Drug Transport Research Articles

Ternary nanofluids due to moving wedge with strong magnetic field and convective condition

The control of temperature distribution and management of heat energy are key problems in an industry. In this study, free convective flow with ternary nanoparticles (Cu, Ag, MgO) was equipped to analyze the impact on magnetic field and thermal radiation through a moving wedge surface. This volumetric concentration by Cu, Ag and MgO nanoparticles is selected by the most 4% to prevent the instability on the nanofluid. A set of applicable modifications was expressed as a change in the nonlinear partial differential equations and the nonlinear ordinary differential equations and it was undertaken mathematically for applying bvp4c on MATLAB package. These outcomes on ternary nanoparticles (Cu–Ag–MgO/blood), and hybrid nanoparticles (Cu–Ag/blood) and copper (Cu) nanoparticles had again correlated. The outcomes display that connecting Cu, Ag and MgO nanofluid raises the drug friction to 3.9% than the hybrid nanofluid. Also, the combination of Cu and Ag nanofluid increases skin friction by 19.58% than Cu nanofluid. This analysis was particularly useful in drug transportation and biomedical study.

Potentiation of Brain Bioavailability Using Thermoreversible Cubosomal Formulation.

The aim of the present study was to develop and evaluate intranasal formulations of the thermoreversible fluoxetine cubosomal in situ gel. This gel was intended for permeation and bioavailability enhancement to target the brain effectively by bypassing the blood-brain barrier (BBB). Fluoxetine-loaded cubosomes were prepared by the homogenization method followed by the cold method approach to develop in situ gel. Fluoxetine-loaded cubosomes displayed a higher encapsulation efficiency (82.60 ± 1.25%) than fluoxetine. This might be due to the solubilizing activity of the polymer to cause partitioning of the lipophilic drug into the aqueous phase during the change from the cubic gel phase to cubosomes. In vitro analysis of fluoxetine-loaded cubosomal in situ gel showed a sustained release profile (93.22 ± 2.47%) due to limited diffusion of fluoxetine. The formation of strong affinity bonds of the drug with GMO (drug transporter) decreased the drug release in comparison to that with fluoxetine-loaded cubosomes (90.68 ± 1.74%). The ex vivo drug release profile revealed the drug release of 96.31 ± 2.88% by the end of 24 h. This is attributed to the higher capability of the intranasal cubosomal in situ gel to prolong the retention and enable better permeation through the nasal mucosa. In male Wistar rats, in vivo biodistribution studies for cubosomal in situ gel administered via the intranasal route at a dose of 3.5 mg/kg demonstrated an increase in pharmacokinetic parameters like the AUC (406 ± 75.35 μg/mL), Cmax (368.07 ± 0.23 μg/mL), Tmax (4 h), and t1/2 (14.06 h). The mucoadhesive nature of the in situ gel led to an increase in the residence time of the gel in the nasal mucosa. The biodistribution study of intranasal in situ cubosomal gel improved the bioavailability 2.21-fold in comparison to that with the cubosomal dispersion but 2.83-fold in comparison to that with the drug solution. Therefore, fluoxetine-loaded cubosomal in situ gel proved as a promising carrier for effective transportation of fluoxetine via the intranasal route with significant brain bioavailability.

Nanomedicine: A New Frontier in Alzheimer's Disease Drug Targeting.

