripheral blood mononuclear cells (PBMCs) in vitro. A quantitative model was developed to capture surrogate anti-murine CCR8 antibody PK/PD and tumour dynamics in mice and RO7502175 PK/PD in cynomolgus monkeys. Subsequently, the model was used to project RO7502175 human PK and receptor occupancy (RO) in patients. Because traditional approaches resulted in a low FiH dose for this molecule, even with its superior preclinical safety profile, an integrated approach based on the totality of preclinical data and modelling insights was used for starting dose selection. This work demonstrates a translational research strategy for collecting and utilizing relevant nonclinical data, developing a mechanistic PK/PD model and using a comprehensive approach to inform clinical study design for RO7502175.

The development of a hiPSC-based platform to identify tissue-dependencies of IDH1 R132H

The application of patient-derived (PD) in vitro tumor models represents the classical strategy for clinical translational oncology research. Using these cellular heterogeneous cultures for the isolation of cancer stem cells (CSCs), suggested to be the main driver for disease malignancy, relies on the use of surrogate biomarkers or is based on CSC-enriching culture conditions. However, the ability of those strategies to exclusively and efficiently enrich for CSC pool has been questioned. Here we present an alternative in vitro CSC model based on the oncogenic transformation of single clone-derived human induced pluripotent stem cells (hiPSC). Hotspot mutations in the DNA encoding for the R132 codon of the enzyme isocitrate dehydrogenase 1 (IDH1) and codon R175 of p53 are commonly occurring molecular features of different tumors and were selected for our transformation strategy. By choosing p53 mutant glial tumors as our model disease, we show that in vitro therapy discovery tests on IDH1-engineered synthetic CSCs (sCSCs) can identify kinases-targeting chemotherapeutics that preferentially target tumor cells expressing corresponding genetic alteration. In contrast, neural stem cells (NSCs) derived from the IDH1R132H overexpressing hiPSCs increase their resistance to the tested interventions indicating glial–to-neural tissue-dependent differences of IDH1R132H. Taken together, we provide proof for the potential of our sCSC technology as a potent addition to biomarker-driven drug development projects or studies on tumor therapy resistance. Moreover, follow-up projects such as comparing in vitro drug sensitivity profiles of hiPSC-derived tissue progenitors of different lineages, might help to understand a variety of tissue-related functions of IDH1 mutations.

The fight against antibiotic resistance: what does the future hold?

The fight against antibiotic resistance is faced with a lack of therapeutic innovation, due to the low return on investment for players in the pharmaceutical sector. Research challenges need to integrate a translational research strategy for the development of new therapeutics in a One Health approach. For synergistic collaboration, public-private partnerships have been set up with financial support mechanisms for the marketing of new anti-infectives, enabling a return on investment for players in the pharmaceutical sector.

Biomaterial strategies to combat implant infections: new perspectives to old challenges

ABSTRACT Peri-implant infection is rapidly becoming an – if not the most – important clinical challenge for indwelling medical devices. To alleviate the global rise in antibiotic use for the treatment of such infections, a plethora of biomaterials/bioengineering-based antimicrobial strategies are emerging to restrict or ideally to eliminate microbial adhesion and biofilm formation on implant surfaces. Yet, the development of such approaches faces specific challenges, like biocompatibility concerns, reduced antimicrobial effectiveness, long-term stability issues and antibiotic resistance development, which limit translation to the clinic. This review provides insights into the antimicrobial activity of current state-of-the-art biomaterial-based approaches to address the aforementioned issues. Translational research strategies and regulatory framework are also emphasised as key elements facilitating clinical implementation of anti-infective biomaterials. This review closes with the vision that the integration of computational tools and experimental databases using artificial intelligence (AI) would provide new insights for the accelerated development of next-generation biomaterial-based antimicrobial strategies.

Inhalable Nanoparticle-based Dry Powder Formulations for Respiratory Diseases: Challenges and Strategies for TranslationalResearch.

