Preclinical Animal Studies Research Articles

5610845 A PHASE 1 STUDY OF CSL888 (HEMOPEXIN) IN ADULT PATIENTS WITH SICKLE CELL DISEASE

Background: Episodes of vaso-occlusive crisis (VOC) are the primary reason for hospitalization among patients with sickle cell disease (SCD). The release of heme from the breakdown of damaged red blood cells is thought to play an important role in contributing to vaso-occlusion in SCD. Free heme promotes activation of endothelium, expression of endothelial cell adhesion molecules and activation of blood cells (neutrophils, monocytes, and platelets) which “stick” to the blood vessel walls. The net result is blockage of blood circulation, resulting in the characteristic pain of VOC. Hemopexin is a 60 kilodalton (kDa) plasma glycoprotein that is mainly expressed in the liver and belongs to the family of acute-phase proteins whose synthesis is induced after an inflammatory event. Hemopexin binds extracellular heme with the highest known affinity (KD < 1pM) of all plasma proteins. In patients with SCD, hemopexin levels are significantly reduced (approximately 85%) compared to healthy controls due to increased consumption. CSL889 is human plasma-derived hemopexin. It is hypothesized that pharmacological administration of CSL889 may decrease heme toxicity, restore normal blood circulation and therefore have beneficial effects in the management of acute VOC in SCD patients. Translation to the clinic is supported by studies performed in vitro demonstrating protection of heme-mediated endothelial cell damage and in vivo using the Townes mouse model of SCD, in which hemopexin was shown ameliorate vaso-occlusion following hemoglobin or hypoxia/reperfusion challenges (Gentinetta et al. 2022). Preclinical repeat dose toxicity studies in animals have evidenced favorable tolerability up to the highest dose level tested. Methods: We describe the design of a Phase 1, first in human, multicenter, open-label study to evaluate the safety, tolerability, and pharmacokinetics (PK) of CSL889 in adult patients with SCD following single intravenous (IV) doses of CSL889 [NCT04285827]. The study will comprise 2 parts. Part A will include patients with SCD in their usual health (not in VOC) who will receive a single dose of CSL889 at one of up to 6 different dose levels. In Part B, patients with SCD who present in VOC requiring intravenous (IV) opioid injections and admission to hospital for further management, will receive a single dose of CSL889 at a level that has been shown to be safe and tolerable in Part A within 36 hours of in-patient admission. All subjects will be followed up for 32 days post-infusion of CSL889. The range of doses to be studied is based on a translational PK model based on data derived from the study of CSL889 in the Townes mouse model of SCD. Results: The primary objective is to determine the safety and tolerability of single doses of CSL889 given to patients with SCD both without (Part A) and with (Part B) active VOC. The secondary objectives are to determine the PK and immunogenicity of CSL889. Exploratory objectives are to determine changes in biomarkers of target engagement (including changes in cell-free heme) and pharmacodynamic biomarkers related to the mechanism of action. Change in pain scores (as measured by Numeric Rating Scale [NRS]) will be additionally evaluated in Part B. Conclusions: Enrollment is in progress. No serious adverse events considered related to the administration of CSL889 have been reported as of 01-Sep-2022. Disclosures: F Wilson, J Jochems, L Lindqvist, K Jung,T Gentinetta, S Costin and GJ Kato are employed by CSL Reference 1. Gentinetta et al, J Clin Med 2022, 11:630

In-vivo studies to determine Hair Growth Potential of Poly Herbal Medicated Hair Oil in Female Swiss Albino Mice

