Search results for: preclinical model

Authors: Aniket Kumar, Jacob Peedicayil

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Major depressive disorder (MDD) is a common and important psychiatric disorder. Several clinical features of MDD suggest an epigenetic basis for its pathogenesis. Since epigenetics (heritable changes in gene expression not involving changes in DNA sequence) may underlie the pathogenesis of MDD, epigenetic drugs such as DNA methyltransferase inhibitors (DNMTi) and histone deactylase inhibitors (HDACi) may be useful for treating MDD. The available literature indexed in Pubmed on preclinical drug trials of epigenetic drugs for the treatment of MDD was investigated. The search terms we used were ‘depression’ or ‘depressive’ and ‘HDACi’ or ‘DNMTi’. Among epigenetic drugs, it was found that there were 3 preclinical trials using HDACi and 3 using DNMTi for the treatment of MDD. All the trials were conducted on rodents (mice or rats). The animal models of depression that were used were: learned helplessness-induced animal model, forced swim test, open field test, and the tail suspension test. One study used a genetic rat model of depression (the Flinders Sensitive Line). The HDACi that were tested were: sodium butyrate, compound 60 (Cpd-60), and valproic acid. The DNMTi that were tested were: 5-azacytidine and decitabine. Among the three preclinical trials using HDACi, all showed an antidepressant effect in animal models of depression. Among the 3 preclinical trials using DNMTi also, all showed an antidepressant effect in animal models of depression. Thus, epigenetic drugs, namely, HDACi and DNMTi, may prove to be useful in the treatment of MDD and merit further investigation for the treatment of this disorder.

Keywords: DNA methylation, drug discovery, epigenetics, major depressive disorder

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Authors: Su Chul Han, Seungwoo Park

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As the increasing incidence of cancer, the technology and modality of radiotherapy have advanced and the importance of preclinical model is increasing in the cancer research. Furthermore, the small animal dosimetry is an essential part of the evaluation of the relationship between the absorbed dose in preclinical small animal and biological effect in preclinical study. In this study, we carried out realistic modeling of the preclinical small animal phantom possible to verify irradiated dose using commercial software. The small animal phantom was modeling from 4D Digital Mouse whole body phantom. To manipulate Moby phantom in commercial software (Mimics, Materialise, Leuven, Belgium), we converted Moby phantom to DICOM image file of CT by Matlab and two- dimensional of CT images were converted to the three-dimensional image and it is possible to segment and crop CT image in Sagittal, Coronal and axial view). The CT images of small animals were modeling following process. Based on the profile line value, the thresholding was carried out to make a mask that was connection of all the regions of the equal threshold range. Using thresholding method, we segmented into three part (bone, body (tissue). lung), to separate neighboring pixels between lung and body (tissue), we used region growing function of Mimics software. We acquired 3D object by 3D calculation in the segmented images. The generated 3D object was smoothing by remeshing operation and smoothing operation factor was 0.4, iteration value was 5. The edge mode was selected to perform triangle reduction. The parameters were that tolerance (0.1mm), edge angle (15 degrees) and the number of iteration (5). The image processing 3D object file was converted to an STL file to output with 3D printer. We modified 3D small animal file using 3- Matic research (Materialise, Leuven, Belgium) to make space for radiation dosimetry chips. We acquired 3D object of realistic small animal phantom. The width of small animal phantom was 2.631 cm, thickness was 2.361 cm, and length was 10.817. Mimics software supported efficiency about 3D object generation and usability of conversion to STL file for user. The development of small preclinical animal phantom would increase reliability of verification of absorbed dose in small animal for preclinical study.

Keywords: mimics, preclinical small animal, segmentation, 3D printer

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Authors: Minseock Seo

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Dental education consists of both theoretical and practical learning for students. When dental students encounter practical courses as a new educational experience, they must also learn to evaluate themselves. The aim of this study was to investigate the self-assessment scores of third-year dental students and compare with the scores graded by the faculty in preclinical endodontic practice in a dental school in Korea. Faculty- and student-assigned scores were calculated from preclinical endodontic practice performed on phantom patients. The students were formally instructed on grading procedures for endodontic treatment. After each step, each item was assessed by the student. The students’ self-assessment score was then compared to the score by the faculty. The students were divided into 4 groups by analyzing the scores of self-assessment and faculty-assessment and statistically analyzed by summing the theoretical and practical examination scores. In the theoretical exam score, the group who over-estimated their performance (H group) was lower than the group with lower evaluation (L group). When comparing the first and last score determined by the faculty, H groups didn’t show any improvement, while the other group did. In H group, the less improvement of the self-assessment, the higher the theoretical exam score. In L group, the higher improvement of the self-assessment, the better the theoretical exam score. The results point to the need to develop students’ self-insight with more exercises and practical training.

Keywords: dental students, endodontic, preclinical practice, self-assessment

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Authors: Charléa M. Smith, Raiden L. Schodowski, Arletty Pinel

