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The development of new medicines suffers from attrition, especially in the development pipeline. Eight out of nine drug candidates entering the clinical testing phase fail, mostly due to poor safety and efficacy. The low predictive value of animal models, used in earlier phases of drug development, for effects in humans poses a major problem. In particular, drug disposition can markedly differentiate in experimental animals versus humans. Meanwhile, classic in vitro methods can be used but these models lack the complexity to mimic holistic physiological processes occurring in the human body, especially organ-organ interactions. Therefore, better predictive methods to investigate drug disposition in the preclinical phase are needed, for which recent developments in multi-organ-on-chip methods are very promising. To be able to capture human physiology as good as possible, multi-organ-on-chips should feature: 1) human cells endogenously expressing main transporters and metabolizing enzymes; 2) organ models relevant for exposure route; 3) individual organs-on-chip connected in a physiologically relevant manner; 4) a tight cellular barrier between the compartments; 5) organ models properly polarized in 3D; 6) allow for sampling in all major compartments; 7) constructed from materials that do not absorb or adsorb the compound of interest; 8) cells should grow in absence of fetal calf serum (FCS) and Matrigel; 9) validated with a panel of compounds with known characteristics in humans; 10) an integrated computer model translating concentrations to the human situation. Here, an overview of available systems is presented and the difficult route towards a fully validated system is discussed.

BACKGROUND Detection of early capillaroscopic alterations in the preclinical phase may prove useful in patients with non-scleroderma connective tissue disease (CTD). We aimed to verify whether certain capillaroscopic alterations, alone or in combination, might be predictive of CTD. METHODS We retrospectively collected data on patients with Raynaud's phenomenon who underwent capillaroscopy conducted by highly expert examiners with a degree in vascular medicine at our institutions. Included subjects were divided in two groups: those developing rheumatic disease during follow-up, and those without subsequent diagnosis of CTD. Notably, we excluded subjects who presented with an evident scleroderma pattern or rheumatic disease during their initial examination. RESULTS We included a total of 76 patients, 60 who developed CTD during follow-up, which spanned in this group 23±7 months, and 16 who did not develop CTD during follow-up, which spanned 23±9 months. The following features were significantly associated with Raynaud's phenomenon: 1) angiotectonic disorder (p

Mannaa K Aldowsari,1 Manea M Al-Ahmari,2 Lujain I Aldosari,3 Mohammed M Al Moaleem,4 Mansoor Shariff,5 Ahmed M Kamili,6 Abdullah Q Khormi,6 Khaled A Alhazmi6 1Department of Pediatric Dentistry and Orthodontics, College of Dentistry, King Saud University, Riyadh, Saudi Arabia; 2Department of Periodontics and Community Dental Sciences, College of Dentistry, King Khalid University, Abha, Saudi Arabia; 3Prosthetic Department, College of Dentistry, King Khalid University, Abha, Saudi Arabia; 4Department of Prosthetic Dental Science, College of Dentistry, Jazan University, Jazan, Saudi Arabia; 5Department of Prothetic Dentistry, King Khalid University, Abha, Saudi Arabia; 6College of Dentistry, Jazan University, Jazan, Saudi ArabiaCorrespondence: Mohammed M Al MoaleemDepartment of Prosthetic Dental Science, College of Dentistry, Jazan University, Jazan, Saudi ArabiaTel +966 550599553Email drmoaleem2014@gmail.comPurpose: The aim of this study was to compare the preclinical and clinical undergraduate dental students’ perceptions of their educational climate (EC). In addition it will be compared with other local and international studies.Materials and Methods: Students enrolled in their third and fourth years (preclinical phase) and students in their fifth and sixth years (clinical phase) of the Bachelor of Dental Science at the University of Jazan, Saudi Arabia, were invited to complete a WhatsApp media survey, which included demographics and the Dundee Ready Education Environment Measure (DREEM). This scale measured students’ overall perceptions of the EC in five domains: learning, teaching, academic self-perception, atmosphere, and social self-perception. Data were analyzed with Student’s t-tests and ANOVA to compare between and within groups.Results: A total of 272 participants, 140 (51.5%) preclinical and 132 (48.5%) clinical students,took part in the study. Students were generally positive about their learning climate, with overall DREEM scores of 125.19 and 126.21 (preclinical) to 124.10 (clinical) out of a possible score of 200 phases. Student’s perceptions of teaching (26.18± 3.24/72.72%) and atmosphere (28.08± 5.29/63.82%) were the highest and lowest scores, respectively, and both scores were positive.Conclusion: No differences between the preclinical and clinical phases of the curriculum point to the structure of learning, teaching, academic, social self-perception in health professional degrees. Further research should investigate the weak points in the social and atmospheric climate.Keywords: educational climate, teaching, DREEM, student perception, education programs

