Preclinical Settings Research Articles

Platysma Myocutaneous Flap for Skull Base Reconstruction: A Cadaveric Feasibility Study.

Objective: As skull base defects become increasingly complex, necessitating more extensive repairs, alternative strategies are needed to address challenging reconstructions and rescue cases of failed primary reconstruction. In this study, we aimed to validate the surgical technique and assess the feasibility of using the platysma myocutaneous flap for skull base reconstruction, using cadaveric specimens in a preclinical setting. Materials and Methods: This descriptive anatomical study was conducted on 2 fresh human cadavers (4 sides). The study assessed the flap's size, range of rotation, suitability for covering the skull base, and the corridor technique for transferring the flap to the skull base. Results: The technique was applied to 2 cadavers, with 4 flaps raised. The average flap length was approximately 15 cm, providing adequate coverage of the ipsilateral carotid artery and anterior skull base, extending from the planum sphenoidale to the cribriform plate and frontal recess. Conclusion: Harvesting a platysma myocutaneous flap is a feasible option for skull base reconstruction, providing adequate coverage for the ipsilateral carotid artery and anterior skull base.

Impact of polycaprolactone, alginate, chitosan and zein nanofiber physical properties on immune cells for safe biomedical applications.

Nanofiber safety, especially immunogenicity, is important for their successful translation to clinical setting. This study provides a comprehensive evaluation of how nanofiber physical properties influence immune cells cultured on them, specifically peripheral blood mononuclear cells (PBMCs). We prepared nanofibers with a wide range of physical properties including various diameters, interfibrillar pore sizes and mat thicknesses, using four main polymers: polycaprolactone, alginate, chitosan, and zein. Our findings show that nanofiber diameters had only a marginal influence on the activity of immune cells, whereas interfibrillar nanofiber pore sizes had a significant effect, and mat thickness proved to have the greatest impact. Cells that penetrated deeper into the thick nanofiber mats ceased to proliferate but did not experience cytotoxicity. Moreover, we discovered that PBMCs penetrating the zein/PVP nanofiber mesh exhibited increased metabolic activity, indicating potential immunogenicity, whereas the other tested non-immunogenic nanofibers reduced it. To best of our knowledge, this study is the first to report on the impact of various nanofiber physical properties on in vitro immune cell behavior, thereby expanding the knowledge in the relatively unexplored field of nanofiber immunological safety. It underscores the need for rigorous preclinical nanofiber assessment and setting new standards for designing nanofiber-based biomedical products.

Polymeric Vehicles for Nucleic Acid Delivery: Enhancing the Therapeutic Efficacy and Cellular Uptake.

Therapeutic gene delivery may be facilitated by the use of polymeric carriers. When combined with nucleic acids to form nanoparticles or polyplexes, a variety of polymers may shield the cargo from in vivo breakdown and clearance while also making it easier for it to enter intracellular compartments. Polymer synthesis design choices result in a wide variety of compounds and vehicle compositions. Depending on the application, these characteristics may be changed to provide enhanced endosomal escape, longer-lasting distribution, or stronger connection with nucleic acid cargo and cells. Here, we outline current methods for delivering genes in preclinical and clinical settings using polymers. Significant therapeutic outcomes have previously been attained using genetic material- delivering polymer vehicles in both in-vitro and animal models. When combined with nucleic acids to form nanoparticles or polyplexes, a variety of polymers may shield the cargo from in vivo breakdown and clearance while also making it easier for it to enter intracellular compartments. Many innovative diagnoses for nucleic acids have been investigated and put through clinical assessment in the past 20 years. Polymer-based carriers have additional delivery issues due to their changes in method and place of biological action, as well as variances in biophysical characteristics. We cover recent custom polymeric carrier architectures that were tuned for nucleic acid payloads such genomemodifying nucleic acids, siRNA, microRNA, and plasmid DNA. In conclusion, the development of polymeric carriers for gene delivery holds promise for therapeutic applications. Through careful design and optimization, these carriers can overcome various challenges associated with nucleic acid delivery, offering new avenues for treating a wide range of diseases.

