Growth hormone-releasing hormone attenuates cardiac hypertrophy and improves heart function in pressure overload-induced heart failure.

It has been shown that growth hormone-releasing hormone (GHRH) reduces cardiomyocyte (CM) apoptosis, prevents ischemia/reperfusion injury, and improves cardiac function in ischemic rat hearts. However, it is still not known whether GHRH would be beneficial for life-threatening pathological conditions, like cardiac hypertrophy and heart failure (HF). Thus, we tested the myocardial therapeutic potential of GHRH stimulation in vitro and in vivo, using GHRH or its agonistic analog MR-409. We show that in vitro, GHRH(1-44)NH2 attenuates phenylephrine-induced hypertrophy in H9c2 cardiac cells, adult rat ventricular myocytes, and human induced pluripotent stem cell-derived CMs, decreasing expression of hypertrophic genes and regulating hypertrophic pathways. Underlying mechanisms included blockade of Gq signaling and its downstream components phospholipase Cß, protein kinase Cε, calcineurin, and phospholamban. The receptor-dependent effects of GHRH also involved activation of Gαs and cAMP/PKA, and inhibition of increase in exchange protein directly activated by cAMP1 (Epac1). In vivo, MR-409 mitigated cardiac hypertrophy in mice subjected to transverse aortic constriction and improved cardiac function. Moreover, CMs isolated from transverse aortic constriction mice treated with MR-409 showed improved contractility and reversal of sarcolemmal structure. Overall, these results identify GHRH as an antihypertrophic regulator, underlying its therapeutic potential for HF, and suggest possible beneficial use of its analogs for treatment of pathological cardiac hypertrophy.

Rigenera protocol in the treatment of surgical wound dehiscence.

The effective management of post-operative wounds is important to prevent potential complications such as surgical-site infections and wound dehiscence. The purpose of this study was to treat wound dehiscence in elderly patients who were subjected to orthopaedic surgical interventions. The dehisced wounds were treated with autologous micro-grafts obtained using a promising CE-certified medical device called Rigeneracons. This instrument is a biological disruptor of human tissues able to specifically select progenitor cells that, as already reported in previous studies, maintain high cell viability but mainly have a high regenerative potential, allowing the repair of damaged tissues. Autologous micro-grafts obtained by Rigeneracons are ready to use and can be applied alone or in combination with biological scaffolds directly on the injured area. We observed in our patients a complete remission of dehisced wounds, on average, after 30 days from micro-grafts application and a total wound re-epithelialisation after 1 year from the surgical intervention. In conclusion, although we reported only three patients, autologous micro-grafts can be considered a promising approach for the treatment of dehisced wounds, improving the wound-healing process and in general the patient's quality of life without using other dressings.

A New Medical Device Rigeneracons Allows to Obtain Viable Micro-Grafts From Mechanical Disaggregation of Human Tissues.

Autologous graft is considered the gold standard of graft materials; however, this approach is still limited due to both small amount of tissue that can be collected and to reduced cell viability of cells that can be obtained. The aim of this preliminary study was to demonstrate the efficacy of an innovative medical device called Rigeneracons® (CE certified Class I) to provide autologous micro-grafts immediately available to be used in the clinical practice. Moreover, Rigeneracons® is an instrument able to create micro-grafts enriched of progenitors cells which maintain their regenerative and differentiation potential. We reported preliminary data about viability cell of samples derived from different kind of human tissues, such as periosteum, cardiac atrial appendage biopsy, and lateral rectus muscle of eyeball and disaggregated by Rigeneracons®. In all cases we observed that micro-grafts obtained by Rigeneracons® displayed high cell viability. Furthermore, by cell characterization of periosteum samples, we also evidenced an high positivity to mesenchymal cell markers, suggesting an optimal regenerative potential.

Adiponectin oligomers are similarly distributed in adequate-for-gestational-age obese children irrespective of feeding in their first year.