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Due to the COVID-19 pandemic, the Faculty of Medical Sciences of The University of the West Indies (UWI) Mona in Kingston, Jamaica, had to rapidly migrate to digital and blended learning. Students in the preclinical stage of the program transitioned to full-time online learning, while students in the clinical stage experienced decreased daily patient contact and the implementation of a blend of online lectures and virtual clinical practice. Such sudden changes were coupled with the institutional pressure of the need to introduce a novel approach to education without much time for preparation, as well as additional strain endured by the faculty, who were overwhelmed by serving as frontline workers. During the period July 20 to August 23, 2021, this study surveyed preclinical and clinical students to capture their experiences with these changes and their recommendations for future use of digital modalities of learning to enhance medical education. It was conducted with a fellow student of the 2021 cohort of the MultiPod mentoring program. A questionnaire was developed and distributed digitally via WhatsApp to all medical students of the UWI Mona campus to assess students’ experiences and perceptions of the advantages, challenges, and impact on individual knowledge proficiencies brought about by the transition to predominantly digital learning environments. 108 students replied, 53.7% preclinical and 46.3% clinical. 67.6% of the total were female and 30.6 % were male; 1.8% did not identify themselves by gender. 67.2% of preclinical students preferred blended learning and 60.3% considered that the content presented did not prepare them for clinical work. Only 31% considered that the online classes were interactive and encouraged student participation. 84.5% missed socialization with classmates and friends and 79.3% missed a focused environment for learning. 80% of the clinical students felt that they had not learned all that they expected and only 34% had virtual interaction with patients, mostly by telephone and video calls. Observing direct consultations was considered the most useful, yet this was the least-used modality. 96% of the preclinical students and 100% of the clinical ones supplemented their learning with additional online tools. The main recommendations from the survey are the use of interactive teaching strategies, more discussion time with lecturers, and increased virtual interactions with patients. Universities are returning to face-to-face learning, yet it is unlikely that blended education will disappear. This study demonstrates that students’ perceptions of their experience during mobility restrictions must be taken into consideration in creating more effective, inclusive, and efficient blended learning opportunities.

Keywords: blended learning, digital learning, medical education, student perceptions

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Authors: Lian Zeng

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Double-Spear 1-H2-1 (DS1-H2-1) is an oncolytic virus and an innovative biological drug candidate. The chemical composition of the drug product is a live attenuated West Nile virus (WNV) containing the human T cell costimulator (CD86) gene. After intratumoral injection, the virus can rapidly self-replicate in the injected site and lyse/kill the tumor by repeated infection among tumor cells. We also established xenograft tumor models in mice to evaluate the drug candidate's efficacy on those tumors. The results from preclinical studies on transplanted tumors in immunodeficient mice showed that DS1-H2-1 had significant oncolytic effects on human-origin cancers: it completely (100%) shrieked human glioma; limited human neuroblastoma growth reached as high as 95% growth inhibition rate (%TGITW). The safety data of preclinical animal experiments confirmed that DS1-H2-1 is safe as a biological drug for clinical use. In the preclinical drug efficacy experiment, virus-drug administration with different doses did not show abnormal signs and disease symptoms in more than 300 tested mice, and no side effects or death occurred through various administration routes. Intravenous administration did not cause acute infectious disease or other side effects. However, the replication capacity of the virus in tumor tissue via intravenous administration is only 1% of that of direct intratumoral administration. The direct intratumoral administration of DS1-H2-1 had a higher rate of viral replication. Therefore, choosing direct intratumoral injection can ensure both efficacy and safety.

Keywords: oncolytic virus, WNV-CD86, immunotherapy drugs, glioma, neuroblastoma

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Authors: Zsanett Bahor, Cristina Nunes-Fonseca, Gillian L. Currie, Emily S. Sena, Lindsay D.G. Thomson, Malcolm R. Macleod

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Psychosis is ranked as the third most disabling medical condition in the world by the World Health Organization. Despite a substantial amount of research in recent years, available treatments are not universally effective and have a wide range of adverse side effects. Since many clinical drug candidates are identified through in vivo modelling, a deeper understanding of these models, and their strengths and limitations, might help us understand reasons for difficulties in psychosis drug development. To provide an unbiased summary of the preclinical psychosis literature we performed a systematic electronic search of PubMed for publications modelling a psychotic disorder in vivo, identifying 14,721 relevant studies. Double screening of 11,000 publications from this dataset so far established 2403 animal studies of psychosis, with the most common model being schizophrenia (95%). 61% of these models are induced using pharmacological agents. For all the models only 56% of publications test a therapeutic treatment. We propose a systematic review of these studies to assess the prevalence of reporting of measures to reduce risk of bias, and a meta-analysis to assess the internal and external validity of these animal models. Our findings are likely to be relevant to future preclinical studies of psychosis as this generation of strong empirical evidence has the potential to identify weaknesses, areas for improvement and make suggestions on refinement of experimental design. Such a detailed understanding of the data which inform what we think we know will help improve the current attrition rate between bench and bedside in psychosis research.

Keywords: animal models, psychosis, systematic review, schizophrenia

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Authors: S. G. Vasantharaju, Viswanath Guptha, Raghavendra Shetty

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Introduction: Aminophylline is a methylxanthine derivative belonging to the class bronchodilator. From the literature survey, reported methods reveals the solid phase extraction and liquid liquid extraction which is highly variable, time consuming, costly and laborious analysis. Present work aims to develop a simple, highly sensitive, precise and accurate high-performance liquid chromatography method for the quantification of Aminophylline in rat plasma samples which can be utilized for preclinical studies. Method: Reverse Phase high-performance liquid chromatography method. Results: Selectivity: Aminophylline and the internal standard were well separated from the co-eluted components and there was no interference from the endogenous material at the retention time of analyte and the internal standard. The LLOQ measurable with acceptable accuracy and precision for the analyte was 0.5 µg/mL. Linearity: The developed and validated method is linear over the range of 0.5-40.0 µg/mL. The coefficient of determination was found to be greater than 0.9967, indicating the linearity of this method. Accuracy and precision: The accuracy and precision values for intra and inter day studies at low, medium and high quality control samples concentrations of aminophylline in the plasma were within the acceptable limits Extraction recovery: The method produced consistent extraction recovery at all 3 QC levels. The mean extraction recovery of aminophylline was 93.57 ± 1.28% while that of internal standard was 90.70 ± 1.30%. Stability: The results show that aminophylline is stable in rat plasma under the studied stability conditions and that it is also stable for about 30 days when stored at -80˚C. Pharmacokinetic studies: The method was successfully applied to the quantitative estimation of aminophylline rat plasma following its oral administration to rats. Discussion: Preclinical studies require a rapid and sensitive method for estimating the drug concentration in the rat plasma. The method described in our article includes a simple protein precipitation extraction technique with ultraviolet detection for quantification. The present method is simple and robust for fast high-throughput sample analysis with less analysis cost for analyzing aminophylline in biological samples. In this proposed method, no interfering peaks were observed at the elution times of aminophylline and the internal standard. The method also had sufficient selectivity, specificity, precision and accuracy over the concentration range of 0.5 - 40.0 µg/mL. An isocratic separation technique was used underlining the simplicity of the presented method.

