Essential Growth Research Articles

Biological characterization of dehydrated amniotic membrane allograft: Mechanisms of action and implications for wound care.

There is a growing clinical demand in the wound care market to treat chronic wounds such as diabetic foot ulcers. Advanced cell and tissue-based products (CTPs) are often used to address challenging chronic wounds where healing has stalled. These products contain active biologics such as growth factors and cytokines as well as structural components that support and stimulate cell growth and assist in tissue regeneration. This study addresses the in vitro biologic effects of a clinically available dehydrated amniotic membrane allograft (DAMA). The broad mechanism of action results from DAMA's biologic composition that leads to stimulation of cell migration cell proliferation, and reduction of pro-inflammatory cytokines. Results show that DAMA possesses growth factors and cytokines such as EGF, FGF, PDGFs, VEGF, TGF-β, IL-8, and TIMPs 1 and 2. Furthermore, in vitro experiments demonstrate that DAMA stimulates cell proliferation, cell migration, secretion of collagen type I, and the reduction of pro-inflammatory cytokines IL-1β, IL-6, and TNF-α. This study findings are consistent with the clinical benefits previously published for DAMA and other CTPs in chronic wounds suggesting that the introduction of DAMA to non-healing, complex wounds helps to improve the wound milieu by providing essential structural components, cytokines, and growth factors to create an appropriate environment for wound healing.

Innovative ways to process poultry waste

This paper provides an overview of methods for processing and recycling chicken droppings. Poultry farms are a source of litter formation in an amount much larger than the main products. The litter contains up to 80% organic matter, many trace elements, all essential amino acids, growth regulators, vitamins, nitrogen and phosphorus. According to the Federal waste catalog, fresh chicken droppings belong to the 3rd hazard class. Fresh dung contains a significant amount of weed seeds, helminth eggs and pathogenic microorganisms. Dung is a source of toxic gases-ammonia, hydrogen sulfide, methane, carbon monoxide. Without recycling, manure becomes a source of environmental pollution. Disposal of chicken droppings is a difficult issue for many farms. Modern trends in the processing and use of poultry manure: 1) direct application to the soil without additional treatment, 2) Processing by passive and active composting, 3) Vermicomposting, 4) Processing with the help of housefly larvae, 5) Dehydration and drying (mechanical, thermal, vacuum), 6) Pyrolysis at t = 450-550 °C, 7) Plasma gasification, 8) thermal depolymerization Technology, 9) Direct combustion in steam and hot water boilers, 10) Microbiological conversion, 11) anaerobic digestion in Methane tanks with the formation of biogas, 12) Dung as a component of compound feed for cattle. The considered technologies of utilization of bird droppings do not fully contribute to the preservation of the environment and production. At the present stage, the industry needs an environmentally friendly and cost-effective biotechnology for processing manure, which makes it possible to turn organic waste into valuable raw materials for obtaining feed, fuels, fertilizers, and substrates for the chemical and microbiological industries. The future of waste management is in nature-like technologies, because in nature, all the necessary processing mechanisms are already in place.

Immuno-Modulation and neuroprotection mediate the therapeutic effect of exosomes in mice model of autism