Hair loss is one of biggest problem of today’s human life throughout World. Alopecia, Baldness and hair loss are commonly found in the men as well as in female. Commonly available medicated hair oils in market for the treatment of hair disease are made up with mineral oil, which is proved to be carcinogenic in nature if applied for longer period of time. Hair plays a vital role in the personality of human and for their cure we use lots of cosmetic products. The fading (pigmentation problem), dandruff, alopecia (loss of hair) is the major problem associated with hairs. An Ayurveda is Indian traditional system of Medicine having major treatment across globe. The aim of study is to develop a poly herbal hair oil (PHO) formulation using Azadirachta indica, Rosa sinensis, Muraya koenigii, Lagenaria siceraria, Bacopa monieri, Lawsonia inermis, Eclipta alba, Embelica officinalis, coconut oil and Til oil, for better growth of hair and diminution in loss of hair (alopecia). The oil was prepared according to Ayurvedic Formulary of India and was standardized according to Protocol for Testing Ayurvedic, Siddha and Unani Medicines, Government of India. The physico-chemical evaluation was carried out for medicated hair oil. The pharmacological evaluations were performed through Pre-clinical Animal studies for qualitative, quantitative and mean- hair length studies.The statistical results of the study have demonstrated that 5% PHO possessed potent action on hair growth in the Female Swiss albino Mice animal’s model investigates as well as these provide a rationale in favor of its uses inside traditionally drug in favor of utilization in Baldness and other hair growth disorders.

International Society of Nephrology first consensus guidance for preclinical animal studies in translational nephrology

Preclinical tests in animal models are key steps in early drug development. Consequently, the International Society of Nephrology held a consensus meeting that connected experts in the global kidney community in order to provide guidance on optimal management of translational animal studies for the development of new drugs to treat kidney disease, entitled "TRANSFORM; TRAnslational Nephrology Science FOR new Medications." The meeting covered various themes, including the following: (i) selection of disease model; (ii) pharmacokinetics; (iii) interventions in late preclinical models; (iv) choice of animal; (v) statistical power; (vi) organoids and organ-on-a-chip models; and (vii) reporting of results. This guidance is the first to be provided on the optimal conduct of translational animal studies for the development of new drugs to treat kidney disease. These recommendations are designed to accelerate development of new drugs for efficacious treatment of kidney diseases, and to improve the prognosis and quality of life of patients with a variety of kidney diseases.

The protective effects of flavonoids and carotenoids against diabetic complications-A review of in vivo evidence.

Diabetes mellitus is a chronic metabolic disorder caused either by inadequate insulin secretion, impaired insulin function, or both. Uncontrolled diabetes is characterized by hyperglycemia which over time leads to fatal damage to both macro-and microvascular systems, causing complications such as cardiovascular diseases, retinopathy and nephropathy. Diabetes management is conventionally delivered through modifications of diet and lifestyle and pharmacological treatment, using antidiabetic drugs, and ultimately insulin injections. However, the side effects and financial cost of medications often reduce patient compliance to treatment, negatively affecting their health outcomes. Natural phytochemicals from edible plants such as fruits and vegetables (F&V) and medicinal herbs have drawn a growing interest as potential therapeutic agents for treating diabetes and preventing the onset and progression of diabetic complications. Flavonoids, the most abundant polyphenols in the human diet, have shown antidiabetic effects in numerous in vitro and preclinical studies. The underlying mechanisms have been linked to their antioxidant, anti-inflammatory and immunomodulatory activities. Carotenoids, another major group of dietary phytochemicals, have also shown antidiabetic potential in recent in vitro and in vivo experimental models, possibly through a mechanism of action similar to that of flavonoids. However, scientific evidence on the efficacy of these phytochemicals in treating diabetes or preventing the onset and progression of its complications in clinical settings is scarce, which delays the translation of animal study evidence to human applications and also limits the knowledge on their modes of actions in diabetes management. This review is aimed to highlight the potential roles of flavonoids and carotenoids in preventing or ameliorating diabetes-related complications based on in vivo study evidence, i.e., an array of preclinical animal studies and human intervention trials. The current general consensus of the underlying mechanisms of action exerted by both groups of phytochemicals is that their anti-inflammatory action is key. However, other potential mechanisms of action are considered. In total, 50 in vivo studies were selected for a review after a comprehensive database search via PubMed and ScienceDirect from January 2002 to August 2022. The key words used for analysis are type-2 diabetes (T2DM), diabetic complications, flavonoids, carotenoids, antioxidant, anti-inflammatory, mechanisms of prevention and amelioration, animal studies and human interventions.

