Growth Factor Type Research Articles

Efficacy of using adipose-derived stem cells and PRP on regeneration of 40 -mm long sciatic nerve defect bridged by polyglycolic-polypropylene mesh in canine model

BackgroundSciatic nerve repair becomes a focus of research in neurological aspect to restore the normal physical ability of the animal to stand and walk. Tissue engineered nerve grafts (TENGs) provide a promising alternative therapy for regeneration of large gap defects. The present study investigates the regenerative capacity of PRP, ADSCs, and PRP mixed ADSCs on a long sciatic nerve defect (40-mm) bridged by a polyglycolic polypropylene (PGA-PRL) mesh which acts as a neural scaffold.Materials and methodsThe study was conducted on 12 adult male mongrel dogs that were randomly divided into 4 groups: Group I (scaffold group); where the sciatic defect was bridged by a (PGA-PRL) mesh only while the mesh was injected with ADSCs in Group II (ADSCs group), PRP in Group III (PRP group). Mixture of PRP and ADSCs was allocated in Group IV (PRP + ADSCs group). Monthly, all animals were monitored for improvement in their gait and a numerical lameness score was recorded for all groups. 6 months-post surgery, the structural and functional recovery of sciatic nerve was evaluated electrophysiologically, and on the level of gene expression, and both sciatic nerve and the gastrocnemius muscle were evaluated morphometrically, histopathologically.ResultsNumerical lameness score showed improvement in the motor activities of both Group II and Group III followed by Group IV and the scaffold group showed mild improvement even after 6 months. Histopathologically, all treated groups showed axonal sprouting and numerous regenerated fascicles with obvious angiogenesis in proximal cut, and distal portion where Group IV exhibited a significant remyelination with the MCOOL technique. The regenerative ratio of gastrocnemius muscle was 23.81%, 56.68%, 52.06% and 40.69% for Group I, II, III and IV; respectively. The expression of NGF showed significant up regulation in the proximal portion for both Group III and Group IV (P ≤ 0.0001) while Group II showed no significant difference. PDGF-A, and VEGF expressions were up-regulated in Group II, III, and IV whereas Group I showed significant down-regulation for NGF, PDGF-A, and VEGF (P ≤ 0.0001).ConclusionADSCs have a great role in restoring the damaged nerve fibers by secreting several types of growth factors like NGF that have a proliferative effect on Schwann cells and their migration. In addition, PRP therapy potentiates the effect of ADSCs by synthesis another growth factors such as PDGF-A, VEGF, NGF for better healing of large sciatic gap defects.

THE USE OF PLATELET-RICH PLASMA IN THE TREATMENT OF ALOPECIA - A REVIEW OF THE LITERATURE

Alopecia is a commonly occurring medical condition. Various types of alopecia are distinguished, with the most common being androgenetic alopecia affecting both men and women. Standard treatments do not always yield the expected results, hence the search for alternative forms of therapy for this condition. Platelet-rich plasma (PRP) has been used in medicine for a long time, but it has gained popularity in aesthetic medicine and dermatology in recent years. The action of PRP includes stimulating collagen formation. The therapeutic effects of PRP therapy in alopecia are achieved through the synergistic action of various types of growth factors. Aim: The aim of our study was to evaluate the effectiveness of platelet-rich plasma therapy for baldness, to compare its effectiveness with other treatment methods and to present this issue to the reader. Methods: Analysis of issues related to baldness and platelet-rich plasma therapy from PubMed sources and comparison of the effectiveness of this therapy with other methods. Conclusions: Treatment with PRP for androgenetic alopecia results in an increase in overall hair density. In chronic plaque alopecia, such therapy leads, among other things, to increased hair regrowth. Combined therapy of PRP with minoxidil in androgenetic alopecia yields better results than using these methods separately. The same applies to combined therapy of PRP with finasteride. However, minoxidil with PRP yields better results than finasteride with PRP.

Alcohol as a Modifiable Risk Factor for Alzheimer's Disease-Evidence from Experimental Studies.

Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by cognitive impairment and memory loss. Epidemiological evidence suggests that heavy alcohol consumption aggravates AD pathology, whereas low alcohol intake may be protective. However, these observations have been inconsistent, and because of methodological discrepancies, the findings remain controversial. Alcohol-feeding studies in AD mice support the notion that high alcohol intake promotes AD, while also hinting that low alcohol doses may be protective against AD. Chronic alcohol feeding to AD mice that delivers alcohol doses sufficient to cause liver injury largely promotes and accelerates AD pathology. The mechanisms by which alcohol can modulate cerebral AD pathology include Toll-like receptors, protein kinase-B (Akt)/mammalian target of rapamycin (mTOR) pathway, cyclic adenosine monophosphate (cAMP) response element-binding protein phosphorylation pathway, glycogen synthase kinase 3-β, cyclin-dependent kinase-5, insulin-like growth factor type-1 receptor, modulation of β-amyloid (Aβ) synthesis and clearance, microglial mediated, and brain endothelial alterations. Besides these brain-centric pathways, alcohol-mediated liver injury may significantly affect brain Aβ levels through alterations in the peripheral-to-central Aβ homeostasis. This article reviews published experimental studies (cell culture and AD rodent models) to summarize the scientific evidence and probable mechanisms (both cerebral and hepatic) by which alcohol promotes or protects against AD progression.

Thyroid dysfunction and the state of the GH/IGF-1 system in adolescents with type 1 diabetes mellitus

Purpose: to determine the relationship between the functional state of the pituitary-thyroid system and the growth hormone/insulin-like growth factor type 1 (GH/IGF-1) system in adolescents with type 1 diabetes mellitus (DM1) during puberty
 Material & Methods: 165 children (85 girls (51,5%) and 80 boys (48,5%) aged 8 to 18 years old who have DM1 and are in the endocrinology department of the State Institution "Institute for Children and Adolescents Health Care at the National Academy of Medical Sciences of Ukraine" (SI "ICAHC NAMS"). The criterion for inclusion in the study was the duration of DM1 for more than one year (from 1 to 16 years). The level of thyrotropin (TSH), free fractions of thyroxin (fT4) and triiodothyronine (fT3), GH and IGF-1 was determined and the ratio (fT3/fT4 and TSH/fT4) was calculated. Study participants were divided into groups depending on the level of sexual development (T1-T4) at the time of the study, assessed by the Marshall & Tanner scale (Marshall & Tanner, 1969; Marshall & Tanner, 1970); functional state of the pituitary-thyroid system: (euthyroidism (TSH/fТ4 <0,19 c.u.), minimal thyroid insufficiency (0,19 c.u. ≤ TSH/fТ4 ≤0,29 c.u.), with subclinical hypothyroidism (TSH/fТ4 >0,29 c.u.) (Turchina et al., 2016).
 Results: it was found that among adolescents with DM1, almost every child has signs of thyroid dysfunction. An increase in the fT3 level and the fT3/fT4 ratio were more often diagnosed. The frequency of increase in the level of TSH and the ratio of TSH/fT4 fluctuated widely and depended on the sexual development of the child. More often, signs of SGH were determined during early puberty (23,5%), which probably exceeded those in prepubertal (16%, Pφ<0,05), proper (8,9%, Pφ<0,05) and late puberty (6,1%, Pφ<0,05). These changes indicate the tension of the thyroid system at the beginning of puberty, which is the basis not only for an increase in the risk of thyroid pathology in this period of puberty, but also for violations of physical and sexual development.
 Conclusions: almost a third of adolescents with DM1 had signs of thyroid insufficiency of varying degrees, which was most often determined during early puberty. The progression of thyroid insufficiency was accompanied by a decrease in the level of GH and IGF-1.

Biocompatible Macroion/Growth Factor Assemblies for Medical Applications.

Growth factors are a class of proteins that play a role in the proliferation (the increase in the number of cells resulting from cell division) and differentiation (when a cell undergoes changes in gene expression becoming a more specific type of cell) of cells. They can have both positive (accelerating the normal healing process) and negative effects (causing cancer) on disease progression and have potential applications in gene therapy and wound healing. However, their short half-life, low stability, and susceptibility to degradation by enzymes at body temperature make them easily degradable in vivo. To improve their effectiveness and stability, growth factors require carriers for delivery that protect them from heat, pH changes, and proteolysis. These carriers should also be able to deliver the growth factors to their intended destination. This review focuses on the current scientific literature concerning the physicochemical properties (such as biocompatibility, high affinity for binding growth factors, improved bioactivity and stability of the growth factors, protection from heat, pH changes or appropriate electric charge for growth factor attachment via electrostatic interactions) of macroions, growth factors, and macroion-growth factor assemblies, as well as their potential uses in medicine (e.g., diabetic wound healing, tissue regeneration, and cancer therapy). Specific attention is given to three types of growth factors: vascular endothelial growth factors, human fibroblast growth factors, and neurotrophins, as well as selected biocompatible synthetic macroions (obtained through standard polymerization techniques) and polysaccharides (natural macroions composed of repeating monomeric units of monosaccharides). Understanding the mechanisms by which growth factors bind to potential carriers could lead to more effective delivery methods for these proteins, which are of significant interest in the diagnosis and treatment of neurodegenerative and civilization diseases, as well as in the healing of chronic wounds.