Alzheimer's disease (AD) is a prevalent neurodegenerative disorder affecting elderly individuals, characterized by progressive cognitive decline leading to dementia. This review examines the challenges posed by anatomical and biochemical barriers such as the blood-brain barrier (BBB), blood-cerebrospinal fluid barrier (BCSFB), and p-glycoproteins in delivering effective therapeutic agents to the central nervous system (CNS) for AD treatment. This article outlines the fundamental role of acetylcholinesterase inhibitors (AChEIs) and NMDA(N-Methyl-D-Aspartate) receptor antagonists in conventional AD therapy and highlights their limitations in terms of brain-specific delivery. It delves into the intricacies of BBB and pglycoprotein-mediated efflux mechanisms that impede drug transport to the CNS. The review further discusses cutting-edge nanomedicine-based strategies, detailing their composition and mechanisms that enable effective bypassing of BBB and enhancing drug accumulation in brain tissues. Conventional therapies, namely AChEIs and NMDA receptor antagonists, have shown limited efficacy and are hindered by suboptimal brain penetration. The advent of nanotechnology-driven therapeutic delivery systems offers promising strategies to enhance CNS targeting and bioavailability, thereby addressing the shortcomings of conventional treatments. Various nanomedicines, encompassing polymeric and metallic nanoparticles (MNPs), solid lipid nanoparticles (SLNs), liposomes, micelles, dendrimers, nanoemulsions, and carbon nanotubes, have been investigated for their potential in delivering anti-AD agents like AChEIs, polyphenols, curcumin, and resveratrol. These nanocarriers exhibit the ability to traverse the BBB and deliver therapeutic payloads to the brain, thereby holding immense potential for effective AD treatment and early diagnostic approaches. Notably, nanocarriers loaded with AChEIs have shown promising results in preclinical studies, exhibiting improved therapeutic efficacy and sustained release profiles. This review underscores the urgency of innovative drug delivery approaches to overcome barriers in AD therapy. Nanomedicine-based solutions offer a promising avenue for achieving effective CNS targeting, enabling enhanced bioavailability and sustained therapeutic effects. As ongoing research continues to elucidate the complexities of CNS drug delivery, these advancements hold great potential for revolutionizing AD treatment and diagnosis.

New Insights on Biosynthesis of Nanoparticles Using Plants Emphasizing the Use of Alfalfa (Medicago sativa L.)

Biological synthesis of nanoparticles (NPs) using alfalfa (Medicago sativa L.) and other plants has several advantages such as lower costs, reduction of pollution, and improvement of the environment and human health. Often, biosynthesis is used to synthesize Ag, Au, and ZnO NPs. Less often are also synthesized Cu and Fe NPs. Synthesis with plant extracts from their parts or callus cultures is a widely used method since extracts contain the most significant number of biomolecules. Synthesis with living plants (in vivo) provides NPs with improved properties for better interactions with plants but is used less often due to the long realization time, the need to control the plants’ growing conditions, and difficulty in controlling the size and shape of the synthesized NPs. Here, we performed a systematic review of various methods for the biological synthesis of different metal NPs with different plants, to highlight advantages and disadvantages of mentioned methods. For discussion, results showed that biosynthesis of NPs allows obtaining NPs with reduced toxicity, and their size and shape depend on the type and number of biomolecules present in plants. Plant biomolecules determine the antibacterial and anticancer properties of NPs, as well as increasing the use of NPs in biomedicine, for better drug transport, therefore medicinal plants or sea plants are mostly used for biosynthesis. NPs which were synthesized in marine plants could be a very effective agent against water bacteria; therefore, if NP biosynthesis takes place in water, biological water purification is possible. Limitations of the study included a great methodological diversity of the synthesis, it is still difficult to systematize the synthesis methods, and it seems that each described study uses a different synthesis protocol; therefore, in future studies, it is necessary to clarify which method can provide the most efficient biosynthesis and develop a unified approach.

Isolation and characterization of mammary epithelial cells derived from Göttingen Minipigs: A comparative study versus hybrid pig cells from the IMI-ConcePTION Project

The value of pig as “large animal model” is a well-known tool for translational medicine, but it can also be beneficial in studying animal health in a one-health vision. The ConcePTION Project aims to provide new information about the risks associated with medication use during breastfeeding, as this information is not available for most commonly used drugs. In the IMI-Conception context, Göttingen Minipigs have been preferred to hybrid pigs for their genetic stability and microbiological control. For the first time, in the present research, three primary cell cultures of mammary epithelial cells were isolated and characterized from Göttingen Minipigs (mpMECs), including their ability to create the epithelial barrier. In addition, a comparative analysis between Göttingen Minipigs and commercial hybrid pig mammary epithelial cells (pMECs) was conducted. Epithelial markers: CKs, CK18, E-CAD, ZO-1 and OCL, were expressed in both mpMECs and pMECs. RT2 Profiler PCR Array Pig Drug Transporters showed a similar profile in mRNA drug transporters. No difference in energy production under basal metabolic condition was evidenced, while under stressed state, a different metabolic behaviour was shown between mpMECs vs pMECs. TEER measurement and sodium fluorescein transport, indicated that mpMECs were able to create an epithelial barrier, although, this turned out to be less compact than pMECs. By comparing mpMECs with mammary epithelial cells isolated from Hybrid pigs (pMECs), although both cell lines have morphological and phenotypic characteristics that make them both useful in barrier studies, some specific differences exist and must be considered in a translational perspective.