Intranasal Delivery of miR133b in a NEO100-Based Formulation Induces a Healing Response in Spinal Cord-Injured Mice.

Despite important advances in the pre-clinical animal studies investigating the neuroinhibitory microenvironment at the injury site, traumatic injury to the spinal cord remains a major problem with no concrete response. Here, we examined whether (1) intranasal (IN) administration of miR133b/Ago2 can reach the injury site and achieve a therapeutic effect and (2) NEO100-based formulation of miR133b/Ago2 can improve effectiveness. 24 h after a cervical contusion, C57BL6 female mice received IN delivery of miR133b/Ago2 or miR133b/Ago2/NEO100 for 3 days, one dose per day. The pharmacokinetics of miR133b in the spinal cord lesion was determined by RT-qPCR. The role of IN delivery of miR133b on motor function was assessed by the grip strength meter (GSM) and hanging tasks. The activity of miR133b at the lesion site was established by immunostaining of fibronectin 1 (FN1), a miR133b target. We found that IN delivery of miR133b/Ago2 (1) reaches the lesion scar and co-administration of miR133b with NEO100 facilitated the cellular uptake; (2) enhanced the motor function and addition of NEO100 potentiated this effect and (3) targeted FN1 expression at the lesion scar. Our results suggest a high efficacy of IN delivery of miR133b/Ago2 to the injured spinal cord that translates to improved healing with NEO100 further potentiating this effect.

Edge effect reduction of high-resolution PET detectors using LYSO and GAGG phoswich crystals

Objective. Small-animal positron emission tomography (PET) is a powerful preclinical imaging tool in animal model studies. The spatial resolution and sensitivity of current PET scanners developed for small-animal imaging need to be improved to increase the quantitative accuracy of preclinical animal studies. This study aimed to improve the identification capability of edge scintillator crystals of a PET detector which will enable to apply a crystal array with the same cross-section area as the active area of a photodetector for improving the detection area and thus reducing or eliminating the inter-detector gaps. Approach. PET detectors using crystal arrays with mixed lutetium yttrium orthosilicate (LYSO) and gadolinium aluminum gallium garnet (GAGG) crystals were developed and evaluated. The crystal arrays consisted of 31 × 31 array of 0.49 × 0.49 × 20 mm3 crystals; they were read out by two silicon photomultiplier arrays with pixel sizes of 2 × 2 mm2 that were placed at both ends of the crystal arrays. The second or first outermost layer of the LYSO crystals was replaced by GAGG crystals in the two crystal arrays. The two crystal types were identified using a pulse-shape discrimination technique to provide better edge crystal identification. Main results. Using the pulse shape discrimination technique, almost all (except for a few edge) crystals were resolved in the two detectors; high sensitivity was achieved by using the scintillator array and the photodetector with the same areas and achieved high resolution by using crystals with sizes equal to 0.49 × 0.49 × 20 mm3. Energy resolutions of 19.3 ± 1.8% and 18.9 ± 1.5%, depth-of-interaction resolutions of 2.02 ± 0.17 mm and 2.04 ± 0.18 mm, and timing resolutions of 1.6 ± 0.2 ns and 1.5 ± 0.2 ns were achieved by the two detectors, respectively. Significance. In summary, novel three-dimensional high-resolution PET detectors consisting of a mixture of LYSO and GAGG crystals were developed. The detectors significantly improve the detection area with the same photodetectors and thus improve the detection efficiency.

Industry Adoption of Organoids and Organs-on-Chip Technology: Toward a Paradox of Choice.