Сүйек тінінің ақауы кезіндегі травматологияда қолданылатын заманауи өсу факторларының қолданылуы

An urgent problem in traumatology and orthopedics remains the closure of bone tissue defects caused by cystic formations, revision operations of open fractures, false joints of long tubular bones and chronic osteomyelitis. Platelet-rich blood plasma is extracted from the patient's own blood and used in all areas of medicine. Cellular processes after tissue damage are controlled, among other things, by platelets and dividing growth factors. Platelets produce a wide range of growth factors and cytokines after attachment, fusion, and fibrin mesh formation. Key cytokines that determine platelets play an important role in cell proliferation, chemotaxis, cell differentiation, and angiogenesis.Morphological bone proteins are a large group of structurally related proteins. BMP is closely related to the processes of bone formation and regeneration. Their mechanism of action includes the transmission of signals about chemotaxis, proliferation and differentiation of osteoporosis progenitor cells and the induction of bone formation by these cells. Extensive preclinical studies have shown that BMP is able to cause bone formation at ectopic sites and treat fractures. Mesenchymal stem cells are heterogeneous populations of stem cells that have similar characteristics and are distributed across several tissues. MSC are multipotent cells capable of repairing damaged mesenchymal tissue and bone marrow. They have the ability to differentiate into a wide range of cell types, such as chondroblasts, fibroblasts and osteoblasts, and can also produce mature cells that usually originate from the endoderm and ectoderm. Thus, mesenchymal cells are good candidates for their use in regenerative medicine and cell therapy. These stem cells can be obtained from the bone marrow in the amount of 1/1000 to 1/100 cells, which is ten times less than that of hematopoietic stem cells. Mesenchymal stem cells can also be obtained from umbilical cord blood and other tissues such as adipose tissue. The analysis of the literature shows that there remains an unsolved problem in modern medicine. With the development of modern technologies, new types of growth factors and replacement of bone defects have been invented, which, in turn, opens up new possibilities in treatment

Genetic Predictors of Development of Diabetic Foot Syndrome in Patients with Diabetes Mellitus

An increase in the population of patients with diabetes mellitus affects the incidence of diabetic foot syndrome (DFS), as its chronic complication. Among the various types of growth factors that play a role in the development of late complications of diabetes, vascular endothelial growth factor, VEGF, is currently in the focus of attention. The study conducted by the authors was aimed at determining the relationship between the G634C polymorphism of the VEGFA rs2010963 gene and the predisposition to the development of diabetic foot syndrome in patients with diabetes mellitus. We examined 96 patients aged 39 to 76 years with diabetes mellitus complicated by diabetic foot syndrome. Based on the studies, it was determined that the G634C polymorphism in the VEGFA gene (rs2010963) is involved in the formation and development of diabetic foot syndrome in patients with diabetes mellitus.

Development of the B-Cell Progenitor Niche Is Dependent on Cells Derived from the Migratory Neural Crest