Keywords: Aminophyllin, preclinical pharmacokinetics, rat plasma, RPHPLC

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Authors: Atiwit Sinyoo, Sekh Thanprasertsuk, Sithiporn Agthong, Pasakorn Watanatada, Shaun Peter Qureshi, Saknan Bongsebandhu-Phubhakdi

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Background: Since the SARS-CoV-2 virus became extensively disseminated throughout the world, online learning has become one of the most hotly debated topics in educational reform. While some studies have already shown the advantage of online learning, there are still questions concerning how online learning affects students’ learning behavior and academic achievement when each student learns in a different way. Hence, we aimed to develop a guide for preclinical medical students to avoid drawbacks and get benefits from online learning that possibly a double-edged sword. Methods: We used a multiple-choice questionnaire to evaluate the learning behavior of second-year Thai medical students in the neuroscience course. All traditional face-to-face lecture classes were video-recorded and promptly posted to the online learning platform throughout this course. Students could pick and choose whatever classes they wanted to attend, and they may use online learning as often as they wished. Academic performance was evaluated as summative score, spot exam score and pre-post-test improvement. Results: More frequently students used online learning platform, the less they attended lecture classes (P = 0.035). High proactive online learners (High PO) who were irregular attendee (IrA) had significantly lower summative scores (P = 0.026), spot exam score (P = 0.012) and pre-post-test improvement (P = 0.036). In the meanwhile, conditional attendees (CoA) who only attended classes with attendance check had significantly higher summative score (P = 0.025) and spot exam score (P = 0.001) if they were in the High PO group. Conclusions: The benefit and drawbacks edges of using an online learning platform were demonstrated in our research. Based on this double-edged sword effect, we believe that online learning is a valuable learning strategy, but students must carefully plan their study schedule to gain the “benefit edge” meanwhile avoiding its “drawback edge”.

Keywords: academic performance, assessment, attendance, online learning, preclinical medical students

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Authors: Razyeh Behbahani, Martin L. Plumer, Ivan Saika-Voivod

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Micromagnetic simulations based on the stochastic Landau-Lifshitz-Gilbert equation are used to calculate dynamic magnetic hysteresis loops relevant to magnetic hyperthermia applications. With the goal to effectively simulate room-temperature loops for large iron-oxide based systems at relatively slow sweep rates on the order of 1 Oe/ns or less, a coarse-graining scheme is proposed and tested. The scheme is derived from a previously developed renormalization-group approach. Loops associated with nanorods, used as building blocks for larger nanoparticles that were employed in preclinical trials (Dennis et al., 2009 Nanotechnology 20 395103), serve as the model test system. The scaling algorithm is shown to produce nearly identical loops over several decades in the model grain sizes. Sweep-rate scaling involving the damping constant alpha is also demonstrated.

Keywords: coarse-graining, hyperthermia, hysteresis loops, micromagnetic simulations

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Authors: Ibraheem Husain, Abul Kalam Najmi, Karishma Chester

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First-in-human (FIH) studies are a critical step in clinical development of any molecule that has shown therapeutic promise in preclinical evaluations, since preclinical research and safety studies into clinical development is a crucial step for successful development of monoclonal antibodies for guidance in pharmaceutical industry for the treatment of human diseases. Therefore, comparison between USFDA and nine pharmacologically guided approaches (PGA) (simple allometry, maximum life span potential, brain weight, rule of exponent (ROE), two species methods and one species methods) were made to determine maximum recommended starting dose (MRSD) for first in human clinical trials using four drugs namely Denosumab, Bevacizumab, Anakinra and Omalizumab. In our study, the predicted pharmacokinetic (pk) parameters and the estimated first-in-human dose of antibodies were compared with the observed human values. The study indicated that the clearance and volume of distribution of antibodies can be predicted with reasonable accuracy in human and a good estimate of first human dose can be obtained from the predicted human clearance and volume of distribution. A pictorial method evaluation chart was also developed based on fold errors for simultaneous evaluation of various methods.

Keywords: clinical pharmacology (CPH), clinical research (CRE), clinical trials (CTR), maximum recommended starting dose (MRSD), clearance and volume of distribution

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Authors: Deepika Saini, Sandeep Jain, Ajay Kumar

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The quinoline scaffold is one of the most widely studied in the discovery of derivatives with various heterocyclic moieties due to its potential antimalarial activities. In the present study, a chalcone series of quinoline derivatives clubbed with pyrazole were synthesized to evaluate their antimalarial property by in vitro schizont maturation inhibition assay against both chloroquine sensitive, 3D7 and chloroquine resistant, RKL9 strain of Plasmodium falciparum. Further, top five compounds were studied for in vivo preclinical study for antimalarial potential against P. berghei in Swiss albino mice. To understand the mechanism of synthesized analogues, they were screened computationally by molecular docking techniques. Compounds were docked into the active site of a protein receptor, Plasmodium falciparum Cysteine Protease Falcipain-2. The compounds were successfully synthesized, and structural confirmation was performed by FTIR, 1H-NMR, mass spectrometry and elemental analysis. In vitro study suggested that the compounds 5b, 5g, 5l, 5s and 5u possessed best antimalarial activity and further tested for in vivo screening. Compound 5u (CH₃ on both rings) with EC₅₀ 0.313 & 0.801 µg/ml against CQ-S & CQ-R strains of P. falciparum respectively and 78.01% suppression of parasitemia. The molecular docking studies of the compounds helped in understanding the mechanism of action against falcipain-2. The present study reveals the binding signatures of the synthesized ligands within the active site of the protein, and it explains the results from in vitro study in their EC₅₀ values and percentage parasitemia.