The emergence of novel respiratory infections (e.g., COVID-19) and expeditious development of nanoparticle-based COVID-19 vaccines have recently reignited considerable interest in designing inhalable nanoparticle-based drug delivery systems as next-generation respiratory therapeutics. Among various available devices in aerosol delivery, dry powder inhalers (DPIs) are preferable for delivery of nanoparticles due to their simplicity of use, high portability, and superior long-term stability. Despite research efforts devoted to developing inhaled nanoparticle-based DPI formulations, no such formulations have been approved to date, implying a research gap between bench and bedside. This review aims to address this gap by highlighting important yet often overlooked issues during pre-clinical development. We start with an overview and update on formulation and particle engineering strategies for fabricating inhalable nanoparticle-based dry powder formulations. An important but neglected aspect in in vitro characterization methodologies for linking the powder performance with their bio-fate is then discussed. Finally, the major challenges and strategies in their clinical translation are highlighted. We anticipate that focused research onto the existing knowledge gaps presented in this review would accelerate clinical applications of inhalable nanoparticle-based dry powders from a far-fetched fantasy to a reality.

Identifying applications of virtual reality to benefit the stroke translational pipeline.

As a leading cause of mortality and morbidity, stroke and its management have been studied extensively. Despite numerous pre-clinical studies identifying therapeutic targets, development of effective, specific pharmacotherapeutics remain limited. One significant limitation is a break in the translational pipeline - promising pre-clinical results have not always proven replicable in the clinic. Recent developments in virtual reality technology might help generate a better understanding of injury and recovery across the whole research pipeline in search of optimal stroke management. Here, we review the technologies that can be applied both clinically and pre-clinically to stroke research. We discuss how virtual reality technology is used to quantify clinical outcomes in other neurological conditions that have potential to be applied in stroke research. We also review current uses in stroke rehabilitation and suggest how immersive programmes would better facilitate the quantification of stroke injury severity and patient recovery comparable to pre-clinical study design. By generating continuous, standardised and quantifiable data from injury onset to rehabilitation, we propose that by paralleling pre-clinical outcomes, we can apply a better reverse-translational strategy and apply this understanding to animal studies. We hypothesise this combination of translational research strategies may improve the reliability of pre-clinical research outcomes and culminate in real-life translation of stroke management regimens and medications.

Anti-racist strategies for clinical and translational research: Design, implementation, and lessons learned from a new course.

Translational research should examine racism and bias and improve health equity. We designed and implemented a course for the Master of Science in Clinical Investigation program of the Northwestern University Clinical and Translational Sciences Institute. We describe curriculum development, content, outcomes, and revisions involving 36 students in 2 years of "Anti-Racist Strategies for Clinical and Translational Science." Ninety-six percent of students reported they would recommend the course. Many reported changes in research approaches based on course content. A course designed to teach anti-racist research design is feasible and has a positive short-term impact on learners.

Nonclinical Pharmacokinetics, Pharmacodynamics, and Translational Model of RO7297089, A Novel Anti-BCMA/CD16A Bispecific Tetravalent Antibody for the Treatment of Multiple Myeloma

RO7297089, an anti-B-cell maturation antigen (BCMA)/CD16A bispecific tetravalent antibody, is being developed as a multiple myeloma (MM) therapeutic. This study characterized nonclinical pharmacokinetics (PK), pharmacodynamics (PD), soluble BCMA (sBCMA), and soluble CD16 (sCD16) changes following administration of RO7297089 to support clinical trials. Unbound and total RO7297089 concentrations were measured in cynomolgus monkeys. RO7297089 exhibited a bi-phasic systemic concentration-time profile, similar to a typical human immunoglobulin 1 antibody. Target engagement by RO7297089 led to a robust increase (~100-fold) in total systemic sBCMA levels and relatively mild increase (~2-fold) in total sCD16 levels. To describe the relationship of nonclinical PK/PD data, we developed a target-mediated drug disposition (TMDD) model that includes the systemic target engagement of membrane BCMA (mBCMA), sBCMA, membrane CD16 (mCD16), and sCD16. We then used this model to simulate the PK/PD relationship of RO7297089 in MM patients by translating relevant PK parameters and target levels, based on the literature and newly generated data such as baseline sCD16A levels. Our model suggested that the impact of TMDD on RO7297089 exposure may be more significant in MM patients due to significantly higher expression levels of both mBCMA and sBCMA compared to healthy cynomolgus monkeys. Based on model simulations, we propose more frequent dosing of RO7297089 compared to regular monthly frequency in the clinic at the beginning of treatment to ensure sustained target engagement. This study demonstrates a translational research strategy for collecting relevant nonclinical data, establishing a TMDD model, and using simulations from this model to inform clinical dose regimens.Graphical