Background & Aim Background: During the recent decade, exosomes that derived from mesenchymal stem cells (MSC-exo) have been spotlighted as a promising therapeutic target for various clinical indications, including neurological disorders. We have previously shown that intranasal administration of MSC-exo, cross the BBB and significantly ameliorate autistic like behavioral phenotype in BTBR and SHANK3 animal models of autism, representing a potential therapeutic strategy to reduce symptoms of autism spectrum disorder (ASD). Objective: In order to study the mechanism of action and the cellular pathways in which the adipose-derived MSC-exo activate their target, we preformed RNA sequencing analysis of primary neurons isolated from SHANK3 mice treated with MSC-exo. Methods, Results & Conclusion Methods: Primary neuronal cell cultures were prepared from newborn SHANK3 homozygotes mice model of autism. Cultures were treated with 40ul MSC-exo (107 particles/ul), isolated from human adipocytes, followed by RNA sequencing. The alterations in gene expression between the treated and intact neurons were analyzed for gene ontology and pathways and were also compared to proteomics analysis of the MSC-exo in order to find regulatory proteins that may lead to these differences. Results: Bioinformatic analysis revealed several up-regulators proteins that might be responsible for the increase in anti-inflammatory and protective factors seen in the mice neurons treated with MSC-exo. One of them is BDNF which is known as an essential growth factor responsible for neuroprotection and neurogenesis. Importantly, no difference in the genetic expression of cancer-related genes were identified following MSC-exo treatment indicating for their safety. Conclusions: Our data suggest that adipose-derived MSC-exo carry therapeutic potential in ASD via alternation in gene-expression related mainly to immuno-modulation, reduce neuro-inflammation and increase neuroprotection and neurogenesis. The beneficial effects of the MSC-exo treatment in mice models is being translated to a novel, easy to administer, therapeutic strategy to reduce the symptoms of ASD.

Roles of insulin-like growth factor II in regulating female reproductive physiology.

The number of growth factors involved in female fertility has been extensively studied, but reluctance to add essential growth factors in culture media has limited progress in optimizing embryonic growth and implantation outcomes, a situation that has ultimately led to reduced pregnancy outcomes. Insulin-like growth factor II (IGF-II) is the most intricately regulated of all known reproduction-related growth factors characterized to date, and is perhaps the predominant growth factor in human ovarian follicles. This review aims to concisely summarize what is known about the role of IGF-II in follicular development, oocyte maturation, embryonic development, implantation success, placentation, fetal growth, and in reducing placental cell apoptosis, as well as present strategies that use growth factors in culture systems to improve the developmental potential of oocytes and embryos in different species. Synthesizing the present knowledge about the physiological roles of IGF-II in follicular development, oocyte maturation, and early embryonic development should, on the one hand, deepen our overall understanding of the potential beneficial effects of growth factors in female reproduction and on the other hand support development (optimization) of improved outcomes for assisted reproductive technologies.

In Vitro Anti-NTHi Activity of Haemophilin-Producing Strains of Haemophilus haemolyticus.

Nontypeable Haemophilus influenzae (NTHi) is a leading causative organism of opportunistic respiratory tract infections. However, there are currently no effective vaccination strategies, and existing treatments are compromised by antibiotic resistance. We previously characterized Haemophilus haemolyticus (Hh) strains capable of producing haemophilin (HPL), a heme-binding protein that restricts NTHi growth by limiting its access to an essential growth factor, heme. Thus, these strains may have utility as a probiotic therapy against NTHi infection by limiting colonization, migration and subsequent infection in susceptible individuals. Here, we assess the preliminary feasibility of this approach by direct in vitro competition assays between NTHi and Hh strains with varying capacity to produce HPL. Subsequent changes in NTHi growth rate and fitness, in conjunction with HPL expression analysis, were employed to assess the NTHi-inhibitory capacity of Hh strains. HPL-producing strains of Hh not only outcompeted NTHi during short-term and extended co-culture, but also demonstrated a growth advantage compared with Hh strains unable to produce the protein. Additionally, HPL expression levels during competition correlated with the NTHi-inhibitory phenotype. HPL-producing strains of Hh demonstrate significant probiotic potential against NTHi colonization in the upper respiratory tract, however, further investigations are warranted to demonstrate a range of other characteristics that would support the eventual development of a probiotic.

Upregulation of Polyamine Transport in Human Colorectal Cancer Cells

Polyamines are essential growth factors that have a positive role in cancer cell growth. Their metabolic pathway and the diverse enzymes involved have been studied in depth in multiple organisms and cells. Polyamine transport also contributes to the intracellular polyamine content but this is less well-studied in mammalian cells. As the polyamine transporters could provide a means of selective drug delivery to cancer cells, a greater understanding of polyamine transport and its regulation is needed. In this study, transport of polyamines and polyamine content was measured and the effect of modulating each was determined in human colorectal cancer cells. The results provide evidence that upregulation of polyamine transport depends on polyamine depletion and on the rate of cell growth. Polyamine transport occurred in all colorectal cancer cell lines tested but to varying extents. The cell lines with the lowest basal uptake showed the greatest increase in response to polyamine depletion. Kinetic parameters for putrescine and spermidine suggest the existence of two separate transporters. Transport was shown to be a saturable but non-polarised process that can be regulated both positively and negatively. Using the polyamine transporter to deliver anticancer drugs more selectively is now a reality, and the ability to manipulate the polyamine transport process increases the possibility of using these transporters therapeutically.