BACKGROUND: Nutrition and growth in early postnatal life have a role in future diseases. Our aim was to investigate adiponectin oligomers in adequate-for-gestational-age obese children with respect to type and duration of feeding in the first year of life. METHODS: Adiponectin oligomers and cardiometabolic risk factors were measured in 113 adequate-for-gestational-age obese children, divided into group A (prolonged breast feeding, >6 mo), group B (short breast feeding, 1-6 mo), and group C (formula feeding from birth). RESULTS: All the parameters were similar among the groups. Adiponectin oligomers did not correlate with gestational age, months of breast feeding, and time of weaning. Total and high-molecular weight adiponectin were differently distributed across gender and pubertal stages (P < 0.02), being lower in males from the start of puberty. Prepregnancy BMI and at the end of the pregnancy were negatively associated (P < 0.04) with total and medium-molecular weight adiponectin in female and male offspring, respectively. CONCLUSIONS: Adiponectin oligomers and metabolic characteristics are similarly distributed in adequate-for-gestational-age obese children, irrespective of the type and duration of the feeding in the first year of life. Gender and mother's BMI in pregnancy are contributors to adiponectin regulation. Further studies will explain whether breastfeeding protects against metabolic impairment later in life.

Involvement of genes related to inflammation and cell cycle in idiopathic short stature.

Idiopathic Short Stature (ISS) defines a condition in which height is <-2SD compared to the mean of a reference population where systemic, endocrinological, nutritional or chromosomal disorders have not been identified and diagnosis is based on exclusion of any known causes of short stature. JAK/STAT pathway is triggered by GH binding to the GH receptor and promotes cellular growth through transcription of GH-responsive genes. In order to identify "candidate genes" differently expressed in ISS subjects with respect to control ones, we analyzed the expression of 84 genes related to JAK/STAT pathway by RT(2) Profiler PCR array approach in a total of 10 subjects. Then, we validated the observed data by Real Time PCR and ELISA assays in a major number of subjects. We found two genes that were differently expressed in ISS subjects with respect to the control group: CXCL9 and FCGR1A/CD64, both significantly up-regulated (fold change 2.17 and 1.70, respectively) and belonging to family of IFN-γ-inducible factors. Further, ISS subjects showed an increased gene expression of IFN-γ and IFI16, higher serum levels of IFN-γ but similar levels of CXCL9 when compared to healthy subjects. In addition, we showed a pubertal modulation of CXCL9 levels. These data suggest that inflammatory and regulatory factors of the cell cycle may be involved in the ISS condition, introducing a new perspective to its etiology.

Isolated GHD: investigation and implication of JAK/STAT related genes before and after rhGH treatment.

Isolated GH deficiency (IGHD) is a rare disorder that occurs as an idiopathic form in most cases. The pathway JAK/STAT promotes cellular growth and it could be implicated in this condition. In order to characterize IGHD in the pediatric population and identify genes differently expressed before and after GH therapy, we performed a quantitative evaluation of 84 genes related to the JAK/STAT pathway which, by promoting cellular growth. RT(2) Profiler PCR Array and the other/subsequent evaluations were performed in three children with severe IGHD before and after 6 months of GH therapy and in three matched normal children. Gene profiling was modified by the IGHD status and the GH therapy, with a modulation of GHR and some inflammatory genes such as CRP. We found a heterozygous nonsense mutation R43X in the GHR gene in two out of three IGHD subjects, despite a good response to therapy. After therapy cardiovascular markers linked to genes as IL6, IL8 and TNF-α displayed a trend toward reduction. Pre- and post therapy status differently affects gene expression. Mutational screening of GHR may be useful in investigating IGHD's etiology. Genes linked to inflammation suggest to evaluate cardiovascular risks also in pediatric IGHD subjects.

Cartilage Micrografts as a Novel Non-Invasive and Non-Arthroscopic Autograft Procedure for Knee Chondropathy: Three-Year Follow-Up Study.

(1) Background: Focal chondral defects of the knee can significantly impair patient quality of life. Although different options are available, they are still not conclusive and have several limitations. The aim of this study was to evaluate the role of autologous cartilage micrografts in the treatment of knee chondropathy. (2) Methods: Eight patients affected by knee chondropathy were evaluated before and after 6 months and 3 years following autologous cartilage micrografts by magnetic resonance imaging (MRI) for cartilage measurement and clinical assessment. (3) Results: All patients recovered daily activities, reporting pain reduction without the need for analgesic therapy; Oxford Knee Score (OKS) was 28.4 ± 6 and 40.8 ± 6.2 and visual analogue scale (VAS) was 5.5 ± 1.6 and 1.8 ± 0.7 before and after 6 months following treatment, respectively. Both scores remained stable after 3 years. Lastly, a significant improvement of the cartilage thickness was observed using MRI after 3 years. (4) Conclusions: Autologous cartilage micrografts can promote the formation of new cartilage, and could be a valid approach for the treatment of knee chondropathy.