Innovative Translation Strategies in the Emergence of Next-Generation Drugs in Precision Cancer Medicine

There has been a conscientious momentum to evolve more efficacious and potent chemotherapeutics that could cure advanced cancers. Although, the conventional cancer therapeutics can cause dramatic tumor regressions in some patients, many patients inexplicably reveal no benefit. This is a unique characteristic of tumor recurrence in human cancers, linked with several resistance mechanisms. Recent past years witnessed enormous ground-breaking advancements in genomic medicine symbolizing a culmination of patients' genomic, proteomic, metabolomic, including cellular profiles which have significantly transformed understanding and therapeutic options for cancer management. Furthermore, the ability of combination chemotherapy to cure advanced cancers, immensely facilitated the prospects of adjuvant chemotherapy. Many global pharmaceuticals have accelerated translational research strategies on proteomics and genomic technologies paving the way to emerge next-generation drugs to strengthen personalized cancer medicine. Numerous forthcoming cancer therapies are at most vital phase in their innovation and development for the unfulfilled clinical need to turn into futuristic cancer treatment strategies. There is a growing optimism about the innovative strategies on emergence of the new generation of immunotherapy, targeted therapies, and Oligonucleotide therapy to improve patient outcomes, and to make real dream of accomplishing personalized cancer therapy.

Chemotherapy-Induced Peripheral Neuropathy and New Therapeutic Targets: Preclinical Data of Drug Repositioning

Chemotherapy-induced peripheral neuropathy (CIPN) is a common adverse effect of neurotoxic anticancer drugs. Its prevalence is close to 60%, but it can vary considerably depending on the anticancer drugs and doses administered. CIPN remains a problematic and long-lasting adverse effect associated with a decline of patient’s quality of life. Moreover, no preventive treatment can be recommended and only duloxetine has a moderate recommendation in the management of CIPN (American Society of Clinical Oncology [ASCO] and the European Society for Medical Oncology [ESMO]). Consequently, oncologists must decrease or stop neurotoxic anticancer regimen to limit CIPN severity, which may in turn have a negative oncological impact on disease control and progression-free survival. Thus, improvement in pharmacological neuropathy management is needed. We consider according to a reverse translational research strategy that this can be achieved either by proposing innovative strategies, improving the use of current analgesic drugs, or drug repositioning. In this article, two strategies of drug repositioning, riluzole and donepezil, will be presenting in the management of CIPN based on the studies in animal models of CIPN.

Decellularized normal and cancer tissues as tools for cancer research.

Today it is widely accepted that molecular mechanisms triggering cancer initiate with a genetic modification. However, a genetic alteration providing the aberrant clone with a growing advantage over neighboring cells is not sufficient to develop cancer. Currently, tumors are considered a heterogeneous population of cells and an extracellular matrix (ECM) that make up a characteristic microenvironment. Interactions between tumor cells and cancer microenvironment define cancer progression and therapeutic response. To investigate and clarify the role of ECM in the regulation of cancer cell behavior and response to therapy, the decellularization of ECM, a widely used technique in tissue engineering, has been recently employed to develop 3D culture model of disease. In this review, we briefly explore the different components of healthy and pathological ECM and the methods to obtain and characterize the ECM from native bioptic tissue. Finally, we highlight the most relevant applications of ECM in translational cancer research strategies: decellularized ECM, ECM-hydrogel and 3D bioprinting.

