Group Of Growth Factors Research Articles

HISTOLOGICAL EVALUATION OF REPARATIVE OSTEOGENESIS IN CRITICAL SIZE FEMORAL BONE DEFECTS IN RATS OF DIFFERENT AGES AFTER INTRODUCTION OF ALLOGRAFTS SATURATED WITH BLOOD PLASMA GROWTH FACTORS

The increase in injuries and gunshot wounds because of the war in Ukraine makes it imperative to find methods for optimizing bone regeneration and filling large-size bone defects. Aim. Study morphological features of reparative osteogenesis when critical size femoral bone defects in rats in the early reproductive and mature stages are filled with allografts saturated with blood plasma growth factors (GF). Methods. Defects (3 × 3 mm) were created in the distal femoral metaphysis of 60 white laboratory rats, 3-months-old (n = 30) and 12-months-old (n = 30). The defects were filled with bone allografts saturated with GF in the two experimental groups (AlloG+GF), and unsaturated bone allografts in the two control groups (AlloG). All groups contained 15 rats of each age. At 14, 28 and 90 days after the surgery, 5 rats from each group were sacrificed, and histological analyses were performed. Results. In the AlloGgroups, excessive formation of connective tissue was observed 14 and 28 days after the surgery, most evident in the 3-monthold rats. In the AlloG+GF groups, bone formation was delayed at 14 days independent of age, while at 28 and 90 days, the area of bone trabeculae did not differ from the values in the AlloG groups. Throughout the experiment, decreases in allograft area (almost all of it was replaced by bone after 90 days) and connective tissue (completely absent in 3-month-old rats after 90 days) were observed in both AlloG+GF groups. The area of bone trabeculae increased in the period from 14 to 28 days. Conclusion. Saturating allografts with blood plasma growth factors facilitates an increase in the rate at which allografts are replaced by bone tissue, independent of the recipient’s age. However, excessive formation of connective tissues in the defect 14 and 28 days after the surgery, especiallyin 3-month-old rats, may negatively affect the mechanical properties of the bone, which should be considered in clinical practice.

Growth factor for therapeutic angiogenesis in ischemic heart disease: A meta-analysis of randomized controlled trials.

Aim: This study was designed to systematically evaluate the effects of growth factor (GF) for therapeutic angiogenesis on ischemic heart disease (IHD) by pooling the results of randomized controlled trials (RCTs). Methods and Results: PubMed, EMBASE, and CENTRAL databases were searched from inception to October 2022. RCTs, investigating the effects of GF therapy on IHD, were included. The risk bias of included study was assessed according to Cochrane tool. Weighted mean difference (WMD), calculated with fixed effect model or random effect model, was used to evaluate the effects of GF therapy on left ventricular ejection fraction (LVEF) and Canadian Cardiovascular Society (CCS) angina class. Relative risk (RR) was used to evaluate the effects of GF therapy on all-cause mortality, major adverse cardiovascular events (MACE) and revascularization. Meta-analysis, meta-regression analysis and publication bias analysis were performed by RevMan 5.3 or Stata 15.1 software. Twenty-nine studies involving 2899 IHD patients (1,577 patients in GF group and 1,322 patients in control group) were included. Compared with the control group, GF therapy did not reduce all-cause mortality (RR: 0.82; 95% CI: 0.54-1.24; p = 0.341), MACE [(RR: 0.83; 95% CI: 0.61-1.12; p = 0.227), revascularization (RR: 1.27, 95% CI: 0.82-1.96, p = 0.290) and CCS angina class (WMD: -0.08, 95% CI: -0.36 to 0.20, p = 0.560). However, GF therapy could increase LVEF during short-term follow-up (<1year). Conclusion: GF for therapeutic angiogenesis was beneficial for increasing LVEF during short-term follow-up (<1year), however, the therapy was not efficacious in decreasing all-cause mortality, MACE and revascularization.