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is globally explored to decode its genomic functionality along with elucidating immunogenic pathways to design and develop an efficient vaccine. Potential immunogenic targets have been screened and validated through preclinical evaluation using experimental models. Computational platform and molecular docking studies are also being conducted to study the immunodynamic mechanisms which involve suitable epitopes of host target cells that respond to the potential vaccine candidate eliciting an immune-mediated reaction. Although SARS-CoV-2 possesses genetic similarities with previously known human coronaviruses, the emergence of novel mutational changes in the immunodominant region of the receptor-binding domain of viral spike protein resulted in high transmissibility and fatality. On a periodical basis, the World Health Organization (WHO) publishes the update on evolving vaccine candidates and encouraging several vaccine developers including multinational companies to join the worldwide campaign against the COVID-19 pandemic. As per the latest WHO landscape draft of evolving vaccine candidates, around 180 teams with respective vaccine candidates across the world are working by utilizing multiple developmental platforms, out of which 35 candidates have entered clinical phase trial and 145 candidates are under the preclinical phase of evaluation. They are also being tested for undesired immunopotentiation without compromising their safety and efficacy. These vaccine candidates along with their advantages and various challenges have been reviewed in this article.

There is growing evidence that inflammatory bowel disease has a preclinical phase that precedes disease symptoms, during which immune system activation has already occurred and inflammatory pathways have been primed, setting the stage for disease to expand and leading up to clinical diagnosis. Gaining insight to this pre-diagnosis period could improve our knowledge about disease pathogenesis and potentially result in the detection of biomarkers that could predict disease development. The ultimate goal of such research is to identify a population at risk for developing IBD, so preventive strategies could be implemented and disease prevention be achieved.

Objectives To assess awareness and knowledge of Interventional Radiology (IR) in a large population of medical students in 2019. Methods An anonymous survey was distributed electronically to 9546 medical students from first to sixth year at three European medical schools. The survey contained 14 questions, including two general questions on diagnostic radiology (DR) and artificial intelligence (AI), and 11 on IR. Responses were analyzed for all students and compared between preclinical (PCs) (first to third year) and clinical phase (Cs) (fourth to sixth year) of medical school. Of 9546 students, 1459 students (15.3%) answered the survey. Results On DR questions, 34.8% answered that AI is a threat for radiologists (PCs: 246/725 (33.9%); Cs: 248/734 (36%)) and 91.1% thought that radiology has a future (PCs: 668/725 (92.1%); Cs: 657/734 (89.5%)). On IR questions, 80.8% (1179/1459) students had already heard of IR; 75.7% (1104/1459) stated that their knowledge of IR wasn’t as good as the other specialties and 80% would like more lectures on IR. Finally, 24.2% (353/1459) indicated an interest in a career in IR with a majority of women in preclinical phase, but this trend reverses in clinical phase. Conclusions Development of new technology supporting advances in artificial intelligence will likely continue to change the landscape of radiology; however, medical students remain confident in the need for specialty-trained human physicians in the future of radiology as a clinical practice. A large majority of medical students would like more information about IR in their medical curriculum; almost a quarter of students would be interested in a career in IR.

Objective Dental students follow different academic performance trajectories in response to increasing study load, based on individual and school factors. Group-based trajectory modeling is useful for clarifying the underlying trajectory patterns of students' academic performance and its determinants. To our knowledge, no studies have used group-based trajectory modeling to examine the effects of individual and school factors on academic performance trajectories in dental students. The objective of this study was to examine the effects of individual and school factors on academic performance trajectories in Japanese dental students using group-based trajectory modeling. Methods The analytical sample consists of 103 dental students admitted to Tokyo Medical and Dental University, Tokyo, Japan, in 2013 and 2014. Students' academic performance was assessed by biannual grade point average (GPA) score and GPA in the preclinical phase (second to fourth grade) was used for this study. We used group-based trajectory modeling to categorize students' GPA trajectories into different groups. A multinomial logistic regression model was fit to examine associations between students' individual and school factors, and odds of being assigned to certain GPA groups. Results GPA trajectories of dental students were classified into 4 different groups. Students' past academic performance in high school was associated with lower GPA trajectories and withdrawal or repeating years. Males were significantly associated with lower GPA trajectories and withdrawal or repeating years, even after adjusting for past academic performance. Conclusions Past lower academic performance and being male were positively associated with lower academic performance trajectories in Japanese dental students.