Electroacupuncture stimulation enhances the permeability of the blood-brain barrier: A systematic review and meta-analysis of preclinical evidence and possible mechanisms.

An important cellular barrier to maintain the stability of the brain's internal and external environment is the blood-brain barrier (BBB). It also prevents harmful substances from entering brain tissue through blood circulation while providing protection for the central nervous system. It should be noted, however, that the intact BBB can be a barrier to the transport of most drugs into the brain via the conventional route of administration, which can prevent them from reaching effective concentrations for the treatment of disorders affecting the central nervous system. Electroacupuncture stimulation has been shown to be effective at opening the BBB in a series of experimental studies. This study systematically analyzes the possibility and mechanism by which electroacupuncture opens the BBB. In PubMed, Web of Science, VIP Database, Wanfang Database, and the Chinese National Knowledge Infrastructure, papers have been published for nearly 22 years aimed at opening the BBB and its associated structures. A comparison of EB content between electroacupuncture and control was selected as the primary outcome. There were also results on vascular endothelial growth factor (VEGF), nerve growth factor (NGF), P-Glycoprotein (P-gp), Matrix Metalloproteinase 9 (MMP-9), and glial fibrillary acidic protein (GFAP). We utilized Review Manager software analysis to analyze correlations between studies with a view to exploring the mechanisms of similarity. Evans Blue infiltration forest plot: pooled effect size of 2.04, 95% CI: 1.21 to 2.87, P < 0.01. These results indicate that electroacupuncture significantly increases EB penetration across the BBB. Most studies have reported that GFAP, MMP-9, and VEGF were upregulated after treatment. P-gp expression decreased as well. Electroacupuncture can open the BBB, and the sparse-dense wave is currently the most effective electroacupuncture frequency for opening the BBB. VEGF plays an important role in opening the BBB. It is also important to regulate the expression of MMP-9 and GFAP and inhibit the expression of P-gp.

Development and Characterization of Charantin Loaded Transferosomes based Transdermal Formulation: An Effective and Patient Friendly Way for Diabetes Management

Transferosomes, marvels of scientific ingenuity, represent exquisitely optimized and ultra- deformable (ultra-flexible) lipid supramolecular aggregates, uniquely capable of traversing the mammalian skin intact. These remarkable carrier systems have harnessed the power of transdermal delivery, enabling the transport of drugs, irrespective of their molecular weight from the tiniest compounds to the most substantial ones. The incorporation of Charantin into transferosomal gel formulation holds immense promise in advancing topical therapeutics. Charantin, a bioactive compound derived from Momordica charantia, possesses potent medicinal properties with antidiabetic, anti-inflammatory, antioxidant, and antimicrobial activities. When integrated into the lipid-based transferosomal system, Charantin's efficacy is significantly amplified due to enhanced skin penetration and improved stability against degradation. The versatile nature of transferosomal gels allows for encapsulating both hydrophilic and lipophilic compounds, making it an ideal carrier for Charantin regardless of its solubility characteristics. Driven by the pursuit of excellence, the present study sought to masterfully optimize the Transferosomes to orchestrate an unparalleled symphony of enhanced skin delivery for Charantin.

Transdermal drug delivery mediated by acoustic vortex beam

Ultrasound-mediated transdermal drug delivery exhibits various advantages such as biocompatibility, controllability and safety, which attracts plenty of interests within biomedical field. Current researches mostly emphasizes the acoustic cavitation generated by planar or focused waves while neglecting other physics that occur during transportation. Our experimental study illustrates the presence of an acoustic vortex (AV) beam that exhibits a lower acoustic intensity and typically means a lower dose of inertial cavitation, yet achieves a more efficient delivery. Such a result calls for the fundamental mechanism of ultrasound-mediated transdermal transfer using the AV beam. In this work, according to our knowledge, the AV beam is firstly introduced to ultrasound-mediated transdermal medication delivery. The transversal acoustic radiation force (T-ARF), which is the primary characteristic carried by the acoustic vortex beam, and its contribution to the transport enhancement are investigated. It is shown that a focused AV (FAV) beam with a maximal acoustic pressure of 200 kPa induces a pN-level T-ARF, which promotes the enlargement of pores on the stratum corneum and thereby enhances the permeability, as compared with a zero-order (non-vortex) counterpart. This contribution of the T-ARF is validated by the experimental transport on the cellulose membrane, which exhibits a significantly increased membrane porosity and delivery efficiency. The favorable results introduce the new degree of freedom into the ultrasound-mediated transdermal drug transport based on AV beam, and thereby promotes the development of a combined control strategy for more precise and efficient transdermal drug delivery in conjunction with the administration of acoustic cavitation.