P-372 The role of the immune system in the physiopathology of infertility in case of adenomyosis: a mouse model study

Abstract Study question Are there any fertility disorders and related local and/or systemic immune changes during the early implantation period in a mouse model of adenomyosis? Summary answer An increase in fertility disorders was observed in adenomyosis mice and coincide with local and systemic immune changes observed during the period of implantation. What is known already Adenomyosis is as a common pathology that could be responsible for fertility alteration. Immune changes in uterus are implicated in adenomyosis physiopathology. One hypothesis is that the physiological immune environment necessary for a successful implantation can be altered in adenomyosis, leading to fertility disorders. Study design, size, duration Randomly selected CD-1 female neonatal pups were orally dosed with oral administration of tamoxifen in order to induce adenomyosis (TAM group), while other received solvent only (control group). At 3 months, CD-1 mice (F1) of both group were put into mating. 36 pregnant mice were included in the TAM group and 30 in the control group. Participants/materials, setting, methods Ultrasounds were performed during pregnancy at E(E=embryonic day)7.5 and E12.5 to evaluate fertility outcomes in mice of the TAM and control group. Mice were sacrificed at E18.5 and histological,morphometric and functional analysis were performed on the placentas. In order to identify local and/or systemic immune changes in the uterus, mice of both group were sacrificed at E4.5 of pregnancy, during the implantation period. Uterine horns and spleen were collected for flow cytometry and RT-qPCR analyzes. Main results and the role of chance We observed a significantly lower number of implantation sites and a significantly higher number of resorption (3.88±2.36 versus 1.00±0.82(p &amp;lt; 0.001)) in TAM compared to control group. Analysis of placentas showed a significantly higher junctional/labyrinthic area ratio (0.60±0.09 versus 0.30±0.05(p = 0.0052)) and a significantly lower expression of Vascular Endothelial Growth-Factor(GF), Platelet endothelial cell adhesion molecule, Insulin-like GF2 and Placental GF in the TAM group compared to the control group, indicating an altered placental vascularization compared to controls. To characterize the immune change during the early implantation period, we analyzed some immune cells populations in the uteri and the spleen: In the TAM group, the number of macrophages(F4/80), Natural Killers(NK) cells(NKP46+/NKG2D+) and dendritic cells (DC)(CD11b+) were significantly decreased compared to control uteri. However, the number of M1 macrophages(Ly6c+hight) and their activation were significantly increased. DC activation was also increased in TAM group. In the spleen, a significant increase in the activation macrophages and DC was observed in adenomyosis group compared to control. In the uteri, the number of LT4(CD4+) cells and number of LTreg cells(CD25+/FOXP3+) were significantly increased in the TAM group compared to control group. In the spleen, a significant increase in LT4 cells count was observed in TAM compared to control group. Limitations, reasons for caution This study is limited by the use of an animal model and the lack of intervention. Wider implications of the findings This study provides evidence that adenomyotic lesions in mice induced fertility disorders and immune modifications at a local and at a systemic level during the early implantation period. These data support the involvement of innate and adaptive immune cells in implantation failure observed in the mouse model of adenomyosis. Trial registration number not applicable

Novel Growth Factor Combination for Improving Rotator Cuff Repair: A Rat In Vivo Study

Background: The lack of healing at the repaired tendon-bone interface is an important cause of failure after rotator cuff repair. While augmentation with growth factors (GFs) has demonstrated promise, the ideal combination must target all 3 tissue types at the tendon-bone interface. Hypothesis: The GF combination of transforming growth factor beta 1, Insulin-like growth factor 1, and parathyroid hormone will promote tenocyte proliferation and differentiation and improve the biomechanical and histological quality of the repaired tendon-bone interface. Study Design: Controlled laboratory study. Methods: In vitro, human tenocytes were cultured in the presence of the GF combination for 72 hours, and cell growth assays and the expression of genes specific to tendon, cartilage, and bone were analyzed. In vivo, adult rats (N = 46) underwent detachment and repair of the left supraspinatus tendon. A PVA-tyramine gel was used to deliver the GF combination to the tendon-bone interface. Histological, biomechanical, and RNA microarray analysis was performed at 6 and 12 weeks after surgery. Immunohistochemistry for type II and X collagen was performed at 12 weeks. Results: When treated with the GF combination in vitro, human tenocytes proliferated 1.5 times more than control (P = .04). The expression of scleraxis increased 65-fold (P = .013). The expression of Sox-9 (P = .011), type I collagen (P = .021), fibromodulin (P = .0075), and biglycan (P = .010) was also significantly increased, while the expression of PPARγ was decreased (P = .007). At 6 and 12 weeks postoperatively, the quality of healing on histology was significantly higher in the GF group, with the formation of a more mature tendon-bone interface, as confirmed by immunohistochemistry for type II and X collagen. The GF group achieved a load at failure and Young modulus >1.5 times higher at both time points. Microarrays at 6 weeks demonstrated upregulation of genes involved in leukocyte aggregation (S100A8, S100A9) and tissue mineralization (Bglap, serglycin, Fam20c). Conclusion: The GF combination promoted protendon and cartilage responses in human tenocytes in vitro; it also improved the histological appearance and mechanical properties of the repair in vivo. Microarrays of the tendon-bone interface identified inflammatory and mineralization pathways affected by the GF combination, providing novel therapeutic targets for further research. Clinical Relevance: The use of this GF combination is translatable to patients and may improve healing after rotator cuff repair.