Genome-wide association study of soybean seed germination under drought stress.

Drought stress, which is increasing with climate change, is a serious threat to agricultural sustainability worldwide. Seed germination is an essential growth phase that ensures the successful establishment and productivity of soybean, which can lose substantial productivity in soils with water deficits. However, only limited genetic information is available about how germinating soybean seeds may exert drought tolerance. In this study, we examined the germinating seed drought-tolerance phenotypes and genotypes of a panel of 259 released Chinese soybean cultivars panel. Based on 4616 Single-Nucleotide Polymorphisms (SNPs), we conducted a mixed-linear model GWAS that identified a total of 15 SNPs associated with at least one drought-tolerance index. Notably, three of these SNPs were commonly associated with two drought-tolerance indices. Two of these SNPs are positioned upstream of genes, and 11 of them are located in or near regions where QTLs have been previously mapped by linkage analysis, five of which are drought-related. The SNPs detected in this study can both drive hypothesis-driven research to deepen our understanding of genetic basis of soybean drought tolerance at the germination stage and provide useful genetic resources that can facilitate the selection of drought stress traits via genomic-assisted selection.

Вопросы формирования денежных средств эмеритальной кассы ведомства Министерства юстиции в нормотворческой деятельности России в начале ХХ в.

The article examines 1909-1910 changes that concerned the formation of an old-age insurance fund of the Ministry of Justice. The problems of financing the old-age insurance fund are revealed. The motives and procedure for adopting the law of 4 February 1910, which established a new system of salary deduction rates for the old-age insurance fund participants, are analysed. The conclusion is made that measures to raise judicial officials’ salary and changes in the system of salary deduction rates led to essential growth of deductions to the old-age insurance fund of the Ministry of Justice.

Human papillomavirus oncoproteins and post-translational modifications: generating multifunctional hubs for overriding cellular homeostasis.

Human papillomaviruses (HPVs) are major human carcinogens, causing around 5% of all human cancers, with cervical cancer being the most important. These tumors are all driven by the two HPV oncoproteins E6 and E7. Whilst their mechanisms of action are becoming increasingly clear through their abilities to target essential cellular tumor suppressor and growth control pathways, the roles that post-translational modifications (PTMs) of E6 and E7 play in the regulation of these activities remain unclear. Here, we discuss the direct consequences of some of the most common PTMs of E6 and E7, and how this impacts upon the multi-functionality of these viral proteins, and thereby contribute to the viral life cycle and to the induction of malignancy. Furthermore, it is becoming increasingly clear that these modifications, may, in some cases, offer novel routes for therapeutic intervention in HPV-induced disease.

14-3-3 proteins contribute to leaf and root development via brassinosteroid insensitive 1 in Arabidopsis thaliana.

Brassinosteroids (BR) are essential growth hormone in plants. Various components involved in signal transduction pathway have been identified as targets of 14-3-3 phospho-binding proteins. Previously, we showed that 14-3-3 proteins directly interact with the Brassinosteroid Insensitive 1 (BRI1), the BR receptor kinase, and are also subject to phosphorylation in a BR-dependent manner. In this study, we aimed to examine a potential interplay between 14-3-3 proteins and BRI1 in plant growth. Morphological phenotypes of a T-DNA insertion mutant line, 14-3-3ψφε, defective in three 14-3-3 isoforms, psi, phi and epsilon, were characterized and compared with bri1-5 and two transgenic lines for BRI1, BRI1-Flag and BRI1-Flag (14-3-3ψφε). We also generated complementation lines carrying each of the three 14-3-3 genes and determined their differences in rosette growth. No significant differences between the wild-type and 14-3-3ψφε seedlings were observed regardless of BR applications. However, BRI1-Flag (14-3-3ψφε) showed a significantly reduced cold tolerance and BR sensitivity in hypocotyl and root development when compared to BRI1-Flag. In addition, narrower leaf shape and smaller rosette size were observed in BRI1-Flag (14-3-3ψφε), while the mutant phenotypes were partially restored in the complementation lines, two of which with 14-3-3φ and 14-3-3ε showed the rosette growth comparable to BRI1-Flag. Taken together, our results suggested that 14-3-3 proteins might positively regulate BRI1 activity and showed that 14-3-3 isoforms have different functional impacts in BR signaling.