Tissue regeneration: an overview from stem cells to micrografts.

Regenerative medicine represents a major challenge for the scientific community. The choice of the biological sources used, such as stem cells and grafts, is crucial. Stem cell therapy is mainly related to the use of mesenchymal stem cells; however, clinical trials are still needed to investigate their safety. The micrografting technique was conceived by Cicero Parker Meek in 1958. It is based on the principle that by increasing the superficial area of skin grafts and reducing the size of its particles, it is possible to cover an area larger than the original donor site. Stem cells are pluripotent cells that have the capacity to differentiate into all cell types and are self-renewing, whereas micrografts derive from a small fragment of an autologous tissue and exhibit limited differentiative potential compared with stem cells. Therefore, stem cells and micrografts cannot be considered equivalent, although in some cases they exhibit similar regenerative potential, which is the focus of this review. Last, stem cell therapies remain limited because of complex and costly processes, making them not very feasible in clinical practice, whereas obtaining micrografts is generally a one-step procedure that does not require any advanced tissue manipulation.

Autologous grafts in the treatment of avascular osteonecrosis of the femoral head.

BACKGROUND: Osteonecrosis of the femoral head (ONFH) is a frequent orthopedic disease leading to destruction of the hip joint and disabling arthritis. Several procedures have been developed to treat the joint deterioration in case of osteonecrosis, trying to avoid or delay an intervention of total hip replacement, especially in young patients. The aim of this study was to analyze the use of autologous bone micrografts derived from cancellous bone in the management of avascular ONFH. The treatment described was implemented using the Rigenera® protocol to obtain autologous micrografts: small fragments of cancellous bone collected by femoral neck, disaggregated and injected in the necrotic area using an empty screw. MATERIALS AND METHODS: Twenty adult patients affected by avascular ONFH were enrolled in this study; all patients reported a preoperative intermittent coxo-arthrosis and limited function of intra and extra rotation of the hip. Inclusion criteria were an Oxford Hip Score between (OHS) 20 and 39, a Harris hip score (HHS) showing pre-operative poor results (lower than 70 points) and a stage II-IIIA and IIIB according with the classification proposed by the Association Research Circulation Osseous (ARCO). RESULTS: Using an MRI evaluation, after six months, the authors observed a complete regression of necrotic area and the restoration of osseous structure. Clinical outcome has been evaluated at 6-12 and 24 months follow-up. At the final F.U. the HHS rised from poor to good results (mean value at final F.U of 84) while the OHS improved significantly already after 21 days from micrografts injection (mean 35.4 ± 7.5) with an increasing trend  until to two-year final FU (mean 37.4 ± 9.5). The full recovery of daily and mild sport activities was reached after 20 and 90 days from intervention, respectively. CONCLUSION: The results of this study are suggestive for a new approach in the treatment of avascular ONFH assuming a process of bone regeneration based on a dual mechanism of action, biological and mechanical, induced by micrografts and injected using an empty screw as vehicle.

Rationale and pre-clinical evidences for the use of autologous cartilage micrografts in cartilage repair.

BACKGROUND: The management of cartilage lesions is an open issue in clinical practice, and regenerative medicine represents a promising approach, including the use of autologous micrografts whose efficacy was already tested in different clinical settings. The aim of this study was to characterize in vitro the effect of autologous cartilage micrografts on chondrocyte viability and differentiation and perform an evaluation of their application in racehorses affected by joint diseases. MATERIALS AND METHODS: Matched human chondrocytes and micrografts were obtained from articular cartilage using Rigenera® procedure. Chondrocytes were cultured in the presence or absence of micrografts and chondrogenic medium to assess cell viability and cell differentiation. For the pre-clinical evaluation, three racehorses affected by joint diseases were treated with a suspension of autologous micrografts and PRP in arthroscopy interventions. Clinical and radiographic follow-ups were performed up to 4 months after the procedure. RESULTS: Autologous micrografts support the formation of chondrogenic micromasses thanks to their content of matrix and growth factors, such as transforming growth factor ß (TGFß) and insulin-like growth factor 1 (IGF-1). On the other hand, no significant differences were observed on the gene expression of type II collagen, aggrecan, and SOX9. Preliminary data in the treatment of racehorses are suggestive of a potential in vivo use of micrografts to treat cartilage lesions. CONCLUSION: The results reported in this study showed the role of articular micrografts in the promoting chondrocyte differentiation suggesting their potential use in the clinical practice to treat articular lesions.