A combination of growth factors and cytokines alter preimplantation mouse embryo development, foetal development and gene expression profiles.

Within the maternal tract, the preimplantation embryo is exposed to an array of growth factors (GFs) and cytokines, most of which are absent from culture media used in clinical IVF. Whilst the addition of individual GFs and cytokines to embryo culture media can improve preimplantation mouse embryo development, there is a lack of evidence on the combined synergistic effects of GFs and cytokines on embryo development and further foetal growth. Therefore, in this study, the effect of a combined group of GFs and cytokines on mouse preimplantation embryo development and subsequent foetal development and gene expression profiles was investigated. Supplementation of embryo culture media with an optimised combination of GFs and cytokines (0.05 ng/ml vascular endothelial GF, 1 ng/ml platelet-derived GF, 0.13 ng/ml insulin-like GF 1, 0.026 ng/ml insulin-like GF 2 and 1 ng/ml granulocyte colony-stimulating factor) had no effect on embryo morphokinetics but significantly increased trophectoderm cell number (P = 0.0002) and total cell number (P = 0.024). Treatment with this combination of GFs and cytokines also significantly increased blastocyst outgrowth area (P < 0.05) and, following embryo transfer, increased foetal weight (P = 0.027), crown-rump length (P = 0.017) and overall morphological development (P = 0.027). RNA-seq analysis of in vitro derived foetuses identified concurrent alterations to the transcriptional profiles of liver and placental tissues compared with those developed in vivo, with greater changes observed in the GF and cytokine treated group. Together these data highlight the importance of balancing the actions of such factors for the regulation of normal development and emphasise the need for further studies investigating this prior to clinical implementation.

Improvement of in vitro proliferation of cockerel spermatogonial stem cells using different combinations of growth factors

ABSTRACT 1. This study examined whether in vitro proliferation and maintenance of cockerel spermatogonial stem cells (SSCs) could be improved by adding different combinations of growth factors (GFs), including glial cell line-derived neurotrophic factor (GDNF), basic fibroblast growth factor (bFGF) or leukaemia inhibitory factor (LIF) into the culture medium. 2. The SSCs were isolated from the testes of immature cockerels. For short-term cultures, a medium supplemented with different combinations of GFs for 7 d in 5 replicates was used. The groups were classified as follows: without GF (control group); with GDNF (G group); with GDNF and bFGF (GF group); and with GDNF, bFGF and LIF (GFL group). The number of colonies and cells per colony, as well as the transcript abundance of STRA8 and OCT4 genes, was determined 7 d after the initial culturing. Immunofluorescence staining of SSEA-1, SSEA-3 and VASA protein markers, besides periodic acid-Schiff (PAS) staining, was carried out. 3. The number of colonies and cells per colony increased in the G, GF and GFL groups, compared to the control group (P < 0.01); however, the highest proliferation and colony formation were observed in the GFL group. The positive immunofluorescence staining of SSEA-1, SSEA-3 and VASA protein markers, as well as PAS staining, confirmed the self-renewal and colonisation of cockerel SSCs. The proliferation results were supported by the increased STRA8 and OCT4 transcript abundance in the treated groups (G, GF and GLF), compared to the control group. The SSC proliferation was associated with the higher transcript abundance of STAR8 and OCT4 genes in the GFL group, compared to the G and GF groups (P < 0.01). 4. The results showed that proliferation and colony-forming capacity of cockerel SSCs were positively improved by GDNF, bFGF and LIF. However, the most significant effect was observed when the medium was supplemented with LIF in combination with GDNF and bFGF.

Bladder Regeneration Using a Polycaprolactone Scaffold with a Gradient Structure and Growth Factors in a Partially Cystectomized Rat Model.