The toxicological role of Myricetin in the progression of human anaplastic thyroid cancer SW1736 cell line

Aims and backgroundAnaplastic thyroid cancer cells lack the capacity to effectively accumulate iodine and are therefore unresponsive to treatment with radioactive iodine. The main objective of this study was to examine the possible therapeutic effects of Myricetin on the SW1736 ATC cell line. In this study, we assessed the influence of Myricetin on iodide absorption, sodium iodide symporter gene expression, and apoptosis induction. Material methodsThe interaction between the 7UUY protein of NIS and Myricetin was investigated using AutoDock Vina. Assessment of cell viability was conducted with the MTT assay, whereas cell apoptosis was evaluated by flow cytometry using the Annexin V-FITC Apoptosis Detection kit. A spectrophotometric test based on the Sandell-Kolthoff reaction was conducted to assess the absorption of iodide by SW1736 cells. QRT-PCR analyses were used to assess the expression levels of NIS mRNA in SW1736 cells. ResultsThe hydrogen bond interaction pattern created by PyMOL revealed the interactions between the target and ligand molecules. The results demonstrated that Myricetin-induced cell death is dependent on apoptosis in this type of thyroid cancer cell line. QRT-PCR analyses revealed significantly higher NIS mRNA (P < 0.001) levels in the Myricetin-treated group than in the non-treated group. Furthermore, Myricetin treatment significantly increased iodide uptake (P value = 0.0053) in the SW1736 thyroid cancer cell line compared to the control group. ConclusionThese findings suggest that Myricetin has potential as a therapeutic agent by promoting growth inhibition, enhancing NIS gene expression, and increasing iodide uptake in SW1736 cells. Additional research is necessary to clarify the fundamental mechanisms and to evaluate the efficacy of Myricetin in preclinical and clinical settings.

Discovery of Pyrazolo[1,5,4-de]quinoxalin-2(3H)-one Derivatives as Highly Potent and Selective PARP1 Inhibitors.

Poly-ADP-ribose-polymerase 1/2 (PARP1/2) inhibitors have been approved for cancers with homologous recombination deficiency (HRD). However, their narrow therapeutic indexes largely due to hematologic toxicities have limited their clinical usefulness. Developing selective PARP1 inhibitors has emerged as an attractive strategy to achieve equivalent antitumor activity while alleviating the hematological toxicity caused by PARP2 inhibition. Herein, we report the discovery of pyrazolo[1,5,4-de]quinoxalin-2(3H)-one 30 as a novel selective PARP1 inhibitor. 30 formed tighter PARP1-DNA trapping than AZD9574, leading to better potency in inhibiting cancer cell proliferation. 30 achieved tumor regression in the BRCA1-mutated MDA-MB-436 xenograft model and showed synergistic efficacy in combination with carboplatin in the SUM149PT xenograft model. In the rat hematological toxicity study, 30 exhibited minimal impact on hematological parameters at 25 mg/kg, while AZD5305 at 1 mg/kg caused 56.5% reduction of reticulocyte. Taken together, we discovered compound 30 with a therapeutic index superior to that of PARP1 inhibitors AZD5305 and AZD9574 in the preclinical setting.

Precision Medicine for Metastatic Colorectal Cancer: Where Do We Stand?

Metastatic colorectal cancer is a leading cause of cancer-related death across the world. The treatment paradigm has shifted away from systemic chemotherapy alone to include targeted therapy and immunotherapy. The past two decades have been characterized by increased investigation into molecular profiling of colorectal cancer. These molecular profiles help physicians to better understand colorectal cancer biology among patients with metastatic disease. Additionally, improved data on genetic pathways allow for specific therapies to be targeted at the underlying molecular profile. Investigation of the EGFR, VEGF, HER2, and other pathways, as well as deficient mismatch repair, has led to the development of multiple targeted therapies that are now utilized in the National Comprehensive Cancer Network guidelines for colon and rectal cancer. While these new therapies have contributed to improved survival for metastatic colorectal cancer, long-term survival remains poor. Additional investigation to understand resistance to targeted therapy and development of new targeted therapy is necessary. New therapies are under development and are being tested in the preclinical and clinical settings. The aim of this review is to provide a comprehensive evaluation of molecular profiling, currently available therapies, and ongoing obstacles in the field of colorectal cancer.