During the last decade, organoid and organs-on-chip technologies have significantly enhanced the ability to model human biology in vitro. For the pharmaceutical industry, this represents an opportunity to augment, or possibly replace, traditional preclinical animal studies with more clinically predictive tools. In the last few years, the marketplace for new human model systems has expanded rapidly. While pharma companies welcome the breadth of new options, ample choice can be paralyzing. Even for experts from the model developer community who are now filling the ranks in theindustry, the pairing of the right model for a specific, fit-for-purpose biological question can be daunting. As a community, theadoption of these models can be hastened in theindustry by publishing high dimensional datasets (e.g., multiomic, imaging, functional, etc.) on existing model systems, termed model-omics, and storing them in publicly accessible databases. This action will allow for quick cross-model comparisons and provide asought-after rationale for either routine or fit-for-purpose use of organoids or organs-on-chip during drug development.

Mesenchymal stem cells in ischemic tissue regeneration.

Diseases caused by ischemia are one of the leading causes of death in the world. Current therapies for treating acute myocardial infarction, ischemic stroke, and critical limb ischemia do not complete recovery. Regenerative therapies opens new therapeutic strategy in the treatment of ischemic disorders. Mesenchymal stem cells (MSCs) are the most promising option in the field of cell-based therapies, due to their secretory and immunomodulatory abilities, that contribute to ease inflammation and promote the regeneration of damaged tissues. This review presents the current knowledge of the mechanisms of action of MSCs and their therapeutic effects in the treatment of ischemic diseases, described on the basis of data from in vitro experiments and preclinical animal studies, and also summarize the effects of using these cells in clinical trial settings. Since the obtained therapeutic benefits are not always satisfactory, approaches aimed at enhancing the effect of MSCs in regenerative therapies are presented at the end.

Practical Guidance for Developing Small-Molecule Optical Probes for In Vivo Imaging.

The WMIS Education Committee (2019-2022) reached a consensus that white papers on molecular imaging could be beneficial for practitioners of molecular imaging at their early career stages and other scientists who are interested in molecular imaging. With this consensus, the committee plans to publish a series of white papers on topics related to the daily practice of molecular imaging. In this white paper, we aim to provide practical guidance that could be helpful for optical molecular imaging, particularly for small molecule probe development and validation in vitro and in vivo. The focus of this paper is preclinical animal studies with small-molecule optical probes. Near-infrared fluorescence imaging, bioluminescence imaging, chemiluminescence imaging, image-guided surgery, and Cerenkov luminescence imaging are discussed in this white paper.

Gut Brain axis: The gut microbiome in peri-operative medicine.