MO099REPROGRAMMING HYPERTENSION PROGRAMMED BY HIGH-FAT DIET: THE ROLE OF GARLIC OIL

Abstract Background and Aims Perinatal high-fat (HF) diet programs high blood pressure (BP) in adult offspring. Hydrogen sulfide (H2S) has shown benefits in hypertension by restoration of nitric oxide (NO) bioavailability and alterations of gut microbiota. Garlic, a naturally dietary source of H2S donors, supplementation has shown benefits in hypertension. We aimed to examine whether maternal garlic oil supplementation can prevent hypertension programmed by maternal and post-weaning high-fat diet in adult offspring and whether its protective effects are related to mediation of H2S-genetaing system, alterations of gut microbiota composition, and microbiota metabolite short chain fatty acids (SCFAs). Method Pregnant rats received either a normal diet (ND) or HF diet (D12331, Research Diets, Inc.) Garlic oil (GO) or vesicle was administered daily by oral gavage at 100 mg/kg/day during pregnancy and lactation. Male offspring were weaned at 3 weeks of age, and onto either ND or HF diet to 16 weeks of age. Male offspring were assigned to four groups (n=8/group): ND, HF, ND+GO, and HF+GO. Garlic supplementation during pregnancy and lactation protected against programmed hypertension in adult male offspring fed with HF diet. All offspring were killed at 16 weeks of age. NO-related parameters were analyzed by HPLC. Plasma levels of SCFA were determined using GC-MS method. Fecal microbial community was analyzed using a combination of 16S rRNA gene and fecal metagenome sequence analysis. Results Garlic supplementation during pregnancy and lactation protected against programmed hypertension in adult male offspring fed with HF diet. Garlic oil supplementation caused a significant increase in plasma levels of acetate, propionate, and butyrate. NO bioavailability was augmented by garlic oil supplementation, represented by decreases of plasma levels of asymmetric and symmetric dimethylarginine (ADMA and SDMA) levels, and increased plasma L-arginine-to-ADMA ratio (AAR). HF intake associated with decreased α-diversity was quantified by Shannon diversity index. The Analysis of similarities (ANOSIM) demonstrated the difference in the gut microbiota among the four groups existed (All p < 0.05), indicating that four groups had distinct enterotypes. Additionally, garlic oil supplementation increased abundance of genus Lactobacillus, but decreased genera Turicibacter and Staphylococcus. Moreover, the linear discriminant analysis effect size (LEfSe) algorithm analysis identified several microbial markers including genera Lactobacillus, Staphylococcus, and Turicibacter. Conclusion The beneficial effects of garlic oil were associated with increased renal mRNA expression and activity of H2S-generating enzymes, increased NO bioavailability, increased plasma SCFA levels, and alterations of gut microbiota composition. Our data revealed associations between H2S-generating pathway in the gut and kidneys, NO system, gut microbiota, and microbiota-derived metabolites in hypertension programmed by HF intake and provided insight to garlic oil as a hypertension reprogramming strategy for further translational research.

Combination Strategies to Augment Immune Check Point Inhibitors Efficacy - Implications for Translational Research.

Immune checkpoint inhibitor therapy has revolutionized the field of cancer immunotherapy. Even though it has shown a durable response in some solid tumors, several patients do not respond to these agents, irrespective of predictive biomarker (PD-L1, MSI, TMB) status. Multiple preclinical, as well as early-phase clinical studies are ongoing for combining immune checkpoint inhibitors with anti-cancer and/or non-anti-cancer drugs for beneficial therapeutic interactions. In this review, we discuss the mechanistic basis behind the combination of immune checkpoint inhibitors with other drugs currently being studied in early phase clinical studies including conventional chemotherapy drugs, metronomic chemotherapy, thalidomide and its derivatives, epigenetic therapy, targeted therapy, inhibitors of DNA damage repair, other small molecule inhibitors, anti-tumor antibodies hormonal therapy, multiple checkpoint Inhibitors, microbiome therapeutics, oncolytic viruses, radiotherapy, drugs targeting myeloid-derived suppressor cells, drugs targeting Tregs, drugs targeting renin-angiotensin system, drugs targeting the autonomic nervous system, metformin, etc. We also highlight how translational research strategies can help better understand the true therapeutic potential of such combinations.