Personalized approach to outpatient management of patients taking tamoxifen by gynecologists

BACKGROUND: 30% of women with luminal breast cancer receiving adjuvant tamoxifen experience disease recurrence within 15 years. This demonstrates the wide variability in clinical response to tamoxifen. Both nongenetic (age, gender, body mass index, duration of drug use) and genetic factors have been described to influence the high variability of response to tamoxifen. Differences in the genes encoding the enzymes CYP2D6, CYP2C, and CYP3A (CYP2D6*4, CYP3A5*3, CYP2C9*2, CYP2C9*3, CYP2C19*2, CYP2C19*3) and the ABCB1 gene (C3435T) may also be the main factors of susceptibility to the occurrence of undesirable effects when taking tamoxifen, which in turn may lead to decreased patient adherence to therapy.&#x0D; AIM: The aim of this study was to create a concept and an algorithm for a personalized approach to outpatient management of patients taking tamoxifen by a gynecologist in connection with the carriage of polymorphisms of cytochrome P450 and drug transporter genes.&#x0D; MATERIALS AND METHODS: In 2017–2018, the outpatient records of 230 patients with breast cancer were analyzed retrospectively. A single-stage pharmacogenetic study of 120 women with stage I–III luminal breast cancer taking tamoxifen was conducted prospectively for the presence of cytochrome P450 gene polymorphisms using the polymerase chain reaction method and assessing associations with adverse drug reactions, and 54 patients were interviewed after five-year follow-up to assess adherence and satisfaction with medical supervision.&#x0D; RESULTS: The likelihood of developing endometrial hyperplasia has been shown to increase while taking tamoxifen with increasing average age, body mass index, duration of tamoxifen use, and postmenopause. Significant associations have been identified between the carriage of the CYP2D6, CYP2C9, CYP2C19, CYP3A5, and ABCB1 gene polymorphisms and the development of adverse drug reactions. Predictive models have been developed to determine the risk of adverse drug reactions. All studied adverse drug reactions associated with various genetic polymorphisms predominated in the group of patients who stopped taking tamoxifen due to poor intolerance. Gynecologists regularly observed 57.4% of patients. Moreover, the higher the adherence to therapy was, the higher was the regularity of observation by a gynecologist.&#x0D; CONCLUSIONS: A plan for outpatient management of patients receiving adjuvant endocrine therapy with tamoxifen by a gynecologist has been developed.

Abstract 7257: Examining the promise of precision medicine in immuno-oncology: Vectors for targeted therapeutic delivery

Abstract At the forefront of therapeutic delivery is an array of vectors and targeting methods that hold immense promise for precision medicine. Vehicles such as viral vectors (AAV and lentivirus), lipid nanoparticles (LNPs) or liposomes, and peptide micelles each possess distinct and inherent properties, empowering researchers with tools to navigate the intricate challenges of specificity and efficiency in drug transport. Herein, we discuss and demonstrate design principles underpinning these vectors, elucidating their unique mechanisms for targeted delivery including:- A high-throughput viral packaging process to enable rapid downstream CRISPR or shRNA screening- Proprietary AAV plasmid synthesis and preparation techniques to maintain ITR integrity and improve gene delivery- Rapid synthesis, in vitro transcription, and novel sequencing of mRNA constructs for complete characterization of critical components such as the polyA tailBy synthesizing advancements in vector technologies, this poster serves as a roadmap for researchers and practitioners navigating the evolving landscape of targeted drug delivery in immuno-oncology. Citation Format: Crystal Richardson, Prassanna Rao, Cassandra Koole, Michael J. Karney, Sumit Kumar. Examining the promise of precision medicine in immuno-oncology: Vectors for targeted therapeutic delivery [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7257.

Malaria: biochemical, physiological, diagnostic, and therapeutic updates.