Efficacy and safety of platelet-rich plasma for the treatment of thin endometrium

Background:Endometrial thickness has been identified as a prognostic factor for pregnancy rate for patients with female infertility. Thin endometrium is defined as <7 mm on the day of ovulation, or on the day of human chorionic gonadotrophin (HCG) injection in fresh in vitro fertilization (IVF) cycles, or the day to start progesterone in frozen-thaw embryo transfer cycles, as stated in the guideline of thin endometrium from the Canadin Fertility and Andrology Society and Chinese expert consensus from the Society of Reproductive Medicine, Chinese Medical Association. Many medicines are used for improving the endometrial thickness and embryo implantation rate of the patients with thin endometirum, but thin endometrium remains a major troublesome clinical problem with limited efficacy.Platelet-rich plasma (PRP), as a growing and robust therapeutic option in musculoskeletal medicine, is a preparation of autologous plasma with a high concentration of platelets, and the therapeutic mechanism is based on the capacity to supply supra physiologic amounts of essential growth factors to provide a regenerative stimulus for promoting repair in tissues with low healing potential. Some randomized controlled trials have reported the application of PRP for patients with thin endometrium with satisfactory effect. However, there is no systematic review on efficacy and safety of PRP as a treatment of thin endometrium.Methods:The data and information will be retrieved from the databases of MEDLINE, Embase, Web of Science, Clinicaltrials.org., Cochrane Library, China Biology Medicine Database, Wan Fang Database, China National Knowledge Infrastructure Database, VIP Science Technology Periodical Database, and OpenGrey for gray literature. The randomized controlled clinical trials are going to be selected before December 20, 2019, in English or Chinese language, with the search terms including “thin endometrium,”“platelet-rich plasma,” “endometrial thickness,” “hemorheology of endometrium,” “pregnancy rate,” and “adverse reactions.” RevMan 5.3 will be used for systematic review and meta-analysis. This protocol will be reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols (PRISMA-P) statement, and the systematic review will be reported with the PRISMA statement.Results and conclusion:The efficacy and safety of PRP for the treatment of thin endometrium will be evaluated, and the conclusion will be published to provide medical evidence for a better clinical decision of patients with thin endometirum.

Psychological Principle And Its Implications In Islamic Education Hasan Langgulung's Perspective

The psychological principle of education can be understood as truth which is the basis or basis for thinking, both at the planning, implementation and evaluation stages of knowledge based on theories from psychology. Therefore, it becomes essential in understanding education, that education also has principles as a place and foothold that is upright, upright in material, upright in interaction, upright in innovation, or honest in its ideals. The type of research used is library research. The content analysis is used as an analysis method in this study. The results of this study can be concluded that: (1) The concept of psychological principles in Islamic education according to Hasan Langgulung is by emphasizing the theory of the learning process and the idea of human creation according to the Islamic view, which includes the nature of creation, essential human potential, cognitive and psychological growth and development and human spirit, so that it can be understood that human beings are creatures consisting of elements of Islamic and spiritual. (2) The implication of the concept of psychological principles in Islamic education is to view learning as a process in preparing the young generation so that they can act as the next generation, transferring knowledge and Islamic values ​​so that they are aligned with the purpose of the human being created, as well as in their daily behaviour. Therefore, in the process of education must pay attention to the development of the soul, as well as the growth of the body of students by referring to the basis, objectives, curriculum, material, and evaluation that carry human functions as abid and khalifatullah which are decorated with righteous deeds.