Sir, The human body is inhabited by a multitude of bacteria, viruses, fungi, phages constituting the microbiota, and their gene pool called the microbiome which is essential for human well-being.[1] The role of gut microbiome in peri-operative medicine is recently being explored. However, most of the literature available is that of animal studies and more extensive research would be needed in humans to establish an association. The mechanism of action of gut-microbiome on various systems of the human body can be explained by the “gut-brain axis.” This is a two-way interaction between the enteric nervous system (ENS) and central nervous system (CNS) [Figure 1]. The gut microbiota secrete various metabolites and products like-short chain fatty acids (SCFA), enzymes, polysaccharides, cytokines, and neurotransmitters, which are released in to the circulation to act on the CNS. The vagus nerve also carries inputs from ENS to CNS. The brain in-turn acts on the gut through the hypothalamic-pituitary-adrenal (HPA) axis and the autonomic nervous system.[2] Immune mediated interaction and alteration of microglial activity are other proposed mechanisms of gut-brain interaction. All these mechanisms have been proven only by preclinical animal studies.[1]Figure 1: Gut brain axis. HPA = Hypothalamic pituitary adrenal axisAnaesthetic agents-like propofol and volatile anaesthetics have been found to alter the gut microbiota composition in animal studies. Han et al. studied gut microbiota of mice after sevoflurane exposure and found that microbiome composition was reduced on day-1, 3, 7, and 14 after sevoflurane anaesthesia compared to the control group. They also noted a significant difference in fecal metabolites of the experimental and control groups.[3] Also an infusion of propofol for 3 hours in rats was found to decrease the number of certain bacterial species for 14 days.[4] Postoperative delirium (POD) and post-surgical pain (PSP) have also been attributed to the gut-microbiome by animal studies. This means, why certain patients have more POD or PSP than others can be determined by their gut-microbiome constitution and may be pre-treatment with pre-biotics, post-biotics, or fecal microbiota transplantation reduces the risk of POD and PSP in these patients. However, this association between POD/PSP and gut-microbiome has been shown mostly in animal studies and human association is yet to be established.[1] Zhang et al. compared the gut-microbiota of rats who developed POD and those who did not develop POD after abdominal surgery. The composition of microbiota was significantly different between the groups. They also conducted fecal microbiota transplantation from rats with POD to antibiotic treated rats, which then developed POD.[5] A human study has proved association of gut microbiome with chronic PSP, where Yao et al. had preoperatively collected gut-microbiome samples for 132 patients undergoing breast cancer surgery. The gut microbiota of 66 patients who developed chronic PSP (CPSP) was significantly different from those who did not develop PSP. Fecal microbiome transplantation from CPSP patients to mice led to development of hyperalgesia in these mice.[6] The gut microbiome composition has been attributed to development of opioid tolerance. Chronic opioid exposure leads to activation of opioid receptors on gut epithelium and destruction of gut mucosal barrier, allowing translocation of gut bacteria leading to an inflammatory response and pain exacerbation.[1] The gut microbiota composition influences many chronic pain conditions like fibromyalgia, headache, neuropathic, visceral, and chronic pelvic pain. The mediators of gut microbiota can alter the neuronal excitability at the dorsal root ganglia and mediate neuro inflammation leading to central sensitization and peripheral sensitization in chronic pain. Thus, targeting the gut-microbiota seems to be a promising treatment of chronic pain.[1,2] In future, gut microbiome analysis might help to screen patients at risk of postoperative cognitive dysfunction, postoperative pain, chronic pain and opioid tolerance and alteration of gut microbiota by use of prebiotics, postbiotics, dietary, and life-style changes might provide therapeutic benefit in such patients. However, this hypothesis is based majorly on animal studies and gut microbiome still needs to be explored in humans. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.

Phase I study of PTM-101 as neoadjuvant therapy for borderline resectable or locally advanced pancreatic ductal adenocarcinoma: A trial in progress.

TPS775 Background: While there have been tremendous advances in cancer treatment, critical challenges remain including limited ability of drugs to successfully reach the tumor, short half-life, and low retention rate on site. Local control of non-metastatic pancreatic adenocarcinoma (PDAC) remains a major challenge. Up to 40% of patients present with locally advanced and borderline resectable anatomy, for whom enhanced local downsizing of disease could improve symptoms and increase overall survival (OS). Targeted therapies with reduced systemic toxicity are needed for the treatment of PDAC since current therapies have not provided meaningful advances. PTM-101 is a paclitaxel-impregnated absorbable product which is designed for direct, sustained release of the therapeutic agent at the tumor site. Preclinical animal studies demonstrate that PTM-101 results in enhanced drug levels in the tumor compared with comparable systemic paclitaxel dosing leading to tumor reduction, metastasis inhibition and survival benefit (Indolfi et al, 2016). Large animal (i.e. pigs) and human cadaver studies show that PTM-101 can successfully be deployed to the peritumoral pancreatic surface by a standard laparoscopic procedure. Further, large animal studies show no evidence of neutropenia, pancreatitis, severe fibrosis or scarring, or infection after placement of PTM-101. Methods: This Phase I trial will assess the addition of PTM-101 prior to mFOLFIRINOX in 6 subjects with newly diagnosed borderline resectable or locally advanced PDAC. The primary objective is to assess the safety, toxicity and feasibility of a single administration of PTM-101. It is hypothesized that PTM-101 will be readily implanted during diagnostic laparoscopy and will result in clinically meaningful delivery of paclitaxel directly towards the tumor area with good tolerance and minimal local systemic exposure of drug. Patients enrolled and treated on study will be monitored closely for local and systemic toxicities as well as preliminary signals of efficacy. Enrollment is in progress and 3 patients have been enrolled and completed prospective follow up at the time of abstract submission. Clinical trial information: ACTRN12621000881831 .