BackgroundTissue engineering can be used for bladder augmentation. However, conventional scaffolds result in fibrosis and graft shrinkage. This study applied an alternative polycaprolactone (PCL)-based scaffold (diameter = 5 mm) with a noble gradient structure and growth factors (GFs) (epidermal growth factor, vascular endothelial growth factor, and basic fibroblast growth factor) to enhance bladder tissue regeneration in a rat model.MethodsPartially excised urinary bladders of 5-week-old male Slc:SD rats were reconstructed with the scaffold (scaffold group) or the scaffold combined with GFs (GF group) and compared with sham-operated (control group) and untreated rats (partial cystectomy group). Evaluations of bladder volume, histology, immunohistochemistry (IHC), and molecular markers were performed at 4, 8, and 12 weeks after operation.ResultsThe bladder volumes of the scaffold and GF group recovered to the normal range, and those of the GF group showed more enhanced augmentation. Histological evaluations revealed that the GF group showed more organized urothelial lining, dense extracellular matrix, frequent angiogenesis, and enhanced smooth muscle bundle regeneration than the scaffold group. IHC for α-smooth muscle actin, pan-cytokeratin, α-bungarotoxin, and CD8 revealed that the GF group showed high formation of smooth muscle, blood vessel, urothelium, neuromuscular junction and low immunogenicity. Concordantly, real-time polymerase chain reaction experiments revealed that the GF group showed a higher expression of transcripts associated with smooth muscle and urothelial differentiation. In a 6-month in vivo safety analysis, the GF group showed normal histology.ConclusionThis study showed that a PCL scaffold with a gradient structure incorporating GFs improved bladder regeneration functionally and histologically.

The distribution pattern and growth factor level in platelet-rich fibrin incorporated skin-derived mesenchymal stem cells: An in vitro study.

Background and Aim:A skin wound in an animal must be cared for to prevent further health issues. Platelet-rich fibrin (PRF) and skin-derived mesenchymal stem cells (SMSCs) have been reported to have potential in increasing the rate of wound healing. This study aimed to analyze the distribution patterns and levels of platelet-derived growth factor (PDGF), insulin-like growth factor (IGF), vascular endothelial growth factor (VEGF), and transforming growth factor-β (TGF-β) in PRF incorporated with SMSCs.Materials and Methods:This study employed a true experiment (in vitro) design with post-test only performed in the control group alone. PRF and SMSCs were extracted from the blood and skin of 16 rabbits. SMSCs were characterized using immunocytochemistry to examine clusters of differentiation for 45, 73, 90, and 105. PRF was incorporated into the SMSCs and then divided into four groups (N=32/n=8): Group A (PRF only), Group B (PRF+SMSCs, incubated for 1 day), Group C (PRF+SMSCs, incubated for 3 days), and Group D (PRF+SMSCs, incubated for 5 days). Scanning electron microscopy was used to examine the distribution pattern of SMSCs between groups. The supernatant serum (Group A) and supernatant medium culture (Group D) were collected for the measurement of PDGF, IGF, VEGF, and TGF-β using an enzyme-linked immunosorbent assay sandwich kit. An unpaired t-test was conducted to analyze the differences between Groups A and D (p<0.01).Results:Group D had the most morphologically visible SMSCs attached to the PRF, with elongated and pseudopodia cells. There was a significant difference between the levels of growth factor in Groups A and D (p=0.0001; p<0.01).Conclusion:SMSCs were able to adhere to and distribute evenly on the surface of PRF after 5 days of incubation. The PRF incorporated SMSCs contained high levels of PDGF, IGF, VEGF, and TGF- β, which may prove to have potential in enhancing wound healing.