INTRODUCTION: The earliest stages of B-cell production occur in the bone marrow (BM), where hematopoietic stem cells (HSCs) differentiate into common lymphoid and myeloid progenitors. Common lymphoid progenitors then undergo progressive differentiation as B cell progenitors (BCPs) prior to exiting the BM and completing their maturation in the spleen and lymph nodes. BCP development is regulated by lymphotrophic cytokines produced by BM mesenchymal stromal cells (MSCs) and osteoprogenitors (OPs). While the factors that regulate the formation and activity of the BCP niche in the BM are unknown, other laboratories have determined that signals from the peripheral nervous system (PNS) direct the formation and activity of the HSC BM niche. In this study, we hypothesized that the PNS also coordinates the formation and activity of the BCP BM niche. METHODS: To test this hypothesis, we targeted Schwann cells (SCs), which are required for peripheral nerve function, via a well-described mouse model of global peripheral nerve dysfunction (MP0-Cre+/-; Lamc1fl/fl, hereafter referred to as mutant). MP0 is expressed in the migratory neural crest from which SCs are derived, and the Lamc1 gene encodes an extracellular matrix protein (laminin-gamma-1) required for perinatal SC morphogenesis and differentiation. In mutant mice, SC development arrests at the 'immature' stage. Mutant SCs do not form myelinating or nonmyelinating SCs, which in mice takes place during the initial three weeks of postnatal development. Mutant mice die between 4-5 weeks of age; therefore 3-3.5 week old mice were used for all studies detailed below. RESULTS: In comparison to controls, mutant mice were lymphopenic. There were no differences in number of red cells, neutrophils or platelets between control and mutant mice. In the bone marrow, Pre-B-cell but not myeloid colony formation was significantly reduced in mutant mice, as were the number of both Pre and Pro B cells. Insulin Like Growth Factor Type 1 (IGF-1), an osteoprogenitor-derived lymphopoietic cytokine required for BCP maturation, was reduced by 60% in mutant bone marrow supernatant. IGF-1 transcript was also reduced in osteoprogenitor/osteoblast cells (CD45-Tert119-CD31-Sca1-CD51+) from mutant BM. Control and mutant femurs were examined by µCT, which identified significant impairment in mutant cortical and trabecular bone structure and density. A fluorescent reporter transgene (ROSAmT/eGFP) was employed to facilitate isolation and characterization of those BM niche cells genetically targeted by MP0-Cre. Using flow cytometry, we determined that less than four percent of osteoprogenitor/osteoblast cells expressed eGFP and were thus derived from the migratory neural crest. None of the MSCs (Tert119-CD31-Sca1+CD51+) expressed eGFP. The relative contribution of the migratory neural crest to each niche cell fraction did not vary between control and mutant BM. Lamc1 transcript from mutant eGFP+ cells was nearly undetectable and significantly less than from control eGFP+cells. Transcripts typically enriched in juvenile and nonmyelinating SCs (Erbb3, Sox10, GFAP, and s-100b) were enriched in eGFP+ but not eGFP- BM niche cells from both control (MP0-Cre+/-; Lamc1fl/+; ROSAmT/eGFP) and mutant (MP0-Cre+/-; Lamc1fl/fl) mice. There was no quantitative difference in IGF1 transcription between control and mutant eGFP+ cells. CONCLUSIONS: From these data, we conclude that postnatal maturation of the migratory neural crest is required for establishment of the BCP niche. While the migratory neural crest cells found within the bone marrow are enriched with SC-transcripts, they also contribute a small fraction of BM stromal cells and potentially some neurons (sympathetic and parasympathetic). Since mutant mice are paretic, it is also possible that weight bearing-induced mechanical forces contribute to osteogenic BCP niche formation. Our work to date does not differentiate between these possibilities, but does provide significant preliminary evidence to support our hypothesis that 'neuronal' development contributes to formation and activity of the BCP niche within the BM.

The role of Bone Morphogenetic Protein-2 in craniofacial osteogenesis: A literature review

Bone Morphogenetic Protein (BMP) is a type of growth factor that belongs to the Transforming Growth Factor Beta (TGF-B) group. Bone Morphogenetic Protein-2 (BMP-2) is recognized as one of the first commercially available osteoblast inductors. When new bone is needed, mesenchymal stem cells can develop into osteoblasts, which then implant as osteocytes in the bone, providing additional structure and support. The principal agent that differentiates stem cells into osteoblasts is BMP-2. BMP-2 will be released into the bone matrix or serum in performing their job. BMP-2 activates the SMAD1/5/8 signal via mediating the physiological action of type I and II serine/threoninekine receptors. The active SMAD protein will form a complex with the SMAD4 protein, translocate DNA to the nucleus, and bind to particular genes like Dlx-2/5, Osx, and transcription. According to a recent study, BMP-2 boosts osteogenic growth. BMPs are effective in the treatment of craniofacial defects in current research. The subjects of this paper are the molecular mechanism of BMPs and their involvement in the clinical application of craniofacial deformity patients.

Effect of Selenium Treatment on Central Insulin Sensitivity: A Proteomic Analysis in β-Amyloid Precursor Protein/Presenilin-1 Transgenic Mice

Prior studies have demonstrated a close association between brain insulin resistance and Alzheimer’s disease (AD), while selenium supplementation was shown to improve insulin homeostasis in AD patients and to exert neuroprotective effects in a mouse model of AD. However, the mechanisms underlying the neuroprotective actions of selenium remain incompletely understood. In this study, we performed a label-free liquid chromatography-tandem mass spectrometry (LC–MS/MS) quantitative proteomics approach to analyze differentially expressed proteins (DEPs) in the hippocampus and cerebral cortex of Aβ precursor protein (APP)/presenilin-1 (PS1) mice following 2 months of treatment with sodium selenate. A total of 319 DEPs (205 upregulated and 114 downregulated proteins) were detected after selenium treatment. Functional enrichment analysis revealed that the DEPs were mainly enriched in processes affecting axon development, neuron differentiation, tau protein binding, and insulin/insulin-like growth factor type 1 (IGF1)-related pathways. These results demonstrate that a number of insulin/IGF1 signaling pathway-associated proteins are differentially expressed in ways that are consistent with reduced central insulin resistance, suggesting that selenium has therapeutic value in the treatment of neurodegenerative and metabolic diseases such as AD and non-alcoholic fatty liver disease (NAFLD).