Malaria has been appraised as a significant vector-borne parasitic disease with grave morbidity and high-rate mortality. Several challenges have been confronting the efficient diagnosis and treatment of malaria. Google Scholar, PubMed, Web of Science, and the Egyptian Knowledge Bank (EKB) were all used to gather articles. Diverse biochemical and physiological indices can mirror complicated malaria e.g., hypoglycemia, dyslipidemia, elevated renal and hepatic functions in addition to the lower antioxidant capacity that does not only destroy the parasite but also induces endothelial damage. Multiple trials have been conducted to improve recent points of care in malaria involving biosensors, lap on-chip, and microdevices technology. Regarding recent therapeutic trials, chemical falcipain inhibitors and plant extracts with anti-plasmodial activities are presented. Moreover, antimalaria nano-medicine and the emergence of nanocarrier (either active or passive) in drug transportation are promising. The combination therapeutic trials e.g., amodiaquine + artemether + lumefantrine are presented to safely counterbalance the emerging drug resistance in addition to the Tafenoquine as a new anti-relapse therapy. Recognizing the pathophysiology indices potentiate diagnosis of malaria. The new points of care can smartly manipulate the biochemical and hematological alterations for a more sensitive and specific diagnosis of malaria. Nano-medicine appeared promising. Chemical and plant extracts remain points of research.

Abstract 5052: Novel drug resistance mechanisms and drug targets in BRAF mutated peritoneal metastasis from colorectal cancer

Abstract Objective: Patients with peritoneal metastasis (PM) from colorectal cancer (CRC) have inferior prognosis and respond poorly to chemotherapy compared to other metastatic locations. This study aims to identify the molecular explanation for the observed clinical behavior and suggest novel treatment strategies in PM-CRC. Design: Tumor samples from a Norwegian national cohort of 230 patients undergoing surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) with mitomycin C (MMC) for PM-CRC were subjected to targeted DNA sequencing, and associations between molecular findings and clinical data were analyzed. mRNA sequencing was conducted on a subset of thirty samples to compare gene expression in tumors harboring mutations in the BRAF or KRAS oncogenes and wild-type tumors. Results: Almost one-third of the patients had mutations in the BRAF oncogene, which were associated with RNF43/R-Spondin aberrations and low expression of negative Wnt regulators (ligand dependent Wnt activation). This molecular profile, with high abundance in PM, could be an underlying mechanism promoting aggressive tumor biology that facilitates metastasis to the peritoneal cavity, and could contribute to the observed poor overall survival of this patient subgroup. BRAF mutations were also associated with gene expression changes in transport solute carrier proteins and drug metabolism enzymes that could influence the efficacy of MMC and irinotecan, commonly used in PM-CRC treatment. BRAF-mutated tumors exhibited increased expression of BTN immune checkpoint molecules, and targeting these checkpoints in addition to ligand dependent Wnt activation could be two novel targeted therapy approaches. Conclusion: BRAF mutations were associated with particularly poor survival in this cohort, possibly related to altered drug transport and metabolism conferring resistance to MMC and irinotecan. Two potential novel therapeutic approaches were identified, suggesting specific targeting of BTN immune checkpoint molecules and the use of inhibitors to target ligand-dependent Wnt activation. Citation Format: Christin Lund-Andersen, Annette Torgunrud, Chakravarthi Kanduri, Vegar J. Dagenborg, Ida S. Frøysnes, Mette M. Larsen, Ben Davidson, Stein Larsen, Kjersti Flatmark. Novel drug resistance mechanisms and drug targets in BRAF mutated peritoneal metastasis from colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5052.

Abstract 2826: Examples of translational preclinical models to mimic cancer drug resistance