Keratoconjunctivitis sicca (KCS) is a multifactorial disease characterized by tear hyperosmolarity, inflammation, and ocular surface damage. Cyclosporine A (CsA) is used as an effective disease-modifying agent to improve the signs and symptoms of KCS by reducing inflammation, which interferes with tear production. This review provides an overview of efficacy, safety, and limitations of currently marketed topical CsA formulations-including CsA ophthalmic emulsion, cationic nanoemulsion, and aqueous nanomicelles-and highlights newer technologies for controlled ocular delivery of CsA and their clinical implications. Long available emulsion formulations of CsA are oil-based and have several limitations, including slow onset of efficacy and low intraocular penetration and bioavailability. Aqueous CsA nanomicelle carriers produce rapid improvement in objective signs of KCS such as corneal and conjunctival staining as early as 4 weeks and have acceptable safety profiles. CsA formulations using semifluorinated alkanes or polyaphrons are currently in clinical development, having recently completed Phase 2 studies. Other carriers for CsA currently in the preclinical phase include microemulsions, polymeric aqueous and lyophilized micelles, and hydrogels; these novel formulations have yet to undergo clinical trials. Formulations that improve tissue availability of CsA may be beneficial in clinical practice by providing faster onset of relief and improving patient adherence.

This paper describes the history of transcatheter aortic valve implantation (TAVI) from its preclinical phase during which visionary pioneers developed its concept and prototype valves against strong head wind to first application in clinical practice (2002) and the clinical and scientific role of an early believer and adopter, the Netherlands (2005).

Primary Sjögren’s syndrome (pSS) is a heterogeneous disease characterised by a wide spectrum of manifestations that vary according to the different stages of the disease and among different subsets of patients. The aim of this qualitative literature review is to summarise the recent advances that have been reported in pSS, ranging from the early phases to the established disease and its complications. We analysed the diagnostic, prognostic, and management aspects of pSS, with a look into future clinical and research developments. The early phases of pSS, usually antedating diagnosis, allow us to investigate the pathophysiology and risk factors of the overt disease, thus allowing better and timely patient stratification. Salivary gland ultrasound (SGUS) is emerging as a valid complementary, or even alternative, tool for histopathology in the diagnosis of pSS, due to a standardised scoring system with good agreement and performance. Other promising innovations include the application of artificial intelligence to SGUS, ultrasound-guided core needle biopsy, and a wide array of novel diagnostic and prognostic biomarkers. Stratifying pSS patients through the integration of clinical, laboratory, imaging, and histopathological data; differentiating between activity-related and damage-related manifestations; and identifying patients at higher risk of lymphoma development are essential steps for an optimal management and individualised treatment approach. As new treatment options are emerging for both glandular and systemic manifestations, there is a need for a more reliable treatment response evaluation. pSS is a complex and heterogeneous disease, and many distinct aspects should be considered in the different stages of the disease and subsets of patients. In recent years, efforts have been made to improve our understanding of the disease, and certainly in the coming years, some of these novelties will become part of our routine clinical practice, thus improving the management of pSS patients.

Background: Multiple-choice questions (MCQs) are used for measuring the student’s progress, and they should be analyzed properly to guarantee the item’s appropriateness. The analysis usually determines three indices of an item; difficulty or passing index (PI), discrimination index (DI), and distractor efficiency (DE). Objectives: This study was aimed to analyze the multiple-choice questions in the preclinical and clinical examinations with different numbers of options in medical program of Universiti Putra Malaysia. Methods: This is a cross-sectional study. Forty multiple-choice questions with four options from the preclinical examination and 80 multiple-choice questions with five options from the clinical examination in 2017 and 2018 were analyzed using optical mark recognition machine and Ms. Excel. The parameters included PI, DI, and DE. Results: The average difficulty level of multiple-choice questions for preclinical and clinical phase examinations were similar in 2017 and 2018 that were considered ‘acceptable’ and ‘ideal’ ranged from 0.55 to 0.60, respectively. The average DIs were similar in all examinations that were considered ‘good’ (ranged from 0.25 to 0.31) except in 2018 clinical phase examination that showed ‘poor’ items (DI = 0.20 ± 0.11). The questions for preclinical phase showed an increase in the number of ‘excellent’ and ‘good’ items in 2018 from 37.5% to 70.0%. There was an increase of 10.0% for preclinical phase, and 6.25% for clinical phase, in the number of items with no non-functioning distractors in 2018. Among all, preclinical multiple-choice questions in 2018 showed the highest mean of DE (71.67%). Conclusions: Our findings suggested that there was an improvement in the questions from preclinical phase while more training on questions preparation and continuous feedback should be given to clinical phase teachers. A higher number of options did not affect the level of difficulty of a question; however, the discrimination power and distractors efficiency might differ.