The golden approach to trauma. Which blood products are needed for optimization of prehospital trauma care?

The golden hour of trauma denotes the critical first hour after severe injury where timely medical response is crucial, although scientific support for this time frame is inconsistent. This study emphasizes optimizing trauma care by tailoring treatment to the specific injury rather than focusing solely on the speed of treatment. The aim is to document the need for improvement in prehospital trauma care, particularly by the use of blood and coagulation products. After apilot study, apurpose-designed online questionnaire targeted at German physicians and rescue service personnel was utilized to collect their views on general trauma care and specifically on the use of blood and coagulation products in prehospital settings. It also assessed the appropriateness of nine specific blood and coagulation products via a5-point Likert scale. The percentages for each item were calculated for both physicians (n = 110) and rescue service personnel (n = 142) separately as well as an overall score to delineate patterns of agreement or disagreement. The study reached 9837 individuals, whereby 371 initially answered the questionnaire and 252 participants from Germany were finally included in the statistical analysis. The majority of both physicians (89.1%) and rescue service personnel (90.8%) agreed on the need to improve prehospital trauma care, particularly through the use of blood and coagulation products. Specifically, 60.9% of physicians and 83.8% of rescue personnel supported the prehospital administration of these products. Red blood cell concentrates and fibrinogen were notably endorsed, with 76.2% and 67.1% approval, respectively, for their potential to enhance survival in patients with significant blood loss; however, opinions varied on other blood products. The data demonstrated areadiness to change the trauma approach and confirmed that effective options are available. The utilization of certain products is supported by existing research, underlining the need for their practical implementation in preclinical settings. Here, the emphasis shifts from the isolated time components to the quality of care delivered in an optimized time interval. Ideally, timely and high-quality care should complement each other, leveraging all available therapeutic resources. This could lead to the development of agolden approach to trauma to optimize outcomes in trauma care.

Evaluation of Preclinical Class I Amalgam Cavity Preparation: A Comparison of Two Assessment Methods

Preclinical assessment forms an effective strategy in undergraduate training. It enhances the continuous development of skills, facilitates early intervention, and optimizes training resources. Constructive feedback provided to the student fosters continuous improvement in preparedness for professional practice and has implications for the development of a learning culture characterized by student activity. This indeed ensures that a smooth transition will be made toward clinical application of skills. The aim of the study was to evaluate examiner`s reliabilities while applying two different assessment methods: a Glance and Grade assessment method and a Checklist and Criteria assessment method. A total of 100 class I amalgam cavity preparations were assessed by three independent examiners to evaluate Class I amalgam cavity preparations on artificial first mandibular molar teeth prepared by second-year undergraduate dental students in a preclinical laboratory setting. Statistical analysis for inter-examiner and intra-examiner variability was tested using one-way ANOVA test and a paired t-test, respectively. Results of this study showed that intra-examiner variability was significantly reduced with Checklist and Criteria assessment method. The inter-examiner variability was present in a Glance and Grade assessment method while with the Checklist and Criteria assessment method, there was an extremely high level of agreement among the examiners. The study's findings indicated considerable variability among examiners using the Glance and Grade assessment method. However, the Checklist and Criteria assessment method demonstrated remarkable consistency among examiners, indicating that it may offer a more standardized and reliable approach to evaluation.

Prognostic bone fracture healing simulations in an ovine tibia model validated with in vivo sensors.

Bone fracture healing is a complex physiological process influenced by biomechanical and biomolecular factors. Mechanical stability is crucial for successful healing, and disruptions can lead to delayed healing or nonunion. Bone commonly heals itself through secondary fracture healing, which is governed by the mechanical strain at the fracture site. To investigate these phenomena, a validated methodology for capturing the mechanoregulatory process in specimen-specific models of fracture healing could provide insight into the healing process. This study implemented a prognostic healing simulation framework to predict healing trajectories based on mechanical stimuli. Sixteen sheep were subjected to a 3 mm transverse tibial mid-shaft osteotomy, stabilized with a custom plate, and equipped with displacement transducer sensors to measure interfragmentary motion over 8 weeks. Computed tomography scans were used to create specimen-specific bone geometries for finite element analysis. Virtual mechanical testing was performed iteratively to calculate strains in the callus region, which guided tissue differentiation and consequently, healing. The predicted healing outcomes were compared to continuous in vivo sensor data, providing a unique validation data set. Healing times derived from the in vivo sensor and in silico sensor showed no significant differences, suggesting the potential for these predictive models to inform clinical assessments and improve nonunion risk evaluations. This study represents a crucial step towards establishing trustworthy computational models of bone healing and translating these to the preclinical and clinical setting, enhancing our understanding of fracture healing mechanisms. Clinical significance: Prognostic bone fracture healing simulation could assist in non-union diagnosis and prediction.