The Culture Dish Surface Influences the Phenotype and Dissociation Strategy in Distinct Mouse Macrophage Populations.

The nature of the culture dish surface and the technique used to detach adherent cells could very likely influence the cell viability and cell membrane protein integrity of harvested macrophages. Several previous studies assessed the detachment efficacies of enzymatic and non-enzymatic methods for harvesting the single cell suspensions of macrophages, but a comprehensive study assessing different dissociation methods and culture conditions for detaching functionally different macrophage populations has not yet been reported. In this study, via the well-established GM-CSF and M-CSF differentiated bone marrow derived macrophage models (GM-BMDMs and M-BMDMs), we compared four commonly used enzymatic (trypsin and accutase) and non-enzymatic (PBS and EDTA) dissociation methods along with necessary mechanical detaching steps (scraping and pipetting) to evaluate the viable cell recovery and cell surface marker integrality of GM-BMDMs and M-BMDMs cultured on standard cell culture dish (TC dish), or on culture dish (noTC dish) that was not conditioned to enhance adherence. The data showed that accutase yielded a better recovery of viable cells comparing with PBS and EDTA, especially for tightly adherent GM-BMDMs on TC dishes, with a relatively higher level of detected cell membrane marker F4/80 than trypsin. An additional gradient centrifugation-based dead cell removal approach could increase the proportion of viable cells for TC cultured GM-BMDMs after accutase dissociation. Furthermore, transcriptome analysis was performed to evaluate the putative influence of culture dishes. At steady state, BMDMs cultured on noTC dishes exhibited more proinflammatory gene expression signatures (e.g. IL6, CXCL2 and ILlβ) and functions (e.g. TNF and IL17 signaling pathways). Similar inflammatory responses were observed upon LPS challenge regardless of culture conditions and differentiation factors. However, in LPS treated samples, the difference of gene expression patterns, signaling pathways and molecular functions between TC and noTC cultured BMDMs were largely dependent on the types of growth factors (M-CSF and GM-CSF). This observation might provide valuable information for in vitro macrophage studies.

Dietary Soy Prevents Alcohol-Mediated Neurocognitive Dysfunction and Associated Impairments in Brain Insulin Pathway Signaling in an Adolescent Rat Model.

Background: Alcohol-related brain degeneration is linked to cognitive-motor deficits and impaired signaling through insulin/insulin-like growth factor type 1 (IGF-1)-Akt pathways that regulate cell survival, plasticity, metabolism, and homeostasis. In addition, ethanol inhibits Aspartyl-asparaginyl-β-hydroxylase (ASPH), a downstream target of insulin/IGF-1-Akt signaling and an activator of Notch networks. Previous studies have suggested that early treatment with insulin sensitizers or dietary soy could reduce or prevent the long-term adverse effects of chronic ethanol feeding. Objective: The goal of this study was to assess the effects of substituting soy isolate for casein to prevent or reduce ethanol’s adverse effects on brain structure and function. Methods: Young adolescent male and female Long Evans were used in a 4-way model as follows: Control + Casein; Ethanol + Casein; Control + Soy; Ethanol + Soy; Control = 0% ethanol; Ethanol = 26% ethanol (caloric). Rats were fed isocaloric diets from 4 to 11 weeks of age. During the final experimental week, the Morris Water maze test was used to assess spatial learning (4 consecutive days), after which the brains were harvested to measure the temporal lobe expression of the total phospho-Akt pathway and downstream target proteins using multiplex bead-based enzyme-linked immunosorbent assays (ELISAs) and duplex ELISAs. Results: Ethanol inhibited spatial learning and reduced brain weight, insulin signaling through Akt, and the expression of ASPH when standard casein was provided as the protein source. The substitution of soy isolate for casein largely abrogated the adverse effects of chronic ethanol feeding. In contrast, Notch signaling protein expression was minimally altered by ethanol or soy isolate. Conclusions: These novel findings suggest that the insulin sensitizer properties of soy isolate may prevent some of the adverse effects that chronic ethanol exposure has on neurobehavioral function and insulin-regulated metabolic pathways in adolescent brains.