Aim: Partnerships have been leveraged to advance the regenerative medicines (RMs) development. This study analyzed the evolution of partnership landscape for regenerative medicines (RMs). Methods: Partnership agreements publicly announced from January 2014 – June 2020 were described. Results: 1169 partnership agreements with total amount of US$63,496 million were identified. Most agreements concerned RMs that were for oncology (25.3%), in the discovery or preclinical phase (66.9%) and gene-based products (45.3%). The most common partnership type is collaborative agreements without licensing. The partnerships between ‘biotechnology companies and not-for-profit organizations’ represented the largest number (n = 416; 35.6%). ‘Big Pharma’ preferred collaboration and licensing agreements with a higher amount. Conclusion: Collaborations between highly specialized players with complementary expertise promote the successful translation of scientific discovery to RMs.

This review discusses the reported studies investigating the use of bioprinting to develop functional organ-on-chip systems from a manufacturing perspective. These organ-on-chip systems model the liver, kidney, heart, lung, gut, bone, vessel, and tumors to demonstrate the viability of bioprinted organ-on-chip systems for disease modeling and drug screening. In addition, the paper highlights the challenges involved in using bioprinting techniques for organ-on-chip system fabrications and suggests future research directions. Based on the reviewed studies, it is concluded that bioprinting can be applied for the automated and assembly-free fabrication of organ-on chip systems. These bioprinted organ-on-chip systems can help in the modeling of several different diseases and can thereby expedite drug discovery by providing an efficient platform for drug screening in the preclinical phase of drug development processes.

Dental education is incorporating computer-assisted design/computer-assisted manufacturing (CAD/CAM) into patient care delivery. The aim of this study was to determine if lean production methods applied to the preclinical phase of dental education would reduce the students' time (efficiency) to complete CAD/CAM indirect restorations (CAD/CAM IR) without compromising the desired quality of the CAD/CAM tooth preparations (effectiveness). In 2016, all third-year students at one U.S. dental school were randomly assigned to control and research groups (approximately 33 per group). The control group was taught using existing methods, while the course was redesigned to incorporate lean methods for the research group. Cycle times of the CAD/CAM IR process for both groups were collected and statistically analyzed to compare the effectiveness of the redesign. Standardized grading forms and tools were used to assess the quality of the CAD/CAM tooth preparations. The research group demonstrated significantly faster preparation times with both crowns and onlays (p0.05) than the control group. The research group also produced CAD/CAM crown and onlay designs at a significantly faster pace than the control group (p0.05). There was no significant difference between the control and research groups associated with the scanning process times (p0.05) nor in the quality of the CAD/CAM tooth preparations (p0.05). This study demonstrated that lean methods applied to pedagogy significantly decreased preparation and design times in a CAD/CAM restorative dentistry course without compromising the quality of the CAD/CAM tooth preparations.

Background Vitis genus comprised about 70 species. Concerning its pharmacological properties, V. vinifera is the most studied one, but there are other species with interest. Scope and approach Therefore, this review aims to provide an updated overview on bioactive phytochemicals present in food products (grapes and wine) of V. vinifera and other Vitis species, as well as in different underused bioresources (stem, leaves, seeds, wine pomace, etc.). Moreover, due to their promising perspectives in the field of anticancer drug discovery, this bioactivity has been covered as well as the contribution that Vitis phenolic compounds has. Findings and conclusions Among the plant products reviewed, grape seed extracts was the most investigated at preclinical phase, hence exhibiting a promising potential as anticancer drugs. However, an evidence-based clinical efficacy is still lacking.

Autoantibodies (AA) and antinuclear antibodies (ANA) serve as key diagnostic and classification criteria for systemic lupus erythematosus (SLE). More than 200 different AA have been reported in SLE, although only a handful (

Los ensayos clínicos toman gran relevancia en el desarrollo de nuevos fármacos al evaluar la farmacocinética, farmacodinamia, eficacia, seguridad y sus posibles efectos adversos. Para que un nuevo fármaco esté disponible para su uso cotidiano en pacientes, desde hace más de cuatro décadas se propuso un modelo que consiste en la realización de estudios de investigación secuenciales que se denominaron fases clínicas I, II, III y IV, las cuales se inician una vez que se han comprobado los efectos del fármaco en modelos celulares y animales (fase preclínica). En este artículo se sintetizan las características generales de cada una de las fases clínicas, pero además se describen las modificaciones que se han realizado en el trascurso de los años, a fin de disponer rápidamente de nuevos fármacos.