Abstract Drug resistance is becoming a major obstacle when treating patients with cancer. Cancer is characterized by an uncontrolled growth of abnormal cells with permanent genome alterations, which lead to severe mutations including resistance mechanisms. Mutations can occur in different resistance pathways, such as inhibition of drug transport, DNA damage repair, drug efflux, EMT (epithelial-mesenchymal transition), drug target alteration and cell death inhibition. Resistance mechanisms are now well studied in vitro, based on mutated cell lines for specific resistance pathways. There is however a gap in our knowledge of resistance mechanisms observed in patient tumor cells. We are challenged to discover cancer resistance treatments in patients and need predictive models of clinical situations. Animal tumor models are the best translational tools to study cancer drug resistance, especially when they closely mimic human pathologies. Such models can bridge the gap between our understanding of cancer resistance in vitro and in tumor patients. In this poster we show different pre-clinical experiments, simulating clinical translational approaches, that led to novel and unique tumor resistant models. Patient Derived Xenograft (PDX) models: Using our breast cancer PDX collection we showed that after repeated treatment with a spindle poison, tumor-bearing mice started to develop resistance and continued tumor growth under drug pressure. Following this successful approach, we initiated the development of a novel ER2-expressing PDX breast tumor model, resistant to hormone therapy by repeated Fulvestrant treatment. Using our colon cancer PDX collection we were able to recapitulate clinical situations by correlating PDX molecular profiles and drug sensitivity. We confirmed the key role of a KRAS mutation in cetuximab resistance. Syngeneic model: In this model, animals were dosed with anti-PDL1 as first line of treatment. All animals were then defined as initial responders or non-responders at the end of the dosing schedule. Following this, a new treatment protocol was initiated with a Tyrosine Kinase inhibitor to study the effect of second line drug treatment in responder and non-responder arms. Human model: In this experiment, we performed a first line Avastin treatment on human colon carcinoma tumor-bearing mice. A tumor resistance to Avastin was observed. During the second line of treatment with a tyrosine kinase inhibitor, we observed an antitumor activity on Avastin resistant animals. In each of these case studies, we developed a novel tumor-resistant mechanism model. In some tumor models, we showed the added value of treating animals with new drugs as second line treatment, after establishing resistance to the first line standard of care treatment. Citation Format: Marc Hillairet de Boisferon, Nicolas Hoffmann, Elodie Rajon, Ismahène Benzaid. Examples of translational preclinical models to mimic cancer drug resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2826.

Abstract 6648: Low-intensity pulsed ultrasound enhances the presentation of brain-derived antigens by facilitating the migration of antigen-presenting cells from the brain to the periphery

Abstract Gliomas, the most common primary brain tumors, remain largely incurable despite advancements in surgical and adjuvant therapies. While immunotherapies offer promising avenues, their efficacy has been limited by formidable anatomical barriers, such as the blood-brain barrier (BBB), which restricts the migration of immune cells into the brain and impedes the efficient drainage of brain-derived antigens, establishing an immune-privileged environment. Consequently, neoplastic formations within the brain often escape detection by the peripheral immune system, complicating therapeutic interventions. The application of low-intensity pulsed ultrasound with microbubbles (LIPU/MB) has emerged as a potential solution, enabling the transient opening of the BBB. This facilitates drug transport and immune cell trafficking, including Chimeric Antigen Receptor (CAR) T cells, into brain tumors. However, challenges such as antigen-loss escape persist with CAR T cells. One proposed solution involves promoting antigen/epitope spreading by inducing the presentation of brain (tumor) antigens to the systemic immune system. To investigate this, we conducted intravital imaging using Colony-stimulating factor receptor 1 (CSFR1) and CX3CR1 reporter mice, visualizing antigen-presenting cell locomotion in the brain before and after LIPU/MB treatment using two-photon microscopy. Within one hour after LIPU/MB, we observed the migration of CSFR1+ and CX3CR1+ immune cells from the brain parenchyma and perivascular space into the bloodstream, a phenomenon absent prior to LIPU/MB treatment. Beyond that, flow cytometry identified CD45intermediateCD11b+-CX3CR1+-TMEM119+-P2RY12+microglia-like' cells in the blood. To further assess the immunological effects of LIPU/MB on brain antigen presentation, we utilized transgenic mice expressing a minigene encoding four immunogenic peptides under the glial fibrillary acidic protein (GFAP) promoter. LIPU/MB treatment was associated with increased proliferation and priming of adoptively transferred CNS antigen-specific naïve T cells in cervical lymph nodes, ultimately homing into the CNS, indicating enhanced antigen presentation. Furthermore, in a subset of glioblastoma (GBM) patients undergoing LIPU/MB combined with doxorubicin and anti-PD-1 blocking antibodies, CD11b+CD14+P2YR12+ microglia were detected in blood samples during cycles 3-6 of treatment. This increase was absent in blood samples from healthy donors.Collectively, our findings suggest that LIPU/MB represents a novel approach to augment brain-antigen presentation in the periphery, holding potential implications for improving the immunotherapeutic management of gliomas.[M.G., V.A.A., A.M.S., and H.O. contributed equally to this work.] Citation Format: Marco Gallus, Victor Andres Arrieta, Atsuro Saijo, Pavlina Chuntova, Akane Yamamichi, Jeffrey Haegelin, Su Phyu, Lan Phung, Shayan A. Amir-Kabirian, Senthilnath Lakshmanachetty, Li Chen, Karl Habashy, Andrew Gould, Christina Amidei, Catalina Lee Chang, Roger Stupp, Michael Canney, Hideho Okada. Low-intensity pulsed ultrasound enhances the presentation of brain-derived antigens by facilitating the migration of antigen-presenting cells from the brain to the periphery [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6648.