The Effectiveness of Autologous Platelet-Rich Plasma PRP In the Therapy of Infertile Women with Poor Ovarian Reserve POR, A Retrospective Chart-Review Study

Platelet-rich plasma (PRP), also known as autologous platelet gel, is “autologous blood with concentrations of platelets above baseline levels, which contains at least seven growth factors”. plasma rich in growth factors (PRGF), and platelet concentrate (PC), is a high concentration of autologous platelets suspended in a small volume of plasma after centrifugation [1]. More than 800 types of protein molecules, cytokines, hormones, and chemo-attractants are carried by the platelets [2]. When platelets get activated, numerous biologically active proteins that stimulate cell proliferation, growth, and differentiation are released. Activated platelets also release various types of growth factors like platelet-derived growth factor (PDGF), transforming growth factor β (TGF-β), fibroblast growth factor (FGF), epidermal growth factor (EGF), insulin-like growth factor (IGF-1), and hepatocyte growth factor (HGF) [3] Table 1.

Deletion of STAT3 from Foxd1 cell population protects mice from kidney fibrosis by inhibiting pericytes trans-differentiation and migration.

Signal transduction and activator of transcription 3 (STAT3) is a key transcription factor implicated in the pathogenesis of kidney fibrosis. Although Stat3 deletion in tubular epithelial cells is known to protect mice from fibrosis, vFoxd1 cells remains unclear. Using Foxd1-mediated Stat3 knockout mice, CRISPR, and inhibitors of STAT3, we investigate its function. STAT3 is phosphorylated in tubular epithelial cells in acute kidney injury, whereas it is expanded to interstitial cells in fibrosis in mice and humans. Foxd1-mediated deletion of Stat3 protects mice from folic-acid- and aristolochic-acid-induced kidney fibrosis. Mechanistically, STAT3 upregulates the inflammation and differentiates pericytes into myofibroblasts. STAT3 activation increases migration and profibrotic signaling in genome-edited, pericyte-like cells. Conversely, blocking Stat3 inhibits detachment, migration, and profibrotic signaling. Furthermore, STAT3 binds to the Collagen1a1 promoter in mouse kidneys and cells. Together, our study identifies a previously unknown function of STAT3 that promotes kidney fibrosis and has therapeutic value in fibrosis.

Success Rate of Growth Factors for Existing Periapical Lesions in Failed Endodontically Treated Teeth in Adult Population: A Systematic Review and Meta-Analysis.

Introduction:In this study, we investigated the success rate of growth factors for existing periapical lesions in failed endodontically treated teeth in an adult population by systematic review and meta-analysis.Materials and Methods:We conducted an online data search based on preferred reporting items for systematic reviews and meta analyses (PRISMA), from databases PUBMED, MEDLINE, and EMBASE, for the application of various types of growth factors in endodontically failed teeth with periapical lesions in adults. These included the “platelet-rich plasma (PRP) and platelet-rich fibrin (PRF),” blood, etc. The data were meta-analyzed using MetaXL 5.3, and GRADE was used to assess the certainty.Results:We observed that success of 0.95 was achieved by the end of a year's follow-up with the application of growth factors for periodontal lesions. We also observed that the teeth responded to thermal tests, indicating regeneration; however, studies were with bias and lower sensitivity.Discussion:\\ Similar to regeneration in immature teeth, growth factors also showed greater success in the treatment of periapical lesions in the failed endodontic teeth in adults.

Phase I/II Clinical Trial of Autologous Activated Platelet-Rich Plasma (aaPRP) in the Treatment of Severe Coronavirus Disease 2019 (COVID-19) Patients.

Background The outbreak of Coronavirus Disease 2019 (COVID-19) has been increasing rapidly. This disease causes an increase in proinflammatory cytokine production that leads to cytokine storm or cytokine release syndrome (CRS). Autologous activated platelet-rich plasma (aaPRP) contains various types of growth factors and anti-inflammatory cytokines that may have the potential to suppress CRS. This study of phase I/II trial was aimed to evaluate the safety and efficacy of aaPRP to treat severe COVID-19 patients. Methods A total of 10 severe COVID-19 patients from Koja Regional Public Hospital (Koja RPH) were admitted to the intensive care unit (ICU). All patients received aaPRP administration three times. Primary outcomes involving the duration of hospitalization, oxygen needs, time of recovery, and mortality were observed. Secondary outcomes involving C-reactive protein (CRP), neutrophil, lymphocyte, and lymphocyte-to-CRP (LCR) and neutrophil-lymphocyte ratio (NLR) were analyzed. Results All patients were transferred to the ICU with a median duration of 9 days. All patients received oxygen at enrollment and nine of ten patients recovered from the ICU and transferred to the ward room. There was one patient who passed away in the ICU due to heart failure. The results of secondary outcomes showed that CRP value and lymphocytes counts were significantly decreased while neutrophils, LCR, and NLR were slightly increased after aaPRP administration. Conclusions Our results of the phase I/II trial demonstrated that the use of aaPRP in severe COVID-19 patients was safe and not associated with serious adverse events, which showed that aaPRP was a promising adjunctive therapy for severe COVID-19 patients.