Staphylococcus aureus normally colonizes the nasal cavity and pharynx. After breaching the normal habitat, the organism is able to cause a number of infections at any site of the body. The development of antibiotic resistance has created a global challenge for treating infections. Therefore, protection by vaccines may provide valuable measures. Currently, several vaccine candidates have been prepared which are either in preclinical phase or in early clinical phase, whereas several candidates have failed to show a protective efficacy in human subjects. Approaches have also been made in the development of monoclonal or polyclonal antibodies for passive immunization to protect from S. aureus infections. Therefore, in this review we have summarized the findings of recently published scientific literature to make a concise report.

The 5-HT 7 receptor (5-HT 7 R) is involved in a broad range of physiological conditions and disorders. Currently, there is no validated clinical positron emission tomography (PET) tracer available; however, we have recently developed a promising 11 C-labeled candidate. In this project, we aimed to further extend our efforts and develop an 18 F-labeled derivative, coined [ 18 F]ENL30. Fluorine-18 has several advantages over carbon-11 especially within the preclinical phase, where a long half-life usually increases evaluation throughput. ENL30 was successfully synthesized in a low albeit sufficient overall yield. Radiolabeling succeeded with a radiochemical yield of approximately 4.5%. Subsequent preclinical PET studies revealed that [ 18 F]ENL30 binds specifically to the 5-HT 7 R but suffered from affinity to σ-receptors. Additionally, we identified [ 18 F]ENL30 to be a P-gp substrate in rats. However, we believe that [ 18 F]ENL30 may prove to be valuable in higher species that exhibit decreased P-gp dependency. If required, σ-receptor binding could, in such studies, be selectively blocked potentially allowing for selective 5-HT 7 R imaging.

Background The plant kingdom represents an unlimited source of phytotherapeutics with promising perspectives in the field of anticancer drug discovery. Purpose In this view, epithelial-mesenchymal transition (EMT) represents a novel and major target in anticancer therapy. Therefore, this narrative review aims to provide an updated overview on the bioactive phytochemicals with anti-EMT activity. Conclusion Among the plant products reviewed, phenylpropanoids were the most investigated at preclinical phase, thus exhibiting a promising potential as anticancer drugs, though an evidence-based clinical efficacy is still lacking.

Background Cynomolgus disease models that are similar to the preclinical stage of human type 2 diabetes mellitus (T2DM) were established by feeding middle‐aged cynomolgus monkeys different high energy diets to study the differential expression of diabetes‐related genes. Methods A total of 36 male monkeys were randomly divided into four groups and fed human diets with high sugar, high fat, double high sugar and fat, and a normal diet. The preclinical diabetes phase was determined by monitoring the metabolic characteristic indices and the results of oral glucose tolerance tests (OGTT). The mRNA expression of 45 diabetes‐related genes in peripheral blood leukocytes was analyzed using real‐time PCR. Results A total of 22, 25, and 21 genes were significantly up‐regulated (P

In presymptomatic Alzheimer’s disease (AD), beta-amyloid plaques (Aβ) and tau tangles accumulate in distinct spatiotemporal patterns within the brain, tracking closely with episodic memory decline. Here, we tested whether age-related changes in the segregation of the brain’s intrinsic functional episodic memory networks—anterior-temporal (AT) and posterior-medial (PM) networks—are associated with the accumulation of Aβ, tau, and memory decline using fMRI and PET. We found that AT and PM networks were less segregated in older than that in younger adults and this reduced specialization was associated with more tau and Aβ in the same regions. The effect of network dedifferentiation on memory depended on the amount of Aβ and tau, with low segregation and pathology associated with better performance at baseline and low segregation and high pathology related to worse performance over time. This pattern suggests a compensation phase followed by a degenerative phase in the early, preclinical phase of AD.

The three-dimensional (3D) multicellular tumor spheroids (MCTs) model is becoming an essential tool in cancer research as it expresses an intermediate complexity between 2D monolayer models and in vivo solid tumors. MCTs closely resemble in vivo solid tumors in many aspects, such as the heterogeneous architecture, internal gradients of signaling factors, nutrients, and oxygenation. MCTs have growth kinetics similar to those of in vivo tumors, and the cells in spheroid mimic the physical interaction of the tumors, such as cell-to-cell and cell-to-extracellular matrix interactions. These similarities provide great potential for studying the biological properties of tumors and a promising platform for drug screening and therapeutic efficacy evaluation. However, MCTs are not well adopted as preclinical tools for studying tumor behavior and therapeutic efficacy up to now. In this review, we addressed the challenges with MCTs application and discussed various efforts to overcome the challenges.