Keywords: antimalarial activity, chalcone, docking, quinoline

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Authors: Muhammad nor Farhan Sa'At, Xin Y. Lim, Terence Y. C. Tan, Siti Hajar M. Rosli, Syazwani S. Ali, Ami F. Syed Mohamed

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INTRODUCTION: Hemp (Cannabis sativa subsp. sativa), commonly used for industrial purposes, differs from marijuana by containing lower levels of delta-9-tetrahydronannabidiol- the principal psychoactive constituent in cannabis. Due to its non-psychoactive nature, there has been growing interest in hemp’s therapeutic potential, which has been investigated through pre-clinical and clinical study modalities. OBJECTIVE: To provide an overview of the current landscape of hemp research, through recent scientific findings specific to the pharmacological effects of the medicinal hemp plant and its derived compounds. METHODS: This review was conducted through a systematic search strategy according to the preferred reporting items for systematic review and meta-analysis-ScR (PRISMA-ScR) checklist on electronic databases including MEDLINE, OVID (OVFT, APC Journal Club, EBM Reviews), Cochrane Library Central and Clinicaltrials.gov. RESULTS: From 65 primary articles reviewed, there were 47 pre-clinical studies related to medicinal hemp. Interestingly, the hemp derivatives showed several potential activities such as anti-oxidative, anti-hypertensive, anti-inflammatory, anti-diabetic, anti-neuroinflammatory, anti-arthritic, anti-acne, and anti-microbial activities. Renal protective effects and estrogenic properties were also exhibited in vitro. CONCLUSION: Medicinal hemp possesses various pharmacological effects tested in vitro and in vivo. Information provided in this review could be used as tool to strengthen the study design of future clinical trial research.

Keywords: Preclinical, Herbal Medicine, Hemp, Cannabis

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Authors: Sara Assi, Berthe Hayar, Claudio Pisano, Nadine Darwiche, Walid Saad

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Nanomedicine, the application of nanotechnology to medicine, is an emerging discipline that has gained significant attention in recent years. Current breakthroughs in nanomedicine have paved the way to develop effective drug delivery systems that can be used to target cancer. The use of nanotechnology provides effective drug delivery, enhanced stability, bioavailability, and permeability, thereby minimizing drug dosage and toxicity. As such, the use of nanoparticle (NP) formulations in drug delivery has been applied in various cancer models and have shown to improve the ability of drugs to reach specific targeted sites in a controlled manner. Cancer is one of the major causes of death worldwide; in particular, colorectal cancer (CRC) is the third most common type of cancer diagnosed amongst men and women and the second leading cause of cancer related deaths, highlighting the need for novel therapies. Retinoids, consisting of natural and synthetic derivatives, are a class of chemical compounds that have shown promise in preclinical and clinical cancer settings. However, retinoids are limited by their toxicity and resistance to treatment. To overcome this resistance, various synthetic retinoids have been developed, including the adamantyl retinoid ST1926, which is a potent anti-cancer agent. However, due to its limited bioavailability, the development of ST1926 has been restricted in phase I clinical trials. We have previously investigated the preclinical efficacy of ST1926 in CRC models. ST1926 displayed potent inhibitory and apoptotic effects in CRC cell lines by inducing early DNA damage and apoptosis. ST1926 significantly reduced the tumor doubling time and tumor burden in a xenograft CRC model. Therefore, we developed ST1926-NPs and assessed their efficacy in CRC models. ST1926-NPs were produced using Flash NanoPrecipitation with the amphiphilic diblock copolymer polystyrene-b-ethylene oxide and cholesterol as a co-stabilizer. ST1926 was formulated into NPs with a drug to polymer mass ratio of 1:2, providing a stable formulation for one week. The contin ST1926-NP diameter was 100 nm, with a polydispersity index of 0.245. Using the MTT cell viability assay, ST1926-NP exhibited potent anti-growth activities as naked ST1926 in HCT116 cells, at pharmacologically achievable concentrations. Future studies will be performed to study the anti-tumor activities and mechanism of action of ST1926-NPs in a xenograft mouse model and to detect the compound and its glucuroconjugated form in the plasma of mice. Ultimately, our studies will support the use of ST1926-NP formulations in enhancing the stability and bioavailability of ST1926 in CRC.