Acylated and unacylated ghrelin promote proliferation and inhibit apoptosis of pancreatic beta-cells and human islets: involvement of 3',5'-cyclic adenosine monophosphate/protein kinase A, extracellular signal-regulated kinase 1/2, and phosphatidyl inositol 3-Kinase/Akt signaling.

Among its pleiotropic actions, ghrelin modulates insulin secretion and glucose metabolism. Herein we investigated the role of ghrelin in pancreatic beta-cell proliferation and apoptosis induced by serum starvation or interferon (IFN)-gamma/TNF-alpha, whose synergism is a major cause for beta-cell destruction in type I diabetes. HIT-T15 beta-cells expressed ghrelin but not ghrelin receptor (GRLN-R), which binds acylated ghrelin (AG) only. However, both unacylated ghrelin (UAG) and AG recognized common high-affinity binding sites on these cells. Either AG or UAG stimulated cell proliferation through Galpha(s) protein and prevented serum starvation- and IFN-gamma/TNF-alpha-induced apoptosis. Antighrelin antibody enhanced apoptosis in either the presence or absence of serum but not cytokines. AG and UAG even up-regulated intracellular cAMP. Blockade of adenylyl cyclase/cAMP/protein kinase A signaling prevented the ghrelin cytoprotective effect. AG and UAG also activated phosphatidyl inositol 3-kinase (PI3K)/Akt and ERK1/2, whereas PI3K and MAPK inhibitors counteracted the ghrelin antiapoptotic effect. Furthermore, AG and UAG stimulated insulin secretion from HIT-T15 cells. In INS-1E beta-cells, which express GRLN-R, AG and UAG caused proliferation and protection against apoptosis through identical signaling pathways. Noteworthy, both peptides inhibited cytokine-induced NO increase in either HIT-T15 or INS-1E cells. Finally, they induced cell survival and protection against apoptosis in human islets of Langerhans. These expressed GRLN-R but showed also UAG and AG binding sites. Our data demonstrate that AG and UAG promote survival of both beta-cells and human islets. These effects are independent of GRLN-R, are likely mediated by AG/UAG binding sites, and involve cAMP/PKA, ERK1/2, and PI3K/Akt.

A Regenerative Approach with Dermal Micrografts in the Treatment of Chronic Ulcers.

BACKGROUND: The etiology of non-healing ulcers depends on both systemic and local factors. The introduction of advanced dressing, negative wound therapy and compression therapy have undoubtedly improved clinical outcomes. The principal aim of study was to demonstrate the efficacy of dermal micrografts in the treatment of ulcers with different etiologies. The second aim was to investigate in vitro the action of micrografts in the regenerative process. METHODS: The dermal micro-grafts were obtained from mechanical disaggregation of small pieces of skin tissue through a medical device called Rigeneracons. RESULTS: We observed in vivo the ability of dermal autologous micrografts to improve the healing of venous, diabetic, pressure and post-traumatic ulcers after few week of treatment accomplished in general with a better quality of life for the patients. In vitro results showed that these micrografts express mesenchymal stem cells (MSCS) marker such as CD34, CD73, CD90 and CD105, and are able to form a viable and proliferative biocomplex with collagen sponge. Finally, the site of ulcers displayed a different expression of epidermal growth factors, insulin-like growth factors, platelet-derived growth factors and their receptors and tumor necrosis factor-ß with respect to healthy skin samples. CONCLUSION: We reported a good outcome for the treatment of chronic ulcers using dermal autologous micrografts. Finally, we suggest that the positivity to MSCs markers and the ability to interact with a scaffold can play a key role in their regenerative properties.

Autologous Periosteum-Derived Micrografts and PLGA/HA Enhance the Bone Formation in Sinus Lift Augmentation.