Association between genotyping of transforming growth factor Beta 1 with oxidative status in type 2 diabetic nephropathy Complications

Objectives: To assess the association between Transforming Growth Factor β1 gene polymorphism (T869C) and type 2 diabetes mellitus with and without nephropathy complications with endogenous antioxidant reduced glutathione levels in type 2 diabetic patients with/without nephropathy complications of Kerbala province: Iraq. Methods: A case-control study was performed at which 100 patients with diabetic nephropathy, 100 patients with only type 2 diabetic and another 100 apparently healthy individuals as control were recruited. Fasting blood glucose, HbA1c%, urea, creatinine and glutathione were measured by spectrophotometric methods using enzymatic procedures. Transforming growth factor β1 gene was genotyped for the T>C (T869C) SNP by PCR-ARMS technique. Results: The genotype and allele frequencies of TGFβ1 gene polymorphism in type 2 diabetes mellitus, type 2 diabetic nephropathy, and control were examined. The transforming growth factor β1 (T869C) C allele, TC and TC + CC genotypes were significantly higher in patients; the T allele and TT genotype were significantly higher in controls (P ≤ 0.001). Glutathione give also a significant result in diabetic patients with and without nephropathy in when compared with controls. Conclusion: The observed data indicated that TGFβ1 (T869C) codon 10, allele C, and C allele-containing genotypes may be susceptible, and the T allele / TT genotype may be protective factors for type 2diabetic nephropathy complications. The results of glutathione showed that it may be one of the causes of presence high oxidants compounds, which is lead to the damage and destruction of mutations in the DNA of the cell.

IGF Signaling Predicts Outcomes and Is a Promising Target Therapy for Acute Myeloid Leukemia

Background : Despite the growing knowledge about acute myeloid leukemia (AML) pathophysiology, it remains a disease with high mortality rates, and the early recognition of patients at higher risk allows adjusted risk- or target-specific therapies. In AML, autocrine insulin like growth factor type 1 (IGF1) and its receptor (IGF1R) activation has been previously described. Free IGF mediate cellular functions through binding to the two IGF receptors, IGF1R and IGF2R. IGF2R binds to and induces degradation of IGF2, preventing IGF2-IGF1R signaling activation, IGF1R activation induces cell proliferation and prevents cell death. Therefore, IGF2R may act as a tumor suppressor and IGF1R has opposite effects. IGF1R pharmacological inhibitors have recently been investigated in the clinical setting for solid tumors, but still underexplored in hematological neoplasms. Aims : To investigate IGF1R and IGF2R mRNA expression in primary samples from AML patients and their impact in clinical outcomes, and to analyze the effects of the IGF1R pharmacological inhibitor linsitinib in AML cell lines. Material and methods : IGF1R and IGF2R mRNA expression levels in AML patients (n=172) were obtained from TCGA AML study (2013) available online on CBioPortal for Cancer Genomics (Cerami et al. 2012; Gao et al. 2013). Gene expression was investigated, by qPCR, in a subset AML cohort (n=101; APL=48, CBF-leukemia=53 [t(8;21)=30, Inv16=23]), and in total bone marrow samples from healthy donors (HD) (n=23). The study was approved by the ethics committee of the Institution. NB4, NB4-R2 and Kasumi-1 cell lines were submitted to linsitinib (0.25, 0.5, 1.0, 2.5, 5.0, 10, 20 or 40 µM) for 72 hours and were evaluated for cell viability (MTT assay), apoptosis (Annexin V/PI), autophagy (acridine orange staining), and protein expression/activation (western blot). Statistical analyses were performed using Student's t-test, Mann-Whitney test, Kruskal-wallis test and Spearman correlation test, as appropriate. For survival analysis, Kaplan-Meyer curves were compared with log-rank test and cox regression analyzes were applied. Results :Patients were dichotomized according to the median IGF1R and IGF2R expression values, and the IGF1R / IGF2R ratio was calculated by division of absolute number of reads coming from RNA-seq data. Patients with high IGF1R / IGF2R showed poorer overall survival (OS) (29% vs. 56%, P <0.01), and disease free survival (DFS) (31% vs. 45%, P =0.015). Individually, high IGF1R (33% vs. 51%; P =0.042) and low IGF2R (32% vs. 52%; P =0.012) were associated with a shorter OS. By Cox regression analysis, IGF1R / IGF2R (P= 0.039), cytogenetic risk stratification (P <0.001), age (P <0.001) and white blood cell counts (P =0.003) independently predicted poorer OS. AML patients harboring t(15;17) or t(8;21) presented higher levels of IGF1R / IGF2R when compared with other AML patients (P≤ 0.01). Using a subset of APL and CBF-leukemia, a higher IGF1R / IGF2R ratio was observed in AML patients with t(15;17) or t(8;21) compared with healthy donors (HD) (P <0.01). IGF1R and IGF2R expression positively correlated in HD (r =0.9296; P <0.001), and negatively correlated in AML TCGA study (r =-0.2366; P =0.0018). In NB4, NB4-R2 and Kasumi-1 cells, linsitinib ≥1 µM reduced cell viability (P <0.05) and significantly increased apoptosis, as demonstrated by increased cleaved caspase 3 and annexin V+ cells. The mean percentage of annexin V+ cells for control, linsitinib 10, 20 and 40 µM were 3,9%, 14%, 32% and 93% for NB4, 6%, 24%, 53% and 96% for NB4-R2 and 7%, 19%, 49% and 96% for Kasumi-1 (all P <0.05), respectively. Linsitinib 10 µM increased autophagy in at least 3 fold-change in all cell lines tested (all P <0.05). Linsitinib 10 µM plus the autophagy inhibitor chloroquine 20 µM increased apoptosis when compared with monotherapy in NB4 cells (45% vs 15%), NB4-R2 cells (68% vs 15%) and Kasumi-1 (35% vs 15%) (all P <0.05). The IGF1R pharmacological inhibitor reduced phosphorylation/activation of IGF1R (Tyr1135), IRS1/2 (Tyr612), AKT1/2/3 (Ser473), P70S6K (Thr421/Ser424), 4EBP1 (Thr70) and ERK1/2 (Thr185/Tyr187). Conclusions :In AML,increased IGF1R / IGF2R predicts poorer survival outcomes and the pharmacological IGF1R inhibitor linsitinib exerts an anticancer activity and downregulates PI3K/AKT and MAPK signaling. In the concept of multi target treatment, IGF1R arise as a promising therapeutic target for patients with AML. DisclosuresNo relevant conflicts of interest to declare.