The first drug specific for cystic fibrosis (CF) was approved in 1993, and since then several other drugs have been approved. Median predicted survival in people with CF has improved from approximately 30 years to 44.4 years over that same period. In 2020, highly-effective modulators of the cystic fibrosis transmembrane conductance regulator became available to approximately 90% of people with CF ages 12 years and older. These transformative therapies will surely reduce morbidity and further extend longevity. The drug development pipeline is filled with therapies that address most aspects of CF disease. As survival and CF therapies have advanced, and the complexity of CF care increases, the process of drug development has become more sophisticated. In addition, detecting meaningful changes in clinical outcomes has become more difficult as the health status of people with CF improves. Design of clinical trials in CF has become more complex, and innovative approaches are required to continue to advance drug development. This review provides a general overview of drug development from the pre-clinical phase through Phase IV. Special considerations with respect to CF are integrated into the discussion of each phase of drug development. The dawn of a new era has arrived for people with CF. As CF care evolves, drug development must continue to evolve as well, until a one-time cure is available to all people with CF.

Contains fulltext : 235103.pdf (Publisher’s version ) (Open Access) OBJECTIVES: The main objective of this review was to map how decision analytic models are used in surgical innovation (in which research phase, with what aim) and to understand how challenges related to the assessment of surgical interventions are incorporated. METHODS: We systematically searched PubMed, Embase, and the Cochrane Library for studies published in 2018. We included original articles using a decision analytic model to compare surgical strategies. We included modeling studies of surgical innovations. General, innovation, and modeling characteristics were extracted, as were outcomes, recommendations, and handling of challenges related to the assessment of surgical interventions (learning curve, incremental innovation, dynamic pricing, quality variation, organizational impact). RESULTS: We included 46 studies. The number of studies increased with each research phase, from 4% (n = 2) in the preclinical phase to 40% (n = 20) in phase 3 studies. Eighty-one studies were excluded because they investigated established surgical procedures, indicating that modeling is predominantly applied after the innovation process. Regardless of the research stage, the aim to determine cost-effectiveness was most frequently identified (n = 40, 87%), whereas exploratory aims (eg, exploring when a strategy becomes cost-effective) were less common (n = 9, 20%). Most challenges related to the assessment of surgical interventions were rarely incorporated in models (eg, learning curve [n = 1, 2%], organizational impact [n = 2, 4%], and incremental innovation [n = 1, 2%]), except for dynamic pricing (n = 10, 22%) and quality variation (n = 6, 13%). CONCLUSIONS: In surgical innovation, modeling is predominantly used in later research stages to assess cost-effectiveness. The exploratory use of modeling seems still largely overlooked in surgery; therefore, the opportunity to inform research and development may not be optimally used.

Neuroblastoma (NB) represents the most common extracranial tumor of childhood. Prognosis is quite variable, ranging from spontaneous regression to aggressive behavior with wide metastatization, high mortality, and limited therapeutic options. Radiotheranostics combines a radiopharmaceutical pair in a unique approach, suitable both for diagnosis and therapy. For many years, metaiodobenzylguanidine (MIBG), labeled with 123I for imaging or 131I for therapy, has represented the main theranostic agent in NB, since up to 90% of NB incorporates the aforementioned radiopharmaceutical. In recent years, novel theranostic agents hold promise in moving the field of NB radiotheranostics forward. In particular, SarTATE, consisting of octreotate targeting somatostatin receptors, has been applied with encouraging results, with 64Cu-SARTATE being used for disease detection and with 67Cu-SARTATE being used for therapy. Furthermore, recent evidence has highlighted the potential of targeted alpha therapy (TAT) for treating cancer by virtue of alpha particles’ high ionizing density and high probability of killing cells along their track. On this path, 211At-astatobenzylguanidine (MABG) has been developed as a potential agent for TAT and is actually under evaluation in preclinical NB models. In this review, we performed a web-based and desktop literature research concerning radiotheranostic approaches in NB, covering both the radiopharmaceuticals already implemented in clinical practice (i.e.,123/1311-MIBG) and those still in a preliminary or preclinical phase.

Plants represent a rich source of structurally diverse secondary metabolites, which can be exploited in the development of new clinically important compounds. Indeed, due to their biodiversity, medicinal plants represent the largest library of compounds that has ever existed. To date less than 1% of this vast biodiversity has been exploited in drug discovery, due to several factors, including the lack of an appropriate multidisciplinary perspective. Here we review the successful application of computer-aided methods in screening a unique and high-diversity in house collection library composed of around 1000 individual natural products, isolated mainly from indigenous plants collected in biodiversity-rich countries, especially of the tropics and subtropics, and enlarged with their semi-synthetic and synthetic derivatives, as well as plant material extracts, up to around 2000 components. During the last ten years, the in house library has provided several lead compounds that have been developed, and in some cases patented, as anticancer and antimicrobial agents. The main classes of the library are described, including (but not limited to) alkaloids, terpenoids, Diels–Alder-type adducts, isoflavones, chalcones, and cannabinoids. The main focus is on the chemical characteristics and biological activity of these identified compounds, with particular attention being given to those currently under patent or in the preclinical phase. We also assess the use of computer-aided methods in screening this unique and diverse in house collection of natural products that, over the last ten years, has provided some lead compounds that have been developed, and in some cases patented, as anticancer and antimicrobial agents. Finally, this review highlights the potential use of plant food extracts as a source of nutraceuticals and functional foods. The multidisciplinary approach described herein may further motivate research groups involved in natural product chemistry to potentially benefit from a limitless source of novel bioactive compounds.