Hedgehog Signaling for Urogenital Organogenesis and Prostate Cancer: An Implication for the Epithelial-Mesenchyme Interaction (EMI).

Hedgehog (Hh) signaling is an essential growth factor signaling pathway especially in the regulation of epithelial–mesenchymal interactions (EMI) during the development of the urogenital organs such as the bladder and the external genitalia (EXG). The Hh ligands are often expressed in the epithelia, affecting the surrounding mesenchyme, and thus constituting a form of paracrine signaling. The development of the urogenital organ, therefore, provides an intriguing opportunity to study EMI and its relationship with other pathways, such as hormonal signaling. Cellular interactions of prostate cancer (PCa) with its neighboring tissue is also noteworthy. The local microenvironment, including the bone metastatic site, can release cellular signals which can affect the malignant tumors, and vice versa. Thus, it is necessary to compare possible similarities and divergences in Hh signaling functions and its interaction with other local growth factors, such as BMP (bone morphogenetic protein) between organogenesis and tumorigenesis. Additionally, this review will discuss two pertinent research aspects of Hh signaling: (1) the potential signaling crosstalk between Hh and androgen signaling; and (2) the effect of signaling between the epithelia and the mesenchyme on the status of the basement membrane with extracellular matrix structures located on the epithelial–mesenchymal interface.

Regulation and function of macrophage colony-stimulating factor (CSF1) in the chicken immune system

Macrophage colony-stimulating factor (CSF1) is an essential growth factor to control the proliferation, differentiation and survival of cells of the macrophage lineage in vertebrates. We have previously produced a recombinant chicken CSF1-Fc fusion protein and administrated it to birds which produced a substantial expansion of tissue macrophage populations. To further study the biology of CSF1 in the chicken, here we generated anti-chicken CSF1 antibodies (ROS-AV181 and 183) using CSF1-Fc as an immunogen. The specific binding of each monoclonal antibody was confirmed by ELISA, Western blotting and immunohistochemistry on tissue sections. Using the anti-CSF1 antibodies, we show that chicken bone marrow derived macrophages (BMDM) express CSF1 on their surface, and that the level appears to be regulated further by exogenous CSF1. By capture ELISA circulating CSF1 levels increased transiently in both layer and broiler embryos around the day of hatch. The levels of CSF1 in broilers was higher than in layers during the first week after hatch. Antibody ROS-AV183 was able to block CSF1 biological activity in vitro and treatment of hatchlings using this neutralising antibody in vivo impacted on some tissue macrophage populations, but not blood monocytes. After anti-CSF1 treatment, CSF1R-transgene reporter expressing cells were reduced in the bursa of Fabricius and cecal tonsil and TIM4+ Kupffer cells in the liver were almost completely ablated. Anti-CSF1 treatment also produced a reduction in overall bone density, trabecular volume and TRAP+ osteoclasts. Our novel neutralising antibody provides a new tool to study the roles of CSF1 in birds.

Determination of Competition Factor for Tree Growth within A Stand

This study has two purposes; the first one is development of a new method in determining a competition factor for Pinus brutia trees grown in a stand, and the second one is development of a theoretical method for determination potential growth of individual trees within a stand. This potential growth can be used to estimate the growth of a tree as if it grows in a competition free area. Competition between trees has a strong effect on growth potential.&nbsp; Dense forests need thinning to ensure providing the essential growth requirements. The developed factor can be used to give the answer for when and how much of stocking should be removed. Two samples of trees were selected, one from an open grown area and the other from forest stands. For each sample many regression equations were developed, for regressing, the diameter growth with different forms of diameter. The developed equations were undergone many tests of precision, to determine the one that best fits the dataset. At last the equation,, and equation &nbsp;were finally selected for regressing the diameter growth with diameter at breast height for trees grown in a stand and open grown trees respectively. These selected equations were used to calculate the competition factor. Furthermore the equation; was finally selected among 23 others to be used for calculating the growth potential of trees grown within a stand.