Artificial intelligence and guidance of medicine in the bubble

Microbubbles are nanosized gas-filled bubbles. They are used in clinical diagnostics, in medical imaging, as contrast agents in ultrasound imaging, and as transporters for targeted drug delivery. They can also be used to treat thrombosis, neoplastic diseases, open arteries and vascular plaques and for localized transport of chemotherapies in cancer patients. Microbubbles can be filled with any type of therapeutics, cure agents, growth factors, extracellular vesicles, exosomes, miRNAs, and drugs. Microbubbles protect their cargo from immune attack because of their specialized encapsulated shell composed of lipid and protein. Filled with curative medicine, they could effectively circulate through the whole body safely and efficiently to reach the target area. The advanced bubble-based drug-delivery system, integrated with artificial intelligence for guidance, holds great promise for the targeted delivery of drugs and medicines.

Bone regeneration in ceramic scaffolds with variable concentrations of PDRN and rhBMP-2

This study evaluated the bone regeneration capacity and mechanical properties of block-type hydroxyapatite (HA)/tricalcium phosphate (TCP) scaffolds in response to different concentrations of polydeoxyribonucleotide (PDRN) and recombinant human bone morphogenic protein 2 (rhBMP-2). Thirty-two male white rabbits were used as a model of calvarial bone defect and classified into eight groups according to type and concentration of growth factor administered, viz., control group (only HA/TCP scaffold), scaffold + PDRN (0.1, 1, 5, and 10 mg/mL each) and scaffold + rhBMP-2 (0.01, 0.05, and 0.1 mg/mL each). The specimens were evaluated using histomorphometric and radiological analyses. Histomorphometric analyses indicated that the administration of PDRN did not increase bone formation. However, significant increases in bone formation were observed with the administration of rhBMP-2 at 0.05 and 0.10 mg/mL on week 8 compared to the control (p < 0.05). Radiological analyses revealed a significant increase in bone formation at week 8 with the administration of PDRN at 5 mg/mL and 10 mg/mL, and rhBMP-2 at 0.05 or 0.10 mg/mL compared to the control (p < 0.05). Our findings show that block-type HA/TCP scaffolds possess sufficient mechanical strength and bone regeneration capacity when used with optimal concentrations of growth factors.