Complex and miniaturized oral drug delivery systems are being developed rapidly for targeted, controlled drug release and improved bioavailability. Standard analytical techniques are widely used to characterize i) drug carrier and active pharmaceutical ingredients before loading into a delivery device (to ensure the solid form), and ii) the entire drug delivery system during the development process. However, in light of the complexity and the size of some of these systems, standard techniques as well as novel sensing technologies and experimental platforms need to be used in tandem. These technologies and platforms are discussed in this review, with a special focus on passive delivery systems in size range from a few 100 µm to a few mm. Challenges associated with characterizing these systems and evaluating their effect on oral drug delivery in the preclinical phase are also discussed.

Oropharyngeal squamous cell carcinoma (OPSCC) develops as a consequence of several mutations in the tumor suppressor pathways or after a progressive infection with high risk human papillomavirus (HPV). The dismal side effects of the current standard of care and the clear involvement of the immune system has led to a surge in clinical trials that aim to reinforce the tumor-specific immune response as a new treatment option. In this review, we have focused on the most recent literature to discuss the new findings and insights on the role of different immune cells in the context of OPSCC and its etiology. We then applied this knowledge to describe potential biomarkers and analyzed the rationale and outcomes of earlier and ongoing immunotherapy trials. Finally, we describe new developments that are still at the preclinical phase and provide an outlook on what the near future may bring, now that several new and exciting techniques to study the immune system at the single cell level are being exploited.

In presymptomatic Alzheimer’s disease (AD), beta-amyloid plaques (Aβ) and tau tangles accumulate in distinct spatiotemporal patterns within the brain, tracking closely with episodic memory decline. Here, we tested whether age-related changes in the segregation of the brain’s functional episodic memory networks - anterior-temporal (AT) and posterior-medial (PM) networks - are associated with the accumulation of Aβ, tau and memory decline using fMRI and PET. We found that AT and PM networks were less segregated in older than younger adults and this reduced specialization was associated with more tau and Aβ in the same regions. The effect of network dedifferentiation on memory depended on the amount of Aβ and tau, with low segregation and pathology associated with better performance at baseline and low segregation and high pathology related to worse performance over time. This pattern suggests a compensation phase followed by a degenerative phase in the early, preclinical phase of AD.

DergiPark: 819194 tmsj Aims: This study aims to identify the thoughts and opinions of medical schools’ students and academicians about the distance medical education and examination system that has been rapidly applied during the COVID-19 pandemic Methods: A ques- tionnaire was prepared via Google Forms which consisted of a total of 3 sections. Informed consent was obtained in the first section and participants were directed to “student” or “academician” section. There were 28 questions for the students and 24 questions for the academicians. Categorical variables were demonstrated as numbers and percentages, whereas continuous variables were presented as minimum, maximum, and mean values. Chi-squared test was used to compare preclinic and clinic year students, and the academicians in preclinic, medical, and surgical fields. Results: A total of 321 participants completed the questionnaire. The mean participant ages were 21.4 years and 41.68 years for the students and the academicians, respectively. Only 30% of the students thought the distance education lessons were beneficial while it was 35.5% for the academicians. 25.8% of the academicians and 29.6% of the students were indecisive on the matter. When the examination process was taken into account 67.7% of the academicians and 56.9% of the students thought the online examinations were not reliable. Conclusion: It is predicted that the pandemic process will continue in the next academic years. Considering the current situation, distance education seems to be the best option to ensure that the learning process can continue while protecting the health of students and academicians. Although distance education is not sufficient by itself in medical education during and after the COVID-19 pandemic, it is a method that should be used in almost every field of medical education, especially in the preclinical phase. Both the distance education, and online examination process require improvements and they are needed to be supported with face to face lectures and practices.