Keywords: nanoparticles, drug delivery, colorectal cancer, retinoids

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Authors: Rita Emília Szabó, Róbert Polanek, Tünde Tőkés, Zoltán Szabó, Szabolcs Czifrus, Katalin Hideghéty

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Purpose: Several feature of zebrafish are making them amenable for investigation on therapeutic approaches such as ionizing radiation. The establishment of zebrafish model for comprehensive radiobiological research stands in the focus of our investigation, comparing the radiation effect curves of neutron and photon irradiation. Our final aim is to develop an appropriate vertebrate model in order to investigate the relative biological effectiveness of laser driven ionizing radiation. Methods and Materials: After careful dosimetry series of viable zebrafish embryos were exposed to a single fraction whole-body neutron-irradiation (1,25; 1,875; 2; 2,5 Gy) at the research reactor of the Technical University of Budapest and to conventional 6 MeV photon beam at 24 hour post-fertilization (hpf). The survival and morphologic abnormalities (pericardial edema, spine curvature) of each embryo were assessed for each experiment at 24-hour intervals from the point of fertilization up to 168 hpf (defining the dose lethal for 50% (LD50)). Results: In the zebrafish embryo model LD50 at 20 Gy dose level was defined and the same lethality were found at 2 Gy dose from the reactor neutron beam resulting RBE of 10. Dose-dependent organ perturbations were detected on macroscopic (shortening of the body length, spine curvature, microcephaly, micro-ophthalmia, micrognathia, pericardial edema, and inhibition of yolk sac resorption) and microscopic (marked cellular changes in skin, cardiac, gastrointestinal system) with the same magnitude of dose difference. Conclusion: In our observations, we found that zebrafish embryo model can be used for investigating the effects of different type of ionizing radiation and this system proved to be highly efficient vertebrate model for preclinical examinations.

Keywords: ionizing radiation, LD50, relative biological effectiveness, zebrafish embryo

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Authors: Angela T. H. Kwan, Saman Arfaie, Joseph Therriault, Zahra Azizi, Firoza Z. Lussier, Cecile Tissot, Mira Chamoun, Gleb Bezgin, Stijn Servaes, Jenna Stevenon, Nesrine Rahmouni, Vanessa Pallen, Serge Gauthier, Pedro Rosa-Neto

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Alzheimer’s disease (AD) can be detected in living people using in vivo biomarkers of amyloid-β (Aβ) and tau, even in the absence of cognitive impairment during the preclinical phase. [¹⁸F]-MK-6420 is a high affinity positron emission tomography (PET) tracer that quantifies tau neurofibrillary tangles, but its ability to predict cognitive changes associated with early AD symptoms, such as memory decline, is unclear. Here, we assess the prognostic accuracy of baseline [18F]-MK-6420 tau PET for predicting longitudinal memory decline in asymptomatic elderly individuals. In a longitudinal observational study, we evaluated a cohort of cognitively normal elderly participants (n = 111) from the Translational Biomarkers in Aging and Dementia (TRIAD) study (data collected between October 2017 and July 2020, with a follow-up period of 12 months). All participants underwent tau PET with [¹⁸F]-MK-6420 and Aβ PET with [¹⁸F]-AZD-4694. The exclusion criteria included the presence of head trauma, stroke, or other neurological disorders. There were 111 eligible participants who were chosen based on the availability of Aβ PET, tau PET, magnetic resonance imaging (MRI), and APOEε4 genotyping. Among these participants, the mean (SD) age was 70.1 (8.6) years; 20 (18%) were tau PET positive, and 71 of 111 (63.9%) were women. A significant association between baseline Braak I-II [¹⁸F]-MK-6240 SUVR positivity and change in composite memory score was observed at the 12-month follow-up, after correcting for age, sex, and years of education (Logical Memory and RAVLT, standardized beta = -0.52 (-0.82-0.21), p < 0.001, for dichotomized tau PET and -1.22 (-1.84-(-0.61)), p < 0.0001, for continuous tau PET). Moderate cognitive decline was observed for A+T+ over the follow-up period, whereas no significant change was observed for A-T+, A+T-, and A-T-, though it should be noted that the A-T+ group was small.Our results indicate that baseline tau neurofibrillary tangle pathology is associated with longitudinal changes in memory function, supporting the use of [¹⁸F]-MK-6420 PET to predict the likelihood of asymptomatic elderly individuals experiencing future memory decline. Overall, [¹⁸F]-MK-6420 PET is a promising tool for predicting memory decline in older adults without cognitive impairment at baseline. This is of critical relevance as the field is shifting towards a biological model of AD defined by the aggregation of pathologic tau. Therefore, early detection of tau pathology using [¹⁸F]-MK-6420 PET provides us with the hope that living patients with AD may be diagnosed during the preclinical phase before it is too late.

Keywords: alzheimer’s disease, braak I-II, in vivo biomarkers, memory, PET, tau

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Authors: Harish Rajak, Preeti Patel

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The application of histone deacetylase inhibitors is a well-known strategy in prevention of cancer which shows acceptable preclinical antitumor activity due to its ability of growth inhibition and apoptosis induction of cancer cell. Molecular docking were performed using Histone Deacetylase protein (PDB ID:1t69) and prepared series of hydroxamic acid based HDACIs. On the basis of docking study, it was predicted that compound 1 has significant binding interaction with HDAC protein and three hydrogen bond interactions takes place, which are essential for antitumor activity. On docking, most of the compounds exhibited better glide score values between -8 to -10 which is close to the glide score value of suberoylanilide hydroxamic acid. The pharmacophore hypotheses were developed using e-pharmacophore script and phase module. The 3D-QSAR models provided a good correlation between predicted and actual anticancer activity. Best QSAR model showed Q2 (0.7974), R2 (0.9200) and standard deviation (0.2308). QSAR visualization maps suggest that hydrogen bond acceptor groups at carbonyl group of cap region and hydrophobic groups at ortho, meta, para position of R9 were favorable for HDAC inhibitory activity. We established structure activity correlation using docking, pharmacophore modeling and atom based 3D QSAR model for hydroxamic acid based HDACIs.

Keywords: HDACIs, QSAR, e-pharmacophore, docking, suberoylanilide hydroxamic acid

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Authors: Abdullah Eqal Al Mazrooei

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In this work, a new nonlinear model will be introduced. The model is in the state-space form. The nonlinearity of this model is in the state equation where the state vector is multiplied by its self. This technique makes our model generalizes many famous models as Lotka-Volterra model and Lorenz model which have many applications in the real life. We will apply our new model to estimate the wind speed by using a new nonlinear estimator which suitable to work with our model.