PIN10 GROWTH FACTORS AND THEIR IMPACT ON HEALTHCARE UTILIZATION AND COST IN CACHECTIC HIV PATIENTS

Cachexia is a syndrome consisting of muscle fatigue, weakness, and weight loss most commonly existing within a comorbid disease such as later stages of HIV or cancer. Cachexia has been linked to increased healthcare utilization, decreased life expectancy, and worsening prognosis. Anabolic steroids and human growth hormone (combined term growth factor (GF)) are treatment options for cachexia, but are themselves controversial due to side effect potentials. The goal of this analysis is to assess the impact of GF treatment healthcare utilization and cost in HIV related cachexia patients. Using a large retrospective claims dataset we identified cachectic HIV patients, dividing them into GF and non-GF groups. We compared the two groups on overall utilization and cost as well as antibiotic use and days supply(DS) of antibiotic. Descriptive statistics included t-tests and chi-square. Logistic regression was used to compare odds of hospitalization, ER, and antibiotic while controlling for significant comorbid diseases. 330 cachectic HIV patients were identified, 54 in the GF group and 276 in the non-GF group. On average, GF patients had significantly less emergency room visits (0.574 GF vs 1.768 NGF, p<0.01) and hospitalizations (0.222 vs 1.304 p<0.01). Mean and median antibiotics DS was high, but not significantly different (120.65 vs 164.33, p=0.24; 31.5 vs 59.5 p=0.26, respectively). Median all-cause cost ($54,281 vs $34,849 p=0.01) and outpatient costs ($52,414 vs $21,680 p<0.01) were higher for the GF group, but mean hospital cost ($2,692 vs $29,145 p<0.01) was lower. After controlling for comorbid diseases, the odds of a hospitalization were 69.5% less (p=0.01) for GF patients. It is of interest that while the GF group had significantly less ER visits and hospitalizations the overall cost for this group was still significantly higher. Further analysis needs to explore the sources of these outpatient costs and discuss their relevance within the disease.

Effects of basic fibroblast growth factor on healing of Mycobacterium tuberculosis infective wound in New Zealand rabbit after debridement

Effects of basic fibroblast growth factor on healing of Mycobacterium tuberculosis infective wound in New Zealand rabbit after debridement

Efficient and cost-effective generation of hepatocyte-like cells through microparticle-mediated delivery of growth factors in a 3D culture of human pluripotent stem cells

Biomedical application of human pluripotent stem cell-derived hepatocyte-like cells (hPSC-HLCs) relies on efficient large-scale differentiation, which is commonly performed by a suspension culture of three-dimensional (3D) multicellular spheroids in bioreactors. However, this approach requires large amounts of growth factors (GFs) and the need to overcome limited diffusional transport posed by the inherent 3D structure of hPSC spheroids. Here, we have hypothesized that localized delivery of GFs by incorporation of GF-laden degradable polymeric microparticles (MPs) within the hPSC spheroids would circumvent such limitations. In this study, GFs for hepatocytic differentiation were encapsulated in gelatin-coated poly (l-lactic acid)/poly (DL-lactic-co-glycolic acid) (PLLA/PLGA) MPs which were subsequently incorporated into the hPSC spheroids. Gene expression analyses demonstrated that MP delivery of the GFs resulted in similar expression levels of hepatocytic markers despite the use of 10-fold less total GFs. The differentiated HLCs in the MP group exhibited ultrastructure and functional characteristics comparable with the conventional soluble GF group. The generated HLCs in the MP group were successfully engrafted in an acute liver injury mouse model and maintained hepatocytic function after implantation. These results suggested that sustained and localized delivery of GFs using MPs might offer a novel approach towards scalable technologies for hepatocytic differentiation and engineer a better 3D microenvironment for cells.

Optimization of release pattern of FGF-2 and BMP-2 for osteogenic differentiation of low-population density hMSCs

In the modern design, most delivery systems for bone regeneration focus on a single growth factor (GF) or a simple mixture of multiple GFs, overlooking the coordination of proliferation and osteogenesis induced by various factors. In this study, core-shell microspheres with poly-l-lactide core-poly(lactic-co-glycolic acid) shell were fabricated, and two GFs, basic fibroblast growth factor 2 (FGF-2) and bone morphogenetic protein 2 (BMP-2) were encapsulated into the core or/and shell. The effects of different release patterns (parallel or sequential manners) of FGF-2 and BMP-2 from these core-shell microspheres on the osteogenic differentiation of low-population density human mesenchymal stem cells (hMSCs) were investigated and the temporal organization of GF release was optimized. In vitro experiments suggested that induction of osteogenic differentiation of low-population density hMSCs by the sequential delivery of FGF-2 followed by BMP-2 from the core-shell microspheres (group S2) was much more efficient than that by the parallel release of the two factors from uniform microspheres (group U). The osteogenic induction by the sequential delivery of BMP-2 followed by FGF-2 from core-shell microspheres (group S1) was even worse than that from microspheres loaded with BMP-2 in both core and shell (group B), although comparable to the cases of parallel delivery of dual GFs (group P). This study showed the advantages of group S2 microspheres in inducing osteogenic differentiation of low-population density hMSCs and the necessity of time sequence studies in tissue engineering while multiple GFs are involved.