Kinetic Modeling of the Genetic Information Processes in a Minimal Cell.

JCVI-syn3A is a minimal bacterial cell with a 543 kbp genome consisting of 493 genes. For this slow growing minimal cell with a 105 min doubling time, we recently established the essential metabolism including the transport of required nutrients from the environment, the gene map, and genome-wide proteomics. Of the 452 protein-coding genes, 143 are assigned to metabolism and 212 are assigned to genetic information processing. Using genome-wide proteomics and experimentally measured kinetic parameters from the literature we present here kinetic models for the genetic information processes of DNA replication, replication initiation, transcription, and translation which are solved stochastically and averaged over 1,000 replicates/cells. The model predicts the time required for replication initiation and DNA replication to be 8 and 50 min on average respectively and the number of proteins and ribosomal components to be approximately doubled in a cell cycle. The model of genetic information processing when combined with the essential metabolic and cell growth networks will provide a powerful platform for studying the fundamental principles of life.

Healing Effects of Photobiomodulation on Diabetic Wounds

Diabetic patients frequently develop chronic ulcers of the lower extremities, which are a frequent cause for hospitalization and amputation, placing strain on patients, their families, and healthcare systems. Present therapies remain a challenge, with high recurrence rates. Photobiomodulation (PBM), which is the non-invasive application of light at specific wavelengths, has been shown to speed up healing of chronic wounds, including diabetic foot ulcers (DFUs). PBM produces photophysical and photochemical changes within cells without eliciting thermal damage. It has been shown to promote tissue regeneration and speed up wound repair by reducing inflammation and oxidative stress, accelerating cell migration and proliferation, and promoting extracellular matrix production and release of essential growth factors. The shortage of rigorous, well-designed clinical trials makes it challenging to assess the scientific impact of PBM on DFUs, and lack of understanding of the underlying mechanisms also hinders the conventional use of this therapy. This review gives a glimpse into diabetic wound healing and PBM, and the effects of PBM on diabetic wound healing.

CK2.3, a Mimetic Peptide of the BMP Type I Receptor, Increases Activity in Osteoblasts over BMP2.

Bone is one of the most important organs in the human body. It provides structure, function, and protection for other vital organs; therefore, bone maintenance and homeostasis are critical processes. As humans age, their bone mineral density decreases, which leads to diseases like osteoporosis. This disease affects one in two women and one in five men aged 50 and over. As the aging population increases, the interest and significance of studying this debilitating bone disease becomes more relevant. Current therapeutic products for osteoporosis have many side effects and can be taken for a limited number of years. Most therapeutic products only focus on decreasing bone resorption, not increasing bone formation. Bone morphogenetic protein 2 is an essential growth factor that drives osteoblast differentiation and activity and is essential for bone formation. However, usage in the clinic is unsuccessful due to several side effects. Recently, a signaling disparity in bone marrow stromal cells within the bone morphogenetic protein pathway that led to decreased bone morphogenetic protein 2 responsiveness was identified in patients diagnosed with osteoporosis. However, it is unclear how other cell populations, especially osteoblasts, which are key players in bone remodeling, are affected and whether the bone morphogenetic protein pathway is affected during osteoporosis. Our research group designed a novel peptide, casein kinase 2.3, that acts downstream of the bone morphogenetic receptor type Ia and increases bone mineralization in murine cells and primary bovine osteoblasts. The aim of the study presented here was to compare the responsiveness of osteoblasts to bone morphogenetic protein 2 and casein kinase 2.3, especially in patients diagnosed with osteoporosis. Mature osteoblasts were extracted from patients diagnosed with osteoporosis or osteoarthritis from Christiana Care Hospital in Newark, Delaware. They were stimulated with either bone morphogenetic protein 2 or casein kinase 2.3, and their effect on osteoblast activity was determined. The osteoporotic patients showed no mineralization response to bone morphogenetic protein 2 stimulation, while the osteoarthritis patients significantly responded to bone morphogenetic protein 2 stimulation. Furthermore, markers for osteoblast activity were increased by casein kinase 2.3, which was in sharp contrast to bone morphogenetic protein 2. This further supports a major bone morphogenetic protein signaling disparity in both the elderly and those suffering with osteoporosis. Both patient types did significantly respond to casein kinase 2.3. Further analysis of the bone morphogenetic protein pathway could lead to new therapeutic products for osteoporosis.