Keywords: nonlinear systems, state-space model, Kronecker product, nonlinear estimator

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Authors: Hami Ashraf, Farid Kosari

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Graft-versus-host disease (GvHD) is a common complication of allogeneic hematopoietic stem cell transplantation that can lead to significant morbidity and mortality. Histopathological examination of affected tissues is an essential tool for diagnosing and grading GvHD in animal models, which are used to study disease mechanisms and evaluate new therapies. In this systematic review, we identified and analyzed original research articles in PubMed, Scopus, Web of Science, and Google Scholar that described grading systems for GvHD in animal models based on histopathological features. We found that several grading systems have been developed, which vary in the tissues and criteria they assess, the severity scoring scales they use, and the level of detail they provide. Skin, liver, and gut are the most commonly evaluated tissues, but lung and thymus are also included in some systems. Our analysis highlights the need for standardized criteria and consistent use of grading systems to enable comparisons between studies and facilitate the translation of preclinical findings to clinical practice.

Keywords: graft-versus-host disease, GvHD, animal model, histopathology, grading system

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Authors: Entisar A. Elgmati

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Recurrent infant diarrhea is studied using daily data collected in Salvador, Brazil over one year and three months. A logistic regression model is fitted instead of Aalen's additive model using the same covariates that were used in the analysis with the additive model. The model gives reasonably similar results to that using additive regression model. In addition, the problem with the estimated conditional probabilities not being constrained between zero and one in additive model is solved here. Also martingale residuals that have been used to judge the goodness of fit for the additive model are shown to be useful for judging the goodness of fit of the logistic model.

Keywords: additive model, cumulative probabilities, infant diarrhoea, recurrent event

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Authors: C. Flynn, Q. Yuan, C. Reinhardt

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Alzheimer’s Disease (AD) is a progressive neurodegenerative disorder affecting broad areas of the cerebral cortex and hippocampus. More than 95% of AD cases are representative of sporadic AD, where both genetic and environmental risk factors play a role. The main pathological features of AD include the widespread deposition of amyloid-beta and neurofibrillary tau tangles in the brain. The earliest brain pathology related to AD has been defined as hyperphosphorylated soluble tau in the noradrenergic locus coeruleus (LC) neurons, characterized by Braak. However, the cause of this pathology and the ultimate progression of AD is not understood. Increasing research points to a connection between the gut microbiota and the brain, and mounting evidence has shown that there is a bidirectional interaction between the two, known as the gut-brain axis. This axis can allow for bidirectional movement of neuroinflammatory cytokines and pathogenic misfolded proteins, as seen in AD. Prebiotics and probiotics have been shown to have a beneficial effect on gut health and can strengthen the gut-barrier as well as the blood-brain barrier, preventing the spread of these pathogens across the gut-brain axis. Our laboratory has recently established a pretangle tau rat model, in which we selectively express pseudo-phosphorylated human tau (htauE14) in the LC neurons of TH-Cre rats. LC htauE14 produced pathological changes in rats resembling those of the preclinical AD pathology (reduced olfactory discrimination and LC degeneration). In this work, we will investigate the effects of pre/probiotic ingestion on AD behavioral deficits, blood inflammation/cytokines, and various brain markers in our experimental rat model of AD. Rats will be infused with an adeno-associated viral vector containing a human tau gene pseudophosphorylated at 14 sites (common in LC pretangles) into 2-3 month TH-Cre rats. Fecal and blood samples will be taken at pre-surgery, and various post-surgery time points. A collection of behavioral tests will be performed, and immunohistochemistry/western blotting techniques will be used to observe various biomarkers. This work aims to elucidate the relationship between gut health and AD progression by strengthening gut-brain relationship and aims to observe the overall effect on tau formation and tau pathology in AD brains.

Keywords: alzheimer’s disease, aging, gut microbiome, neurodegeneration

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Authors: Zakaria Baka, Halima Alem

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Cancer is a major worldwide health problem that has caused around ten million deaths in 2020. In addition, efforts to develop new anti-cancer drugs still face a high failure rate. This is partly due to the lack of preclinical models that recapitulate in-vivo drug responses. Indeed conventional cell culture approach (known as 2D cell culture) is far from reproducing the complex, dynamic and three-dimensional environment of tumors. To set up more in-vivo-like cancer models, 3D bioprinting seems to be a promising technology due to its ability to achieve 3D scaffolds containing different cell types with controlled distribution and precise architecture. Moreover, the introduction of microfluidic technology makes it possible to simulate in-vivo dynamic conditions through the so-called “cancer-on-chip” platforms. Whereas several cancer types have been modeled through the cancer-on-chip approach, such as lung cancer and breast cancer, only a few works describing ovarian cancer models have been described. The aim of this work is to combine 3D bioprinting and microfluidic technics with setting up a 3D dynamic model of ovarian cancer. In the first phase, alginate-gelatin hydrogel containing SKOV3 cells was used to achieve tumor-like structures through an extrusion-based bioprinter. The desired form of the tumor-like mass was first designed on 3D CAD software. The hydrogel composition was then optimized for ensuring good and reproducible printability. Cell viability in the bioprinted structures was assessed using Live/Dead assay and WST1 assay. In the second phase, these bioprinted structures will be included in a microfluidic device that allows simultaneous testing of different drug concentrations. This microfluidic dispositive was first designed through computational fluid dynamics (CFD) simulations for fixing its precise dimensions. It was then be manufactured through a molding method based on a 3D printed template. To confirm the results of CFD simulations, doxorubicin (DOX) solutions were perfused through the dispositive and DOX concentration in each culture chamber was determined. Once completely characterized, this model will be used to assess the efficacy of anti-cancer nanoparticles developed in the Jean Lamour institute.