Effect of Chinese herbs on immunoglobulin A nephropathy: a randomized controlled trial

ObjectiveThe accumulation of extracellular matrix (ECM) is one of the main causes of renal fibrosis. Emerging evidence suggests that the metabolic enzyme of ECM is associated with renal fibrosis. In this study, we applied randomly controlled trial to check the curative effect of Chinese herbs on patients with immunoglobulin A nephropathy (IgAN). MethodsTwenty-six patients were randomly divided into group A (control group) treated with Western Medicine and group B (treatment group) treated with combination of Traditional Chinese Medicine (TCM) and Western Medicine. Blood and urine tests were done before treatment and after 8-week treatment. ResultsThe levels of the main composition of extracellular matrix (MC-ECM), the metabolic enzyme of ECM (ME-ECM) and some cytokines in group B decreased more obviously than those in group A after 8-week treatment. So did the level of 24-hour urine protein. However, Metal matrix protease (MMP)-2 and vascular endothelial growth factor in group B increased more obviously than those in group A after 8-week treatment. No effects on the renal function were found in both groups. ConclusionOur study provided important information on using the combination of TCM with Western Medicine to inhibit the progression of renal fibrosis in patients with IgAN.

Effect of growth factors-coated electrospun nanofibrous films on the growth of bone marrow mesenchymal stem cells

Objective To explore the impact of growth factors-coated electrospun [poly(L-lactideco-e-caprolactone) (PLCL)]/fibrinogen nanofibrous films on the growth of rabbit bone marrow mesenchymal stem cells (BMSCs).Methods Electrospun nanofibrous films were fabricated from PLCL solution and fibrinogen solution.The nanofibrous films which were immersed into fibronectin solution and growth factors solution [vascular endothelial growth factor (VEGF),basic fibroblast growth factor (bFGF)] sequentially served as experimental group A films,those which were immersed into growth factors solution only as experimental group B films,and those without given any treatment as control group.The in vitro release results of growth factors in groups A and B were detected by using enzyme-linked immunosorbent assay (ELISA).BMSCs were obtained from rabbits by density gradient centrifugation and inoculated on the films.The adhesion and proliferation results of BMSCs on different films were detected by methyl thiazol tetrazolium (MTT) assay.Results In both experimental groups A and B,the growth factors were released in vitro for over 10 days,the released amount of the growth factor in the two groups was gradually reduced with time,and the reduction rate in group B was higher than in group A.The absorbance values in group B (0.37 ±0.06) and control group (0.35 ±0.09) were significantly lower than in group A (0.47 ±0.04) during the first 12 h (P ＜ 0.01).The cell proliferation rate was higher in group A than in group B and control group (P ＜ 0.05).Conclusion Electrospun PLCL/fibrinogen nanofibrous films,which surface is modified by fibronectin and growth factors (VEGF,bFGF) sequentially,have good performance in growth factors sustained release and cell compatibility. Key words: Bone marrow mesenchymal stem cells ; Electrospinning; Nanofibrous; Surface modification ; Tissue engineering

Efficacy of Growth Factors Compared to Chemotherapy in Low-Risk Myelodysplastic Syndromes.