Nontuberculous mycobacteria (NTM) represent an increasingly prevalent etiology of soft tissue infections in animals and humans. NTM are widely distributed in the environment and while, for the most part, they behave as saprophytic organisms, in certain situations, they can be pathogenic, so much so that the incidence of NTM infections has surpassed that of Mycobacterium tuberculosis in developed countries. As a result, a growing body of the literature has focused attention on the critical role that drug susceptibility tests and infection models play in the design of appropriate therapeutic strategies against NTM diseases. This paper is an overview of the in vitro and in vivo models of NTM infection employed in the preclinical phase for early drug discovery and vaccine development. It summarizes alternative methods, not fully explored, for the characterization of anti-mycobacterial compounds.

We report a correlation between trends of hemodynamic parameters including pulmonary artery pressures (PAP) and heart rate recorded by CardioMEMS device (St. Jude Medical, St. Paul, MN, USA) and presentation of gastrointestinal (GI) bleeding in two patients with left ventricular assist devices. We observed a decline in PAP levels prior to symptom onset and reduction in hemoglobin level in both patients. Early recognition of hemodynamic changes by CardioMEMS device might help clinicians to detect the preclinical phase of GI bleeding and intervene before patients develop severe symptoms and associated morbidity.

Intravenous (IV) route is preferred for rapid onset of action, avoiding first pass metabolism and achieving site specific delivery. Development of IV formulations for poorly water soluble drugs poses significant challenges. Formulation approaches like salt formation, co-solvents, surfactants and inclusion complexation using cyclodextrins are used for solubilisation. However, these approaches are not applicable universally and have limitations in extent of solubilisation, hypersensitivity, toxicity and application to only specific type of molecules. IV nanosuspension have been attracting attention as a viable strategy for development of IV formulations of poorly water-soluble drugs. Nanosuspension consists of nanocrystals of poorly water soluble drug suspended in aqueous media and stabilized using minimal concentration of stabilizers. Recent years have witnessed their potential in formulations for toxicological studies and clinical trials. However various challenges are associated with the translational development of IV nanosuspensions. Therefore, the objective of the current review is to provide a holistic view of formulation development and desired properties of IV nanosuspensions. It will also focus on advancements in characterization tools, manufacturing techniques and post-production processing. Challenges associated with translational development and regulatory aspects of IV nanosuspension will be addressed. Additionally, their role in preclinical evaluation and special applications like targeting will also be discussed with the help of case studies. The applications of IV nanosuspensions shall expand as their applications move from preclinical phase to commercialization.

Nanotechnology has emerged as a favorable alternative for the treatment and identification of various neurodegenerative conditions. Nanomedicine is a division of a newly developing arena of nanotechnology, and is a quickly evolving discipline. By gaining entrance to several zones of the body that were previously assumed to be inaccessible, nanotechnology-based procedures have shown high potential to identify illnesses and deliver action in ways which were once unimaginable. In addition, scientists continue to search for the compound brain variations involved in the development of Alzheimer’s illness. Brain shocks as far back as a decade can cause memory and reasoning problems. During this preclinical phase of Alzheimer’s disease, people appear to be symptom-free, but changes are occurring in the brain that could be addressed earlier with proper treatment. Currently, the construction of various nanomedicine procedures has exposed some benefits to access the blood brain barrier, offering new analysis and treatment methods for diseases like Alzheimer’s.

Alzheimer's Disease (AD) is the first cause of dementia and represents a serious medical problem that severely affects social, sanitary, and economic aspects of life and its populations. Late-onset AD (age at onset >65 years) is the most frequent form. This is a complex disorder most likely caused by multiple genetic and environmental susceptibility factors. The pathophysiological process of AD is thought to begin many years before the appearance of dementia symptoms. This preclinical phase of AD would provide a critical opportunity for therapeutic intervention. In this chapter, we explore the relationship between AD neuropathology and neuronal bioenergetics in transgenic animal models of AD. We compare bioenergetic parameters obtained from isolated mitochondria and synaptosomes, addressing advantages and disadvantages of each biological preparation. Furthermore, we speculate that targeting synaptosomal bioenergetic defects could slow or prevent the neurodegenerative process and restore neuronal function.

The biological discrepancies between animal and human models have led to increased costs and low efficiency of discovery of new drugs, for drug screening applications. Human organoids are the current golden standard for the development of humanized platforms, for a more reliable preclinical phase of drug discovery. Here, we review the main features that place stem cells as a leader in disease modeling applications, and their importance for cell therapy. Especially, we focus on the use of human pluripotent stem cell (hPSC)–derived organoids as the most suitable option for designing new drug screening platforms that will allow high throughput analysis, compared to current options. Moreover, integration of different representative organoids within a single microfluidic platform—a multiorganoid approach— can lead to results that better mimic the in vivo behavior, analyzing the system as a whole, and combining the interactions between different tissues.