Automatic knowledge graph population with model-complete text comprehension for pre-clinical outcomes in the field of spinal cord injury

The paradigm of evidence-based medicine requires that medical decisions are made on the basis of the best available knowledge published in the literature. Existing evidence is often summarized in the form of systematic reviews and/or meta-reviews and is rarely available in a structured form. Manual compilation and aggregation is costly, and conducting a systematic review represents a high effort. The need to aggregate evidence arises not only in the context of clinical trials, but is also important in the context of pre-clinical animal studies. In this context, evidence extraction is important to support translation of the most promising pre-clinical therapies into clinical trials or to optimize clinical trial design. Aiming at developing methods that facilitate the task of aggregating evidence published in pre-clinical studies, in this paper a new system is presented that automatically extracts structured knowledge from such publications and stores it in a so-called domain knowledge graph. The approach follows the paradigm of model-complete text comprehension by relying on guidance from a domain ontology creating a deep relational data-structure that reflects the main concepts, protocol, and key findings of studies. Focusing on the domain of spinal cord injuries, a single outcome of a pre-clinical study is described by up to 103 outcome parameters. Since the problem of extracting all these variables together is intractable, we propose a hierarchical architecture that incrementally predicts semantic sub-structures according to a given data model in a bottom-up fashion. At the heart of our approach is a statistical inference method that relies on conditional random fields to infer the most likely instance of the domain model given the text of a scientific publication as input. This approach allows modeling dependencies between the different variables describing a study in a semi-joint fashion. We present a comprehensive evaluation of our system to understand the extent to which our system can capture a study in the depth required to enable the generation of new knowledge. We conclude the article with a brief description of some applications of the populated knowledge graph and show the potential implications of our work for supporting evidence-based medicine.

Cannabis companies and the sponsorship of scientific research: A cross-sectional Canadian case study.

Corporations across sectors engage in the conduct, sponsorship, and dissemination of scientific research. Industry sponsorship of research, however, is associated with research agendas, outcomes, and conclusions that are favourable to the sponsor. The legalization of cannabis in Canada provides a useful case study to understand the nature and extent of the nascent cannabis industry's involvement in the production of scientific evidence as well as broader impacts on equity-oriented research agendas. We conducted a cross-sectional, descriptive, meta-research study to describe the characteristics of research that reports funding from, or author conflicts of interest with, Canadian cannabis companies. From May to August 2021, we sampled licensed, prominent Canadian cannabis companies, identified their subsidiaries, and searched each company name in the PubMed conflict of interest statement search interface. Authors of included articles disclosed research support from, or conflicts of interest with, Canadian cannabis companies. We included 156 articles: 82% included at least one author with a conflict of interest and 1/3 reported study support from a Canadian cannabis company. More than half of the sampled articles were not cannabis focused, however, a cannabis company was listed amongst other biomedical companies in the author disclosure statement. For articles with a cannabis focus, prevalent topics included cannabis as a treatment for a range of conditions (15/72, 21%), particularly chronic pain (6/72, 8%); as a tool in harm reduction related to other substance use (10/72, 14%); product safety (10/72, 14%); and preclinical animal studies (6/72, 8%). Demographics were underreported in empirical studies with human participants, but most included adults (76/84, 90%) and, where reported, predominantly white (32/39, 82%) and male (49/83, 59%) participants. The cannabis company-funded studies included people who used drugs (37%) and people prescribed medical cannabis (22%). Canadian cannabis companies may be analogous to peer industries such as pharmaceuticals, alcohol, tobacco, and food in the following three ways: sponsoring research related to product development, expanding indications of use, and supporting key opinion leaders. Given the recent legalization of cannabis in Canada, there is ample opportunity to create a policy climate that can mitigate the harms of criminalization as well as impacts of the "funding effect" on research integrity, research agendas, and the evidence base available for decision-making, while promoting high-priority and equity-oriented independent research.

Stress-induced changes in nociceptive responding post-surgery in preclinical rodent models.