In the matter of simulation and buildings: some critical reflections

Is there firm evidence suggesting that the deployment of building performance simulation in the design process has actually a significant impact on buildings’ subsequent long-term environmentally relevant performance? More importantly, do we have conclusive evidence for the frequently stated environmental mitigation potential of the building sector, given a number of essential global boundary conditions, including, for instance, population and urbanization growth? The pursuit of these questions could contribute to a more realistic appraisal of the environmentally relevant potential and limitations of both performance simulation deployment and sustainable building practices.

SETBP1 Mutations Accelerate NRAS-Mutant Leukemia

Juvenile myelomonocytic leukemia (JMML) is an aggressive, rare form of early childhood leukemia driven by Ras pathway mutations. Mutations in SET binding protein 1 (SETBP1) are a strong predictor of relapse in JMML, and are associated with reduced five-year event-free survival. Although some mechanisms of oncogenesis have been established for SETBP1 mutations, it remains unclear why they are associated with poor prognosis and relapse. The goal of this study was to understand how SETBP1 modulates the biology of Ras-driven leukemias and to determine whether there are therapeutic vulnerabilities of SETBP1-JMML that can be exploited. Here, we present novel findings on the synergy of SETBP1 and NRAS, and provide pre-clinical evidence for therapeutic intervention. To address our central question of how SETBP1 mutations modulate Ras pathway-driven leukemia, we first set out to determine whether mutant SETBP1 promotes the growth of hematopoietic progenitors in the context of a Ras pathway mutation. To this end, we performed mouse hematopoietic colony forming unit assays in the absence of exogenous cytokines. Both NRAS-G12D and PTPN11-E76K alone formed a modest number of colonies, and the addition of SETBP1-D868N significantly augmented colony number with either Ras pathway mutation. The combination of NRAS-G12D and SETBP1-D868Nconfer robust serial replating, indicating that the SETBP1-D868N promotes oncogenic transformation and progenitor self-renewal in the NRAS-G12D mutant cells. To understand how SETBP1 modulates therapeutic response, a novel NRAS/SETBP1-mutant cell line was generated and analyzed with a chemical screen of essential cell growth and survival pathways. This screen revealed dependencies on the mTOR/AKT/PI3K and Raf/MEK/ERK pathways. An immunoblot analysis revealed that mutant SETBP1 enhanced NRAS-driven ERK and mTOR pathway activation. Inhibitors of these pathways, such as rapamycin and trametinib were highly efficacious against our cell line. The combination of trametinib and rapamycin had sub-nanomolar efficacy in our NRAS/SETBP1-hematopoietic cell line and exhibited greater than bliss additivity at several time points. To evaluate the efficacy in vivo, our SETBP1/NRAS-mutant cell line was injected into mice. At the onset of disease, mice were given once-daily treatment of trametinib, rapamycin, combination treatment, or DMSO control. The median survival of mice receiving DMSO was 19.5-days post-transplant, compared to 21 days for rapamycin, 35 days for the combination treatment, and 42 days for trametinib. Treatment with trametinib significantly increased the median survival to beyond rapamycin or DMSO, doubling the survival time of the mice. Our data demonstrates that SETBP1 mutations accelerate NRAS-driven oncogenesis and enhance MAPK pathway activation by NRAS-G12D. Despite enhanced transforming potential, SETBP1-mutant cells are still sensitive to inhibitors of the RAS/ERK/MAPK pathway. Trametinib, an inhibitor of this pathway, doubles overall survival in our murine model of NRAS/SETBP1-mutant leukemia, thus providing encouraging pre-clinical data for the use of trametinib in SETBP1-mutant disease. Disclosures No relevant conflicts of interest to declare.