Multi-organ kinetic modeling for Na[18F]F pre-clinical total-body PET studies.

Total-body positron emission tomography (PET), already well-established in the pre-clinical setting, makes it possible to study multi-parameters in biological systems as a whole, rather than focusing on single tissues analysis. Simultaneous kinetic analysis of multiple organs poses some daunting new challenges. To explore quantifying the pharmacokinetics of Na[18F]F in multiple dissimilar murine organs simultaneously in vivo with total-body PET imaging using different compartmental models for each organ and a shared cardiovascular system. Six mice underwent a 60-min total-body PET scan following intravenous bolus injection of Na[18F]F. Compartmental models were constructed for each organ (heart, lungs, liver, kidneys, and bone) using an image derived input function. Non-linear least squares fitting of a model that connects the five organs to a shared cardiovascular system was used to analyze both the first 3 min of data and the full hour. Analysis was repeated 5000 times using different initial parameter values for each duration, permitting analysis of correlations between parameters. The models give a good qualitative account of the activity curves irrespective of the duration of the data; however, the quality of the fits to 3 min of data (average is 2.72) was generally better. Comparison of perfusion values to literature values was possible for the liver and lungs with the former (liver, 0.540±0.177mL/ml/min) being well-above expectations and the latter (lungs, 0.184±0.413mL/ml/min) in rough agreement. Correlations between microparameter values (especially affecting k2) caused very noticeable problems for data modeling from both the kidneys and the femur. The present study demonstrates an approach to performing kinetic modeling for multiple organs simultaneously with Na[18F]F. The observed correlations between microparameter values remain a challenge. Nonetheless, many microparameters can be estimated reliably with a quantitative analysis of perfusion being possible for some organs.

Preclinical evaluation of the CD38-targeting engineered toxin body MT-0169 against multiple myeloma.

Despite significant progress in the treatment of multiple myeloma (MM), relapsed/refractory patients urgently require more effective therapies. We here describe the discovery, mechanism of action, and preclinical anti-MM activity of engineered toxin body MT-0169, a next-generation immunotoxin comprising a CD38-specific antibody fragment linked to a de-immunized Shiga-like toxin A subunit (SLTA) payload. We show that specific binding of MT-0169 to CD38 on MM cell lines triggers rapid internalization of SLTA, causing cell death via irreversible ribosome inhibition, protein synthesis blockade, and caspase 3/7 activation. In co-culture experiments, bone marrow mesenchymal stromal cells did not induce drug resistance against MT-0169. In the preclinical setting, MT-0169 effectively lysed primary MM cells from newly diagnosed and heavily pretreated MM patients, including those refractory to daratumumab, with minimal toxicity against nonmalignant hematopoietic cells. MM cell lysis showed a significant correlation with their CD38 expression levels but not with cytogenetic risk, tumor load, or number of prior lines of therapy. Finally, MT-0169 showed efficient in vivo anti-MM activity in various mouse xenograft models, including one in which MM cells are grown in a humanized bone marrow-like niche. These findings support clinical investigation of MT-0169 in relapsed/refractory MM patients, including those refractory to CD38-targeting immunotherapies.

Antisense oligonucleotides as a precision therapy for developmental and epileptic encephalopathies.