The myelodysplastic syndromes (MDS) represent a heterogeneous group of disorders with different underlying disease biologies and prognoses. Low-risk MDS, defined as patients with refractory anemia (RA) or refractory anemia with ringed sideroblasts (RARS), with International Prognostic Scoring System (IPSS) scores of 0–1.0, are associated with relatively good prognosis. No study has evaluated outcomes in this population comparing treatment with growth factors (GF) to chemotherapy (Chemo).METHODS: A MEDLINE search on the keywords MDS, RA, RARS, treatment, growth factors and chemotherapy was performed. Only original articles with pathologically confirmed RA or RARS that included the patient characteristics and effect of therapy in individual cases were included. Treatments were categorized as either GF (erythropoietin, granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor) or Chemo (differentiating agents, immunomudulators, cytotoxic agents). IPSS was calculated if not reported, when possible. Outcomes were categorized as response, disease progression, or death. Responses were standardized and recalibrated according to the International Working Group (IWG) criteria, as complete response, partial response, or hematologic improvement. T-tests were performed for continuous variables, chi-square for categorical, and a Cox proportional hazards model for survival controlling for known risk factors.RESULTS: Of 653 potential articles from 1985 to 2005, 137 papers representing 2,301 patients with low-risk MDS were reviewed. Individual patient data was available in 799 cases. Baseline characteristics were (mean, standard deviation): age 67 ± 12, hemoglobin 8.4 ± 8.57, ANC 1.55 ± 4.78, platelet count 116 ± 144, erythropoietin level 236 ± 968. Ninety-one percent of patients were transfusion-dependent, requiring a median of 3 pRBC transfusions per month (range 0–6). Patients had IPSS scores from 0–1.0 in 90% and were diagnosed a median of 12 months prior to therapy initiation. Neither of those two variables differed between the GF and Chemo groups. Four hundred and seventeen patients were received Chemo, amongst whom 39 deaths were recorded, and 382 patients received GF (5 died). Of those treated with GF, 45% responded, compared to 41.5% for those treated with chemo (p=0.31). The average response time for Chemo and GF was 10.8 months (n=141) vs 8.0 months (n=112, p<0.01). There was no difference in unadjusted survival time between those treated with Chemo and GF patients (n=799, hazard ratio=2.07 favoring GF, p=0.14) as shown below: [Display omitted] After controlling for age and baseline transfusion needs, the Cox proportional hazards model found no difference for the survival between the two groups (n=607, hazard ratio=2.25, p=0.14).CONCLUSIONS: For patients with low-risk MDS, response rates to GF and Chemo are similar. Despite a significantly prolonged response time to Chemo compared to GF, there was no difference in survival, even when controlling for differences in age and transfusion needs. Decision tools need to be developed to determine which therapy to choose in patients with low-risk MDS.

Dose-dependent effects of combined IGF-I and TGF-beta1 application in a sheep cervical spine fusion model.

Combined IGF-I and TGF-beta1 application by a poly-(D,L-lactide) (PDLLA) coated interbody cage has proven to promote spine fusion. The purpose of this study was to determine whether there is a dose-dependent effect of combined IGF-I and TGF-beta1 application on intervertebral bone matrix formation in a sheep cervical spine fusion model. Thirty-two sheep underwent C3/4 discectomy and fusion. Stabilisation was performed using a titanium cage coated with a PDLLA carrier including no growth factors in group 1 ( n=8), 75 micro g IGF-I plus 15 micro g TGF-beta1 in group 2 ( n=8), 150 micro g IGF-I plus 30 micro g TGF-beta1 in group 3 ( n=8) and 300 micro g IGF-I plus 60 micro g TGF-beta1 in group 4 ( n=8). Blood samples, body weight and temperature were analysed. Radiographic scans were performed pre- and postoperatively and after 1, 2, 4, 8, and 12 weeks. At the same time points, disc space height and intervertebral angle were measured. After 12 weeks, the animals were killed and fusion sites were evaluated using quantitative computed tomographic (CT) scans to assess bone mineral density, bone mineral content and bony callus volume. Biomechanical testing was performed and range of motion, and neutral and elastic zones were determined. Histomorphological and histomorphometrical analysis were carried out and polychrome sequential labelling was used to determine the time frame of new bone formation. In comparison to the group without growth factors (group 1), the medium- and high-dose growth factor groups (groups 3 and 4) demonstrated a significantly higher bony callus volume on CT scans, a higher biomechanical stability, an advanced interbody bone matrix formation in histomorphometrical analysis, and an earlier bone matrix formation on fluorochrome sequence labelling. Additionally, the medium- and high-dose growth factor groups (groups 3 and 4) demonstrated a significantly higher bony callus volume, a higher biomechanical stability in rotation, and an advanced interbody bone matrix formation in comparison to the low-dose growth factor group (group 2). No significant difference could be determined between the medium- and the high-dose growth factor groups (groups 3 and 4, respectively). The local application of IGF-I and TGF-beta1 by a PDLLA-coated cage significantly improved results of interbody bone matrix formation in a dose-dependent manner. The best dose-response relationship was achieved with the medium growth factor dose (150 micro g IGF-I and 30 micro g TGF-beta1). With an increasing dose of these growth factors, no further stimulation of bone matrix formation was observed. Although these results are encouraging, safety issues of combined IGF-I and TGF-beta1 application for spinal fusion still have to be addressed.