Chronic post-surgical pain affects up to 85% of individuals depending on the type of surgery, the extent of inflammation, tissue and/or nerve damage. Pre-surgical stress is associated with greater pain intensity, prolonged recovery and is one of the main risk factors for the development of chronic post-surgical pain. Clinically valid animal models provide an important means of examining the mechanisms underlying the effects of stress on post-surgical pain and identifying potential novel therapeutic targets. This review discusses the current data from preclinical animal studies examining the effect of stress on post-surgical pain, the potential underlying mechanisms and gaps in the knowledge that require further investigation.

Preclinical evaluation of an investigational 21-valent pneumococcal conjugate vaccine, V116, in adult-rhesus monkey, rabbit, and mouse models.

Despite the widespread effectiveness of pneumococcal conjugate vaccines on the overall incidence of invasive pneumococcal disease, the global epidemiological landscape continues to be transformed by residual disease from non-vaccine serotypes, thus highlighting the need for vaccines with expanded disease coverage. To address these needs, we have developed V116,an investigational 21-valent non-adjuvanted pneumococcal conjugate vaccine (PCV),containingpneumococcal polysaccharides (PnPs) 3, 6A, 7F, 8, 9N, 10A, 11A,12F, 15A, 16F, 17F, 19A, 20, 22F, 23A, 23B, 24F, 31, 33F, 35B, anda de-O-acetylated 15B(deOAc15B) individually conjugated to the nontoxic diphtheria toxoid CRM197 carrier protein. Preclinical studies evaluated the immunogenicity of V116 inadult monkeys, rabbits, and mice. Following one dose, V116 was found to be immunogenic in preclinical animal species and induced functional antibodies for all serotypes included in the vaccine, in addition to cross-reactive functional antibodies to serotypes 6C and 15B. In these preclinical animal studies, the increased valency of V116 did not result in serotype-specific antibody suppression when compared to lower valent vaccines V114 or PCV13. In addition, when compared with naïve controls, splenocytes from V116 to immunized animals demonstrated significant induction of CRM197-specific T cells in both IFN-γ and IL-4 ELISPOT assays, as well as Th1 and Th2 cytokine induction through in vitro stimulation assays, thus suggesting the ability of V116 to engage T cell dependent immune response pathways to aid in development of memory B cells. V116 also demonstrated significant protection in mice from intratracheal challenge with serotype 24F, a novel serotype not contained in any currently licensed vaccine.

Burn assessment: A critical review on care, advances in burn healing and pre-clinical animal studies

Burn assessment: A critical review on care, advances in burn healing and pre-clinical animal studies

Adrenal Grafts in the Central Nervous System: Chromaffin and Chromaffin Progenitor Cell Transplantation.

Chromaffin cells are neuroendocrine cells that synthesize and release catecholamines and neuroactive molecules. They have been used experimentally in animal models and preclinical studies as a source for cell replacement therapy in Parkinson's disease. The long-term cell survival of these cells in the nervous system is limited, and the observed motor improvements are highly variable. An alternative source for transplantation is chromaffin progenitor cells. These cells have the capacity of self-renewal and to form spheres under low attachment conditions. They release higher quantities of dopamine than chromaffin cells and can differentiate into dopaminergic-like neurons in vitro. The transplantation of these cells into Parkinson's disease animal models has shown to induce stronger motor improvements and better survival rates than chromaffin cells. However, several aspects of chromaffin progenitor cell transplantation remain to be elucidated. Here, we describe methods to isolate and culture chromaffin and chromaffin progenitor cells from the adult cattle adrenal glands. We also describe the procedure for their transplantation into the nervous system and give recommendations for their histological analysis.