Drug-Drug Interactions of FXI Inhibitors: Clinical Relevance.

Inhibitors of the factor FXI represent a new class of anticoagulant agents that are facing clinical approval for the treatment of acute coronary syndrome (ACS), venous thromboembolism (VTE), and stroke prevention of atrial fibrillation (AF). These new inhibitors include chemical small molecules (asundexian and milvexian), monoclonal antibodies (abelacimab, osocimab, and xisomab), and antisense oligonucleotides (IONIS-FXIRX and fesomersen), and thus, they have very peculiar and different pharmacokinetic and pharmacodynamic properties. Besides their clinical efficacy and safety, based on their pharmacological heterogeneity, the use of these drugs in patients with comorbidities may undergo drug-drug interactions (DDIs) with other concomitant therapies. Although only little clinical evidence is available, it is possible to predict clinically relevant DDI by taking into consideration their pharmacokinetic properties, such as the CYP450-dependent metabolism, the interaction with drug transporters, and/or the route of elimination. These characteristics may be useful to differentiate their use with the direct oral anticoagulant (DOAC) anti -FXa (rivaroxaban, apixaban, edoxaban) and thrombin (dabigatran), whose pharmacokinetics are strongly dependent from P-gp inhibitors/inducers. In the present review, we summarize the current clinical evidence on DDIs of new anti FXI with CYP450/P-gp inhibitors and inducers and indicate potential differences with DOAC anti FXa.

Assessing Blood-Brain Barrier Function in the Context of Pain Management.

One essential component of the neurovascular system is known as the blood-brain barrier (BBB). This highly effective biological barrier plays a pivotal role in regulating the brain's internal microenvironment and carefully controlling the passage of various chemicals into and out of the brain. Notably, it serves as a safeguard for the brain, particularly when it comes to the selective transportation of drugs like opioids and non-steroidal anti-inflammatory medications (NSAIDs), which are commonly used in the management of chronic pain. It's important to note that during the development of chronic pain, the activation of microglia and astrocytes can potentially disrupt or damage the integrity of the BBB. In this comprehensive review, we aim to delve into the intricate interplay between the blood-brain barrier and the transportation of pain-relieving drugs, shedding light on the challenges and mechanisms involved in this process.

Criminalistic characteristics of the involvement of minors in the illegal production, production, purchase, storage, transportation, transportation or sale of narcotics, psychotropic substances or their analogues

The article defines the concept of the criminalistic characteristics of the involvement of minors in illegal production, manufacture, acquisition, storage, transportation, forwarding or sale of narcotic drugs, psychotropic substances or their analogues and outlines its main structural elements. In the course of the research, it was determined that the forensic characteristics of criminal offenses is a system of generalized data on the most typical signs of a certain type (group) of criminal illegal acts, which are manifested in the method and mechanism of the act, the circumstances of its commission, the person of the subject of the criminal offense, other circumstances, natural the interrelationship of which is the basis for the scientific and practical performance of the tasks of criminal proceedings.&#x0D; The element-component composition of the criminalistic characteristics of the involvement of minors in the illegal production, manufacture, acquisition, storage, transportation, forwarding or sale of narcotic drugs, psychotropic substances or their analogues, as based on the practice of law enforcement agencies and forensic studies of the data system, includes: the subject of the offense (means and substances listed in Article 307 of the Criminal Code of Ukraine, namely narcotic drugs, psychotropic substances, their analogues and precursors); ways of preparing, committing, concealing and opposing the investigation as the behavior of individuals; trace picture (includes material traces: traces of production, manufacture, storage, transportation, sale or purchase of narcotic drugs; traces of drug use; traces of the influence of narcotic drugs on the human body) and ideal ones, which are reflected in human memory and find their expression as testimony of witnesses, victims, suspects)); typological features of the identity of the criminal and the identity of the victim (peculiarities of socio-demographic characteristics of persons who involve minors and victimization of minors).