Sinus lift augmentation is a procedure required for the placement of a dental implant, whose success can be limited by the quantity or quality of available bone. To this purpose, the first aim of the current study was to evaluate the ability of autologous periosteum-derived micrografts and Poly(lactic-co-glycolic acid) (PLGA) supplemented with hydroxyl apatite (HA) to induce bone augmentation in the sinus lift procedure. Secondly, we compared the micrograft's behavior with respect to biomaterial alone, including Bio-Oss® and PLGA/HA, commercially named Alos. Sinus lift procedure was performed on 24 patients who required dental implants and who, according to the study design and procedure performed, were divided into three groups: group A (Alos + periosteum-derived micrografts); group B (Alos alone); and group C (Bio-Oss® alone). Briefly, in group A, a small piece of periosteum was collected from each patient and mechanically disaggregated by Rigenera® protocol using the Rigeneracons medical device. This protocol allowed for the obtainment of autologous micrografts, which in turn were used to soak the Alos scaffold. At 6 months after the sinus lift procedure and before the installation of dental implants, histological and radiographic evaluations in all three groups were performed. In group A, where sinus lift augmentation was performed using periosteum-derived micrografts and Alos, the bone regeneration was much faster than in the control groups where it was performed with Alos or Bio-Oss® alone (groups B and C, respectively). In addition, the radiographic evaluation in the patients of group A showed a radio-opacity after 4 months, while after 6 months, the prosthetic rehabilitation was improved and was maintained after 2 years post-surgery. In summary, we report on the efficacy of periosteum-derived micrografts and Alos to augment sinus lift in patients requiring dental implants. This efficacy is supported by an increased percentage of vital mineralized tisssue in the group treated with both periosteum-derived micrografts and Alos, with respect to the control group of Alos or Bio-Oss® alone, as confirmed by histological analysis and radiographic evaluations at 6 months from treatment.

Treatment of Oncological Post-surgical Wound Dehiscence with Autologous Skin Micrografts.

BACKGROUND/AIM: The closure of postoperative wounds is essential in order to prevent surgical site infections or wound dehiscence, mainly in oncological patients. We aimed to demonstrate the efficacy of autologous micrografts in the management of wound dehiscence in an oncology patient undergoing decompressive spinal laminectomy. CASE REPORT: A 57-year-old man with IgG multiple myeloma and medullary plasmocytoma C7-T3, was to undergo decompressive spinal laminectomy and vertebral fixation leading to a wound dehiscence with exposed instrumentation. Autologous micrografts were obtained by Rigenera protocol and directly applied to the dehisced wound. After 60 days of negative pressure wound therapy, we observed reduction of the diameter and depth of wound dehiscence, with a coverage of instrumentation, without complete re-epithelialization, that instead was reached by application of autologous micrografts after 70 days. CONCLUSION: The Rigenera protocol may be the solution for complex wounds in oncological and immune-compromised patients where other treatments are contraindicated.

An innovative regenerative treatment of scars with dermal micrografts.

BACKGROUND: Pathological scars occur following injuries and are often considered esthetically unattractive. Several strategies have been attempted to improve these types of scars using both surgical and nonsurgical methods. The most common treatments include cryotherapy, intralesional corticosteroid injections, 5-fluorouracil, bleomycin, interferon, and verapamil. AIMS: In this study, we aim to investigate the effectiveness of dermal autologous micrografts in the treatment of pathological scars resulting from burns, trauma, or any iatrogenic source. METHODS: We used a new clinical practice called Rigenera Protocol to obtain autologous micrografts which were in turn injectable in the patients. RESULTS: A significant improvement was observed in appearance and texture of the exaggerated scars in all cases following already 4 months of autologous micrograft treatment We have also shown that these micrografts are composed of mesenchymal stem cells and in addition, histological evaluation verified restoration of the structural layers immediately below the epidermis and a horizontal realignment of collagen fibers in the papillary dermis. CONCLUSION: Our results clearly demonstrate the optimal outcomes obtained following treatment with dermal micrografts on exaggerated scars with different etiologies. However, further studies are required to confirm the efficacy of this new technique.

Obestatin promotes proliferation and survival of adult hippocampal progenitors and reduces amyloid-ß-induced toxicity.