Developmental and epileptic encephalopathies (DEEs) comprise a complex spectrum of neurological disorders characterized by neurodevelopmental delay and early-onset seizures primarily caused by diverse genetic mutations. Traditional treatments have largely been symptomatic, focusing on seizure control without addressing the underlying genetic causes. The advent of gene therapy, particularly through antisense oligonucleotides (ASOs), offers a promising avenue toward targeted therapeutic interventions. ASOs by virtue of their ability to modulate gene expression at the mRNA level represent a sophisticated approach to counteract the effects of pathogenic mutations. This review delves into the recent advancements in ASO technology, highlighting its application in preclinical and clinical settings for DEEs. We present evidence of the efficacy of ASOs in ameliorating disease phenotypes invitro and invivo, alongside promising outcomes from ongoing clinical trials. The therapeutic landscape for DEEs is on the cusp of significant transformation, underscored by the potential of ASOs to offer precise, personalized, treatments that extend beyond symptomatic relief to potentially rectify the genetic underpinnings of these disorders.

Advancing CRISPR-Based Solutions for COVID-19 Diagnosis and Therapeutics.

Since the onset of the COVID-19 pandemic, a variety of diagnostic approaches, including RT-qPCR, RAPID, and LFA, have been adopted, with RT-qPCR emerging as the gold standard. However, a significant challenge in COVID-19 diagnostics is the wide range of symptoms presented by patients, necessitating early and accurate diagnosis for effective management. Although RT-qPCR is a precise molecular technique, it is not immune to false-negative results. In contrast, CRISPR-based detection methods for SARS-CoV-2 offer several advantages: they are cost-effective, time-efficient, highly sensitive, and specific, and they do not require sophisticated instruments. These methods also show promise for scalability, enabling diagnostic tests. CRISPR technology can be customized to target any genomic region of interest, making it a versatile tool with applications beyond diagnostics, including therapeutic development. The CRISPR/Cas systems provide precise gene targeting with immense potential for creating next-generation diagnostics and therapeutics. One of the key advantages of CRISPR/Cas-based therapeutics is the ability to perform multiplexing, where different sgRNAs or crRNAs can target multiple sites within the same gene, reducing the likelihood of viral escape mutants. Among the various CRISPR systems, CRISPR/Cas13 and CARVER (Cas13-assisted restriction of viral expression and readout) are particularly promising. These systems can target a broad range of single-stranded RNA viruses, making them suitable for the diagnosis and treatment of various viral diseases, including SARS-CoV-2. However, the efficacy and safety of CRISPR-based therapeutics must be thoroughly evaluated in pre-clinical and clinical settings. While CRISPR biotechnologies have not yet been fully harnessed to control the current COVID-19 pandemic, there is an optimism that the limitations of the CRISPR/Cas system can be overcome soon. This review discusses how CRISPR-based strategies can revolutionize disease diagnosis and therapeutic development, better preparing us for future viral threats.

Donor-Specific Blood Transfusion in Lung Transplantation.

Lung transplantation is still hindered by a high rate of chronic rejection necessitating profound immunosuppression with its associated complications. Donor-specific blood transfusion is a pre-transplant strategy aimed at improving graft acceptance. In contrast with standard stored blood or donor-specific regulatory T cells transfusions, this approach utilizes fresh whole blood from the donor prior to allograft transplantation, encompassing all cell types and plasma. The precise mechanisms underlying donor-specific blood transfusion-induced tolerance remain incompletely understood. Associations with regulatory/helper T cells, modulation of mononuclear phagocytic cells or microchimerism have been suggested. While numerous (pre-)clinical studies have explored its application in solid organ transplants like liver, kidney, and intestine, limited attention has been given to the setting of lung transplantation. This comprehensive review summarizes existing knowledge on the mechanisms and outcomes of donor-specific blood transfusion in solid organ transplants both in preclinical and clinical settings. We also address the potential benefits and risks associated with donor-specific blood transfusion in the field of lung transplantation, offering insights into future research directions.

Advances in cell therapy research

Cell therapy represents an important area of biotechnology, with the potential to treat and even cure a variety of diseases that cannot be cured by traditional therapies. Cell therapy is currently a widely studied treatment in both preclinical and clinical settings, and many cell therapy products are undergoing clinical trials. This article reviews the application of cell therapy in a variety of diseases and the policy of stem cell therapy in China.

Toxicity and Dermatokinetic Analysis of Ibrutinib in Human Skin Models.