Keywords: 3D bioprinting, ovarian cancer, cancer-on-chip models, microfluidic techniques

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Authors: Parimalah Velo, Ahmad Zakaria

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Introduction: Monte Carlo simulations of preclinical imaging systems allow opportunity to enable new research that could range from designing hardware up to discovery of new imaging application. The simulation system which could accurately model an imaging modality provides a platform for imaging developments that might be inconvenient in physical experiment systems due to the expense, unnecessary radiation exposures and technological difficulties. The aim of present study is to validate the Monte Carlo simulation of thyroid phantom imaging using Geant4-GATE for Siemen’s e-cam single head gamma camera. Upon the validation of the gamma camera simulation model by comparing physical characteristic such as energy resolution, spatial resolution, sensitivity, and dead time, the GATE simulation of thyroid phantom imaging is carried out. Methods: A thyroid phantom is defined geometrically which comprises of 2 lobes with 80mm in diameter, 1 hot spot, and 3 cold spots. This geometry accurately resembling the actual dimensions of thyroid phantom. A planar image of 500k counts with 128x128 matrix size was acquired using simulation model and in actual experimental setup. Upon image acquisition, quantitative image analysis was performed by investigating the total number of counts in image, the contrast of the image, radioactivity distributions on image and the dimension of hot spot. Algorithm for each quantification is described in detail. The difference in estimated and actual values for both simulation and experimental setup is analyzed for radioactivity distribution and dimension of hot spot. Results: The results show that the difference between contrast level of simulation image and experimental image is within 2%. The difference in the total count between simulation and actual study is 0.4%. The results of activity estimation show that the relative difference between estimated and actual activity for experimental and simulation is 4.62% and 3.03% respectively. The deviation in estimated diameter of hot spot for both simulation and experimental study are similar which is 0.5 pixel. In conclusion, the comparisons show good agreement between the simulation and experimental data.

Keywords: gamma camera, Geant4 application of tomographic emission (GATE), Monte Carlo, thyroid imaging

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Authors: Mehrnaz Mostafavi

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Nanoliposomes, minute lipid-based vesicles at the nano-scale, show promise in the realm of photothermal therapy (PTT). This study presents an extensive overview of nanoliposomes in PTT, exploring their distinct attributes and the significant progress in this therapeutic methodology. The research delves into the fundamental traits of nanoliposomes, emphasizing their adaptability, compatibility with biological systems, and their capacity to encapsulate diverse therapeutic substances. Specifically, it examines the integration of light-absorbing materials, like gold nanoparticles or organic dyes, into nanoliposomal formulations, enabling their efficacy as proficient agents for photothermal treatment Additionally, this paper elucidates the mechanisms involved in nanoliposome-mediated PTT, highlighting their capability to convert light energy into localized heat, facilitating the precise targeting of diseased cells or tissues. This precise regulation of light absorption and heat generation by nanoliposomes presents a non-invasive and precisely focused therapeutic approach, particularly in conditions like cancer. The study explores advancements in nanoliposomal formulations aimed at optimizing PTT outcomes. These advancements include strategies for improved stability, enhanced drug loading, and the targeted delivery of therapeutic agents to specific cells or tissues. Furthermore, the paper discusses multifunctional nanoliposomal systems, integrating imaging components or targeting elements for real-time monitoring and improved accuracy in PTT. Moreover, the review highlights recent preclinical and clinical trials showcasing the effectiveness and safety of nanoliposome-based PTT across various disease models. It also addresses challenges in clinical implementation, such as scalability, regulatory considerations, and long-term safety assessments. In conclusion, this paper underscores the substantial potential of nanoliposomes in advancing PTT as a promising therapeutic approach. Their distinctive characteristics, combined with their precise ability to convert light into heat, offer a tailored and efficient method for treating targeted diseases. The encouraging outcomes from preclinical studies pave the way for further exploration and potential clinical applications of nanoliposome-based PTT.

Keywords: nanoliposomes, photothermal therapy, light absorption, heat conversion, therapeutic agents, targeted delivery, cancer therapy

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Authors: Mechlouch Ridha Fethi

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This paper presents a recent mathematical model in political sciences concerning democracy. The model is represented by a logarithmic equation linking the Relative Index of Democracy (RID) to Participation Ratio (PR). Firstly the meanings of the different parameters of the model were presented; and the variation curve of the RID according to PR with different critical areas was discussed. Secondly, the model was applied to a virtual group where we show that the model can be applied depending on the gender. Thirdly, it was observed that the model can be extended to different language models of democracy and that little use to assess the state of democracy for some International organizations like UNO.

Keywords: democracy, mathematic, modelization, quantification

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Authors: Le Kang

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On the research question of 'how to achieve USR', this contribution reflects the concept of university social responsibility, identify three achievement models of USR as the society - diversified model, the university-cooperation model, the government - compound model, also conduct a case study to explore characteristics of Chinese achievement model of USR. The contribution concludes with discussion of how the university, government and society balance demands and roles, make necessarily strategic adjustment and innovative approach to repair the shortcomings of each achievement model.

Keywords: modern university, USR, achievement model, compound model

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Authors: Zhou Jianhong

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Model averaging is a desirable approach to deal with model uncertainty, which, however, has rarely been explored for Poisson regression. In this paper, we propose a model averaging procedure based on an unbiased estimator of the expected Kullback-Leibler distance for the Poisson regression. Simulation study shows that the proposed model average estimator outperforms some other commonly used model selection and model average estimators in some situations. Our proposed methods are further applied to a real data example and the advantage of this method is demonstrated again.