The ghrelin gene-derived peptide obestatin promotes survival in different cell types through a yet undefined receptor; however, its potential neuroprotective activities are still unknown. Here, obestatin effects were investigated on proliferation and survival of adult rat hippocampal progenitor cells (AHPs). Obestatin immunoreactivity was found in AHPs; moreover, obestatin binding to AHPs was displaced by the GLP-1R agonist Ex-4 and antagonist Ex-9. Furthermore, obestatin increased cell proliferation and survival in growth factor deprived medium and inhibited apoptosis; these effects were blocked by Ex-9. The underlying mechanisms involved Gαs/cAMP/PKA/CREB signaling, phosphorylation of ERK1/2 and PI3K/Akt, and the PI3K targets GSK-3ß/ß-catenin and mTOR. Obestatin also counteracted Aß1-42-induced detrimental effects through inhibition of GSK-3ß activity and Tau hyperphosphorylation, main hallmarks of neuronal death in Alzheimer's disease. These findings indicate a novel protective role for obestatin in AHPs and candidate this peptide as potential therapeutic target for increasing neurogenesis and for approaching neurodegenerative disorders.

Tissue Characterization after a New Disaggregation Method for Skin Micro-Grafts Generation.

Several new methods have been developed in the field of biotechnology to obtain autologous cellular suspensions during surgery, in order to provide one step treatments for acute and chronic skin lesions. Moreover, the management of chronic but also acute wounds resulting from trauma, diabetes, infections and other causes, remains challenging. In this study we describe a new method to create autologous micro-grafts from cutaneous tissue of a single patient and their clinical application. Moreover, in vitro biological characterization of cutaneous tissue derived from skin, de-epidermized dermis (Ded) and dermis of multi-organ and/or multi-tissue donors was also performed. All tissues were disaggregated by this new protocol, allowing us to obtain viable micro-grafts. In particular, we reported that this innovative protocol is able to create bio-complexes composed by autologous micro-grafts and collagen sponges ready to be applied on skin lesions. The clinical application of autologous bio-complexes on a leg lesion was also reported, showing an improvement of both re-epitalization process and softness of the lesion. Additionally, our in vitro model showed that cell viability after mechanical disaggregation with this system is maintained over time for up to seven (7) days of culture. We also observed, by flow cytometry analysis, that the pool of cells obtained from disaggregation is composed of several cell types, including mesenchymal stem cells, that exert a key role in the processes of tissue regeneration and repair, for their high regenerative potential. Finally, we demonstrated in vitro that this procedure maintains the sterility of micro-grafts when cultured in Agar dishes. In summary, we conclude that this new regenerative approach can be a promising tool for clinicians to obtain in one step viable, sterile and ready to use micro-grafts that can be applied alone or in combination with most common biological scaffolds.

Dual effects of IGFBP-3 on endothelial cell apoptosis and survival: involvement of the sphingolipid signaling pathways.

Insulin-like growth factor binding protein (IGFBP)-3 has both growth-inhibiting and growth-promoting effects at the cellular level. The cytotoxic action of several anticancer drugs is linked to increased ceramide generation through sphingomyelin hydrolysis or de novo biosynthesis. Herein, we investigated the role of IGFBP-3 on apoptosis of human umbilical vein endothelial cells (HUVEC) and its relationship with ceramide levels. We report that IGFBP-3 exerts dual effects on HUVEC, potentiating doxorubicin-induced apoptosis but enhancing survival in serum-starved conditions. Ceramide was increased by IGFBP-3 in the presence of doxorubicin and decreased when IGFBP-3 was added alone to cells cultured in serum-free medium. The protection exerted by the ceramide synthase inhibitor fumonisin B1 over doxorubicin-induced apoptosis was enhanced by IGFBP-3 with concomitant reduction of ceramide levels. IGFBP-3 alone activated sphingosine kinase (SK) and increased SK1 mRNA; the SK inhibitor N,N-dimethylsphingosine (DMS) blocked IGFBP-3 antiapoptotic effect. Moreover, IGFBP-3 increased IGF-I mRNA and dramatically enhanced IGF-I release. IGF-I receptor (IGF-IR) and its downstream signaling pathways Akt and ERK were phosphorylated by IGFBP-3, whereas inhibition of IGF-IR phosphorylation with tyrphostin AG1024 suppressed the antiapopoptic effect of IGFBP-3. Finally, IGFBP-3 increased endothelial cell motility in all experimental conditions. These findings provide evidence that IGFBP-3 differentially regulates endothelial cell apoptosis by involvement of the sphingolipid signaling pathways. Moreover, the survival effect of IGFBP-3 seems to be mediated by the IGF-IR.