Background/Objectives: Ibrutinib (IBR) is a tyrosine kinase inhibitor under investigation in preclinical and clinical settings as an alternative treatment for melanoma. Nevertheless, the limited oral bioavailability of IBR and the need for high doses of the drug to kill melanoma cells are major drawbacks for this purpose. Considering that melanoma is restricted to the skin at early stages, the topical application of IBR might constitute an effective and safer administration route. In this study, we determined IBR's toxicity and dermatokinetics using human primary cells and human organotypic skin explant cultures (hOSECs). Methods: After demonstrating that human primary fibroblasts and keratinocytes present IBR target genes, the cytotoxicity of the drug was determined using the MTT and annexin V/PI staining assays. IBR toxicity in the skin was assessed using the TTC assay, and the irritation potential was established using histological assessment. Finally, IBR cutaneous permeation was assessed ex vivo to determine the drug dermatokinetics. Results: Our findings reveal that IBR exerts dose-dependent toxicity towards skin cells, presenting an IC50 in the same range as melanoma cells. The topical application of the drug successfully reduced irritation and toxicity in the skin, and the drug was shown to successfully permeate the stratum corneum and reach the viable skin layers in therapeutic concentrations. Conclusions: Overall, our data encourage the topical application of IBR to treat melanoma, paving the way for future studies in this theme.

Methodological aspects of correlative, multimodal, multiparametric breast cancer imaging: from data acquisition to image processing for AI-based radioproteomics in a preclinical setting

Preclinical high-field magnetic resonance imaging (MRI) systems offer a diverse array of MRI techniques, providing rich multiparametric MRI (mpMRI) platforms for studying numerous biological parameters. mpMRI platforms prove particularly indispensable when investigating tumors that exhibit profound intratumoral heterogeneity, such as breast cancer. A thoughtful comprehension of the origins of intratumoral heterogeneity is imperative for the judicious assessment of new targeted therapies and treatment interventions. Furthermore, when data from mpMRI are complemented with data from other in vivo imaging modalities, such as positron emission tomography (PET), and correlated with data from ex vivo modalities, such as matrix-assisted laser desorption imaging mass spectrometry (MALDI IMS), the in vivo parameters can be further elucidated at a molecular level and microscopic scale. Nevertheless, extracting meaningful scientific insights from such complex datasets necessitates the utilization of machine learning (ML) approaches to discern region-specific radiomic features. The development of correlative, multimodal imaging (CMI) workflows, such as one incorporating MRI, PET and MALDI IMS, is inherently challenging, given the many technological and methodological challenges related to multimodal data acquisition as well as the physiological limitations of the laboratory mice of the investigation. Standardization efforts in image acquisition and processing are required to increase the reproducibility and translatability of CMI data. To address the challenges of developing standardized CMI workflows and stimulate dialog regarding this area of need, we present a practical workflow to investigate tumor heterogeneity in breast cancer xenografts across various spatial scales. Our workflow entails simultaneous functional MRI and PET acquisitions in living mice, followed by correlation with post-imaging MALDI IMS and histologic data. Additionally, we propose data preprocessing steps for potential ML applications. We illustrate the feasibility of this workflow through two examples, showcasing its effectiveness in comparing in vivo and ex vivo images to evaluate tumor metabolism and hypoxia in mice with breast cancer xenografts.

A review on achromatopsia: Exploring genetic basis, diagnostic innovations, and therapeutic prospects

Achromatopsia (ACHM) is a rare inherited retinal disorder characterized by partial or complete color blindness, which impacts individuals' quality of life and daily functioning. This review delves into the genetic basis, diagnostic innovations, and therapeutic prospects associated with ACHM. The main objective is to comprehensively explore the current understanding of ACHM, including genetic mutations, diagnostic techniques, and management approaches, while also discussing potential therapeutic interventions. Achromatopsia primarily results from mutations in genes encoding cone photoreceptor proteins, such as GNAT2, ATF6, PDE6H, PDE6C, CNGA3, and CNGB3. Various diagnostic methods, including electroretinography (ERG) and optical coherence tomography (OCT), are pivotal in confirming ACHM diagnosis by assessing cone function and structural abnormalities in dysfunctional cone cells. This review also highlights gene therapy interventions aimed at restoring cone function, highlighting promising advancements in preclinical and clinical settings. Additionally, it discusses the clinical features of ACHM, such as reduced visual acuity, photophobia, and color vision impairment, emphasizing the need for tailored management strategies to increase patients' quality of life. This review underscores the complex genetic landscape of ACHM and the importance of accurate diagnosis through advanced diagnostic modalities such as ERG and OCT. While there is currently no cure for ACHM, management approaches focus on symptom alleviation and improving patients' daily functioning. Gene therapy has emerged as a promising avenue for potential treatment, with ongoing research aiming to address the underlying genetic defects and restore cone photoreceptor function. The findings of this review hold clinical relevance by providing insights into the pathogenesis, diagnosis, and management of ACHM, guiding healthcare professionals in delivering personalized care to affected individuals. Continued research and advancements in gene therapy offer hope for future therapeutic interventions, highlighting the importance of updating the latest developments in the field of ACHM.