органогеРациональные комбинации в фармакотерапии железодефицита

Iron deficiency remains one of the most common deficiencies worldwide. An inadequate and unbalanced diet may cause a lack of other nutrients necessary for hematopoiesis, which increases the risk of iron deficiency and makes it difficult to treat. Various pharmacotherapeutic approaches are being studied and applied, including combination medications, which in addition to iron consist of folic acid, copper/manganese gluconate, ascorbic acid, multivitamins, serine, and cyanocobalamin. Folate is a component that affects both the efficacy and safety of pharmacotherapy for iron deficiency. Preclinical animal studies comparing the dynamics of hematological indices confirmed a more rapid achievement of target values with the simultaneous use of iron and folic acid. Clinical studies in a group of pregnant women with iron-deficiency anemia (IDA) demonstrated that folic acid in combination with iron was more effective than iron as monotherapy. The combination of iron and folic acid is also rational in terms of increasing safety: folic acid prevents iron accumulation in the liver and the associated development of fibrosis. Ironinduced liver injury is related to oxidative stress catalyzed by iron overload. Folic acid regulates the transcription of genes involved in oxidative stress in the liver and the activity of 5'-AMP-activated protein kinase. Key words: iron deficiency, folic acid, hematopoiesis, rational pharmacotherapy

Experimental glaucoma microstent implantation in two animal models and human donor eyes-an ex vivo micro-computed tomography-based evaluation of applicability.

Minimally invasive glaucoma surgery (MIGS) has become an important treatment approach for primary open angle glaucoma. Restoration of aqueous humour drainage by means of alloplastic implants represents a promising treatment option and is itself subject of methodological development. An adequate positioning in the targeted tissue regions is essential is important for the performance of our in-house developed Rostock glaucoma microstent (RGM). The aim of this study was to evaluate the applicability of two animal models and human donor eyes regarding RGM placement. Eyes were obtained from rabbits, pigs, and human body donations. After orbital exenterations, RGMs were placed in the anterior chamber draining in the subconjunctival space. X-ray contrast was increased by incubation in aqueous iodine solution for subsequent detailed micro-computed tomography (micro-CT)-based visualization and analysis. In contrast to the human and porcine eyes, the stent extended far to the posterior pole with a more pronounced curvature along the globe in the rabbit eyes due to their smaller size. However, dysfunctional deformations were not depicted. Adequate positioning of the stent's inflow area in the anterior chamber and the outflow area in the Tenon space was achieved in both the animal models and the human eye. Micro-CT has proven to be a valuable tool for postoperative ex vivo evaluation of glaucoma drainage devices in its entire complexity. With regard to morphology, the porcine eye is the ideal animal model to test implantation procedures of the RGM. Nevertheless, rabbit eye morphology facilitates successful implantation results and provides all prerequisites for preclinical animal studies.

Adipose-Derived Stromal Cells for Chronic Wounds: Scientific Evidence and Roadmap Toward Clinical Practice.

Chronic wounds, ie, non-healing ulcers, have a prevalence of ~1% in the general population. Chronic wounds strongly affect the quality of life and generate considerable medical costs. A fraction of chronic wounds will heal within months of appropriate treatment; however, a significant fraction of patients will develop therapy-refractory chronic wounds, leading to chronic pain, infection, and amputation. Given the paucity of therapeutic options for refractory wounds, cell therapy and in particular the use of adipose-derived stromal cells (ASC) has emerged as a promising concept. ASC can be used as autologous or allogeneic cells. They can be delivered in suspension or in 3D cultures within scaffolds. ASC can be used without further processing (stromal vascular fraction of the adipose tissue) or can be expanded in vitro. ASC-derived non-cellular components, such as conditioned media or exosomes, have also been investigated. Many in vitro and preclinical studies in animals have demonstrated the ASC efficacy on wounds. ASC efficiency appears to occurs mainly through their regenerative secretome. Hitherto, the majority of clinical trials focused mainly on safety issues. However more recently, a small number of randomized, well-controlled trials provided first convincing evidences for a clinical efficacy of ASC-based chronic wound therapies in humans. This brief review summarizes the current knowledge on the mechanism of action, delivery and efficacy of ASC in chronic wound therapy. It also discusses the scientific and pharmaceutical challenges to be solved before ASC-based wound therapy enters clinical reality.