Translational research in action: The use of technology to disseminate information to parents during the COVID-19 pandemic.

This paper addresses the research problem of how to reach, engage and support parents in home‐educating young children during the first national COVID‐19 lockdown in England (March–June 2020), which was addressed through using technology. An internet‐mediated research (IMR) approach is used to investigate the effectiveness of using technology and translational research as strategies for disseminating a rapidly produced digital guide, for promoting play‐based learning at home, to parents. Lockdown with the closure of early years provision led to parents finding themselves isolated at home with young children. Early years educators were managing a unique set of circumstances where communication with families, including those ‘harder‐to‐reach’ was contextually problematic. Qualitative data using IMR captured online interactions by unobtrusive and obtrusive methods; unsolicited emails and social media comments and questionnaire responses. Conventional content analysis identified emerging themes of access, availability, reliability and readability. Analysis showed a combination of factors impacted on the speed and scale of sharing and downloading the digital guide. First, being digitally ready as platforms were already used by early years educators and Local Authorities. Second, the professional drive of Local Authorities and early years educators to support families during the crisis and third, the availability of an easily accessible online resource seen as valuable in improving play‐based learning at home. Practitioner notesWhat is already known about this topic? There are high levels of digital readiness in the United Kingdom.Technology is one method used by early years settings to communicate with parents.Parental engagement is challenging. What this paper adds? A translational research strategy (to share research‐informed‐knowledge with stakeholders) and internet‐mediated research (to gather data from stakeholders) combine effectively for use within the early years sector to disseminate research knowledge to parents and support home learning environments.The high levels of technology readiness of early years educators and parents in England provides opportunities for disseminating information and improving home learning environments.Accessing and sharing documents online may involve parents but is insufficient to engage. Implications for practice and/or policy Early years settings need to be more proactive in engaging with parents online.Technology provides opportunities to develop interaction and the sharing of information with parents.Digital media should be used as additional communication strategies and should not replace the fundamental importance of face‐to‐face‐interaction.

Maternal Garlic Oil Supplementation Prevents High-Fat Diet-Induced Hypertension in Adult Rat Offspring: Implications of H2S-Generating Pathway in the Gut and Kidneys.

Perinatal high-fat (HF) diet induces hypertension in adult offspring. Garlic, a naturally dietary source of Hydrogen sulfide (H2 S) donor, has been shown benefits in hypertension. The article examines whether maternal garlic oil supplementation can prevent hypertension induced by HF diet and elucidate its protective effects. Pregnant rats are given either a normal diet or HF diet. Rat dams are given garlic oil or vehicle daily by oral gavage at 100mg kg-1 day-1 during pregnancy and lactation. Male offspring are sacrificed at 16 weeks of age. Garlic oil supplementation during pregnancy and lactation protected against hypertension induced by HF diet in adult male offspring. The beneficial effects of garlic oil are associated with increased renal mRNA expression and activity of H2 S-generating enzymes, increased NO bioavailability, increased plasma short chain fatty acid levels, and alterations of gut microbiota composition. Garlic oil supplementation increases abundance of genus Lactobacillus, but decreases genera Turicibacter and Staphylococcus. The data reveals associations between H2 S-generating pathway in the gut and kidneys, NO system, gut microbiota, and microbiota-derived metabolites in hypertension induced by HF intake and provide insight to garlic oil as a hypertension reprogramming strategy for further translational research.

Vitiligo: Translational research and effective therapeutic strategies.

This is an exciting phase of vitiligo research with the current understanding of vitiligo pathogenesis and its translation to successful treatment. The pathogenetic origin of vitiligo revolves around autoimmunity with supporting role from many other factors like oxidative stress, inherent melanocyte defects, or defective keratinocytes and fibroblasts. Vitiligo can be classified into segmental or non-segmental depending upon the clinical presentation, or it can be classified as progressing or stable based on the activity of the disease. Vitiligo treatments need to be stratified depending upon which type of vitiligo we are treating and at which phase the vitiligo patient presents to us. There are two different aims of treatment of vitiligo. The first involves rescuing the melanocytes from the damage to arrest the depigmentation. The second strategy focuses on replenishing the melanocytes so that successful repigmentation is achieved. It is also important to maintain the disease in a stable phase or prevent relapse. As stability in non-segmental vitiligo is a dynamic process, maintenance of the stability of repigmentation is also an important consideration in the management of vitiligo. In this review, we shall briefly discuss the current options and future insight into the management of vitiligo.