Glutamate concentration of medial prefrontal cortex is inversely associated with addictive behaviors: a translational study

In both preclinical and clinical settings, dysregulated frontostriatal circuits have been identified as the underlying neural substrates of compulsive seeking/taking behaviors manifested in substance use disorders and behavioral addictions including internet gaming disorder (IGD). However, the neurochemical substrates for these disorders remain elusive. The lack of comprehensive cognitive assessments in animal models has hampered our understanding of neural plasticity in addiction from these models. In this study, combining data from a rat model of compulsive taking/seeking and human participants with various levels of IGD severity, we investigated the relationship between regional glutamate (Glu) concentration and addictive behaviors. We found that Glu levels were significantly lower in the prelimbic cortex (PrL) of rats after 20-days of methamphetamine self-administration (SA), compared to controls. Glu concentration after a punishment phase negatively correlated with acute drug-seeking behavior. In addition, changes in Glu levels from a drug naïve state to compulsive drug taking patterns negatively correlated with drug-seeking during both acute and prolonged abstinence. The human data revealed a significant negative correlation between Glu concentration in the dorsal anterior cingulate cortex (dACC), the human PrL counterpart, and symptoms of IGD. Interestingly, there was a positive correlation between Glu levels in the dACC and self-control, as well as mindful awareness. Further analysis revealed that the dACC Glu concentration mediated the relationship between self-control/mindful awareness and IGD symptoms. These results provide convergent evidence for a protective role of dACC/PrL in addiction, suggesting interventions to enhance dACC glutamatergic functions as a potential strategy for addiction prevention and treatment.

Clinical usability and efficacy of a robotic bone fracture reduction system: A pilot animal study

Challenges in minimally invasive surgeries, such as intramedullary nailing for long bone fractures, include radiation overexposure for patients and surgeons, potential malreduction, and physical burden on surgeons in maintaining the reduction status. A robotic bone fracture reduction system was developed in this study to address these problems. The system consists of a hexapod with six degrees of freedom, with a fracture reduction device and a master device. This study aimed to evaluate the novel system in a preclinical setting. The length of the six axes in the system can be adjusted to precisely control the length, angle, and rotation so that no additional traction is required. Fluoroscopic images can be remotely examined to reduce the risk of radiation exposure for surgeons. In this study, alignment accuracy and radiation exposure were measured using 32 bovine bone fracture models, and these surgical outcomes were compared to those of conventional manual surgery to verify the clinical usability and effectiveness of the system. The alignment accuracy was assessed by analyzing length, angulation, and rotation. The four surgeons participating in this study were divided into two groups (expert and novice) according to their clinical experience. All parameters in robotic surgery significantly decreased by approximately 4 mm and 8° on average (p ≤ 0.05) compared to conventional surgery. The mean radiation exposure in robot-assisted surgery was 0.11 mSv, showing a significant decrease compared to conventional surgery (p < 0.05). Reduction accuracy was higher in robotic surgery performed by the novice group than in conventional surgery performed by the expert group; however, standard deviation values were inversed. In conclusion, the bone fracture reduction robot system increased the alignment accuracy through precise control while reducing radiation exposure in surgeons, as the surgery was performed remotely. The use of this system is predicted to improve the accuracy and reproducibility of the surgery and the safety of medical staff.11Abbreviations: CT, computed tomography; FRD, fracture reduction device; FRMD, fracture reduction master device; SD, standard deviation