DeepPLM_mCNN: An approach for enhancing ion channel and ion transporter recognition by multi-window CNN based on features from pre-trained language models

Accurate classification of membrane proteins like ion channels and transporters is critical for elucidating cellular processes and drug development. We present DeepPLM_mCNN, a novel framework combining Pretrained Language Models (PLMs) and multi-window convolutional neural networks (mCNNs) for effective classification of membrane proteins into ion channels and ion transporters. Our approach extracts informative features from protein sequences by utilizing various PLMs, including TAPE, ProtT5_XL_U50, ESM-1b, ESM-2_480, and ESM-2_1280. These PLM-derived features are then input into a mCNN architecture to learn conserved motifs important for classification. When evaluated on ion transporters, our best performing model utilizing ProtT5 achieved 90% sensitivity, 95.8% specificity, and 95.4% overall accuracy. For ion channels, we obtained 88.3% sensitivity, 95.7% specificity, and 95.2% overall accuracy using ESM-1b features. Our proposed DeepPLM_mCNN framework demonstrates significant improvements over previous methods on unseen test data. This study illustrates the potential of combining PLMs and deep learning for accurate computational identification of membrane proteins from sequence data alone. Our findings have important implications for membrane protein research and drug development targeting ion channels and transporters. The data and source codes in this study are publicly available at the following link: https://github.com/s1129108/DeepPLM_mCNN.

Impact of ABCB1 genetic polymorphism on carbamazepine dose requirement among Southern Indian persons with epilepsy.

Carbamazepine (CBZ) is one of the oldest, yet first line drugs for treating epilepsy. However, there is a large inter-individual difference in requirement of maintenance dose and one third of persons treated with antiepileptic drugs (AEDs) exhibit drug resistance to therapy. One of the proposed mechanisms for the drug resistance was increased expression of efflux transporter P-glycoprotein. The pharmacogenetic studies of drug transporters (ABCB1) done in combination therapies of AEDs were inconclusive. Hence, we have attempted to study the impact of ABCB1 3435C>T genetic polymorphism and CBZ monotherapy in persons with epilepsy (PWE) from South India, which is a genetically distinct population. With this background, this study was aimed to determine the dose of CBZ in ABCB1 3435C>T genotypes and to determine the distribution of ABCB1 3435C>T genotypes (which codes P-glycoprotein) between responders and non-responders to CBZ therapy. A cross sectional study was conducted in 200 persons with epilepsy, who were categorised as responders and non-responders according to ILAE (international league against epilepsy) criteria. Eligible participants were enrolled from the epilepsy clinic of the neurology department and five ml of blood was collected. DNA extraction and genotyping were done by phenol-chloroform method and real time polymerase chain reaction (RT-PCR), respectively. The mean maintenance dose of carbamazepine was statistically significant among different genotypes (p<0.05) of ABCB1 3435C>T (526 vs. 637 mg/day in CC vs. TT genotype). There was no significant association between ABCB1 3435C>T polymorphism (p=0.827) and CBZ resistance in PWE. Duration of disease and age of onset were found to be significant in predicting the response to CBZ therapy. We report that ABCB1 3435C>T polymorphism is significantly associated with an increase in dose requirement of CBZ in persons with epilepsy from South India.

Polyethylene glycol and immunology: aspects of allergic reactions and their mechanisms, as well as ways to prevent them in clinical practice.

In modern medical practice, where polyethylene glycol is widely used as a component of various drugs, such as vaccines, chemotherapy drugs, and antibiotics, including vaccines, the issue of allergic reactions to this substance is becoming increasingly important. The purpose of this study is to review and systematise data on various aspects of allergic reactions to polyethylene glycol with the aim of better understanding their pathogenesis, clinical manifestations, diagnostic methods, and possible treatment approaches. The study analysed literature data in modern databases, such as MEDLINE, PubMed, and Scopus, on allergic reactions to polyethylene glycol, using the keywords: "PEG", "polyethylene glycol", "allergy", "side effect". The main aspects of allergy to this substance were highlighted, including mechanisms of development, diagnostic methods, and possible treatment strategies. The analysis found that allergic reactions to polyethylene glycol can manifest in a variety of ways, including anaphylaxis and systemic reactions. A possible role for the immune response has been identified, including the production of IgE and IgM antibodies, complement activation, and accelerated clearance in response to polyethylene glycol, in blood plasma. Data are also provided on how to diagnose an increased risk of an allergic reaction in patients who have previously received drugs with this type of drug transporter and in patients receiving high molecular weight types of polyethylene glycol. The results of this review contribute to a better understanding of allergic reactions to polyethylene glycol and provide information for the development of more effective diagnostic and treatment methods.