From preclinical to clinical models of acute respiratory distress syndrome

Various preclinical models that mimic the clinical causes of acute respiratory distress syndrome (ARDS) have been used to better understand the mechanisms of acute lung injury and its repair and to investigate novel therapies targeting such mechanisms. Despite important preclinical and clinical research efforts in recent decades, few candidate therapies with promising preclinical effects have been successfully translated into the clinical scenario, which could be attributable to the intrinsic limitations of the models as well as to the incorrect identification of appropriate phenotypes of patients to target with novel therapies that have proven beneficial in select preclinical models. However, current translational research strategies based on the use of multiple complementary preclinical and clinical models hold the promise of revolutionizing intensive care by using granular knowledge that should allow for a better diagnosis, greater predictability of the disease course, and the development of targeted therapies while ensuring patient safety through reduced adverse effects. Our goal was to summarize the strengths and limitations of the available models of ARDS, including animal, in vitro, and clinical models, and to discuss the current challenges and perspectives for research.

Granulocyte-Colony Stimulating Factor Reduces Cocaine-Seeking and Downregulates Glutamatergic Synaptic Proteins in Medial Prefrontal Cortex.

Psychostimulant use disorder is a major public health issue, and despite the scope of the problem there are currently no Food and Drug Administration (FDA)-approved treatments. There would be tremendous utility in development of a treatment that could help patients both achieve and maintain abstinence. Previous work from our group has identified granulocyte-colony stimulating factor (G-CSF) as a neuroactive cytokine that alters behavioral response to cocaine, increases synaptic dopamine release, and enhances cognitive flexibility. Here, we investigate the role of G-CSF in affecting extinction and reinstatement of cocaine-seeking and perform detailed characterization of its proteomic effects in multiple limbic substructures. Male Sprague Dawley rats were injected with PBS or G-CSF during (1) extinction or (2) abstinence from cocaine self-administration, and drug seeking behavior was measured. Quantitative assessment of changes in the proteomic landscape in the nucleus accumbens (NAc) and medial prefrontal cortex (mPFC) were performed via data-independent acquisition (DIA) mass spectrometry analysis. Administration of G-CSF during extinction accelerated the rate of extinction, and administration during abstinence attenuated cue-induced cocaine-seeking. Analysis of global protein expression demonstrated that G-CSF regulated proteins primarily in mPFC that are critical to glutamate signaling and synapse maintenance. Taken together, these findings support G-CSF as a viable translational research target with the potential to reduce drug craving or seeking behaviors. Importantly, recombinant G-CSF exists as an FDA-approved medication which may facilitate rapid clinical translation. Additionally, using cutting-edge multiregion discovery proteomics analyses, these studies identify a novel mechanism underlying G-CSF effects on behavioral plasticity.SIGNIFICANCE STATEMENT Pharmacological treatments for psychostimulant use disorder are desperately needed, especially given the disease's chronic, relapsing nature. However, there are currently no Food and Drug Administration (FDA)-approved pharmacotherapies. Emerging evidence suggests that targeting the immune system may be a viable translational research strategy; preclinical studies have found that the neuroactive cytokine granulocyte-colony stimulating factor (G-CSF) alters cocaine reward and reinforcement and can enhance cognitive flexibility. Given this basis of evidence we studied the effects of G-CSF treatment on extinction and reinstatement of cocaine seeking. We find that administration of G-CSF accelerates extinction and reduces cue-induced drug seeking after cocaine self-administration. In addition, G-CSF leads to downregulation of synaptic glutamatergic proteins in medial prefrontal cortex (mPFC), suggesting that G-CSF influences drug seeking via glutamatergic mechanisms.