Keywords: model averaging, poission regression, Kullback-Leibler distance, statistics

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Authors: L. Madouni, M. Ould Ouali, N. E. Hannachi

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Two constitutive models for concrete are available in ABAQUS/Explicit, the Brittle Cracking Model and the Concrete Damaged Plasticity Model, and their suitability and limitations are well known. The aim of the present paper is to implement a damage-friction concrete constitutive model and to evaluate the performance of this model by comparing the predicted response with experimental data. The constitutive formulation of this material model is reviewed. In order to have consistent results, the parameter identification and calibration for the model have been performed. Several numerical simulations are presented in this paper, whose results allow for validating the capability of the proposed model for reproducing the typical nonlinear performances of concrete structures under different monotonic and cyclic load conditions. The results of the evaluation will be used for recommendations concerning the application and further improvements of the investigated model.

Keywords: Abaqus, concrete, constitutive model, numerical simulation

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Authors: Sarah Crawford, Gerry Lesley

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This research is a pre-clinical assessment of anti-cancer effects of novel non-steroidal diethyl stilbestrol-like estrogen analogs in estrogen-receptor positive/ progesterone-receptor positive human breast cancer microtumors of MCF 7 cell line. Tamoxifen analog formulation (Tam A1) was used as a single agent or in combination with therapeutic concentrations of 4-hydroxytamoxifen, currently used as a long-term treatment for the prevention of breast cancer recurrence in women with estrogen receptor positive/ progesterone receptor positive malignancies. At concentrations ranging from 30-50 microM, Tam A1 induced microtumor disaggregation and cell death. Incremental cytotoxic effects correlated with increasing concentrations of Tam A1. Live tumor microscopy showed that microtumos displayed diffuse borders and substrate-attached cells were rounded-up and poorly adherent. A complete cytotoxic effect was observed using 40-50 microM Tam A1 with time course kinetics similar to 4-hydroxytamoxifen. Combined treatment with TamA1 (30-50 microM) and 4-hydroxytamoxifen (10-15 microM) induced a highly cytotoxic, synergistic combined treatment response that was more rapid and complete than using 4-hydroxytamoxifen as a single agent therapeutic. Microtumors completely dispersed or formed necrotic foci indicating a highly cytotoxic combined treatment response. Moreover, breast cancer microtumors treated with both 4-hydroxytamoxifen and Tam A1 displayed lower levels of long-term post-treatment regrowth, a critical parameter of primary drug resistance, than observed for 4-hydroxytamoxifen when used as a single agent therapeutic. Tumor regrowth at 6 weeks post-treatment with either single agent 4-hydroxy tamoxifen, Tam A1 or a combined treatment was assessed for the development of drug resistance. Breast cancer cells treated with both 4-hydroxytamoxifen and Tam A1 displayed significantly lower levels of post-treatment regrowth, indicative of decreased drug resistance, than observed for either single treatment modality. The preclinical data suggest that combined treatment involving the use of tamoxifen analogs may be a novel clinical approach for long-term maintenance therapy in patients with estrogen-receptor positive/progesterone-receptor positive breast cancer receiving hormonal therapy to prevent disease recurrence. Detailed data on time-course, IC50 and tumor regrowth assays post- treatment as well as a proposed mechanism of action to account for observed synergistic drug effects will be presented.

Keywords: 4-hydroxytamoxifen, tamoxifen analog, drug-resistance, microtumors

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Authors: Arslan Murtaza

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Model Driven Architecture (MDA) is technique presented by OMG (Object Management Group) for software development in which different models are proposed and converted them into code. The main plan is to identify task by using PIM (Platform Independent Model) and transform it into PSM (Platform Specific Model) and then converted into code. In this review paper describes some challenges and issues that are faced in MDA, type and transformation of models (e.g. CIM, PIM and PSM), and evaluation of MDA-based methodologies.

Keywords: OMG, model driven rrchitecture (MDA), computation independent model (CIM), platform independent model (PIM), platform specific model(PSM), MDA-based methodologies

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Authors: Hami Ashraf, Mohammad Heydarnejad

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Introduction: The landscape of cancer treatment has been revolutionized by immunotherapy, offering novel therapeutic avenues for diverse cancer types. Animal models play a pivotal role in the development and elucidation of these therapeutic modalities. Nevertheless, the manifestation of Graft-versus-Host Disease (GVHD) in such models poses significant challenges, muddling the interpretation of experimental data within the ambit of cancer immunotherapy. This study is dedicated to scrutinizing the role of GVHD as a confounding factor in animal models used for cancer immunotherapy, alongside proposing viable strategies to mitigate this complication. Method: Employing a systematic review framework, this study undertakes a comprehensive literature survey including academic journals in PubMed, Embase, and Web of Science databases and conference proceedings to collate pertinent research that delves into the impact of GVHD on animal models in cancer immunotherapy. The acquired studies undergo rigorous analysis and synthesis, aiming to assess the influence of GVHD on experimental results while identifying strategies to alleviate its confounding effects. Results: Findings indicate that GVHD incidence significantly skews the reliability and applicability of experimental outcomes, occasionally leading to erroneous interpretations. The literature surveyed also sheds light on various methodologies under exploration to counteract the GVHD dilemma, thereby bolstering the experimental integrity in this domain. Conclusion: GVHD's presence critically affects both the interpretation and validity of experimental findings, underscoring the imperative for strategies to curtail its confounding impacts. Current research endeavors are oriented towards devising solutions to this issue, aiming to augment the dependability and pertinence of experimental results. It is incumbent upon researchers to diligently consider and adjust for GVHD's effects, thereby enhancing the translational potential of animal model findings to clinical applications and propelling progress in the arena of cancer immunotherapy.

Keywords: graft-versus-host disease, cancer immunotherapy, animal models, preclinical model

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