Ethnic differences in adipocytokines in severly obese children and adolescents in Singapore

Master'sMASTER OF SCIENC

Molecular mechanisms for activation of non-canonical TGFβ pathways and their importance during prostate cancer progression

Prostate cancer is the most common invasive cancer diagnosed in men and a major and growing health problem in Western countries. Deregulation of different pathways has been implicated in progression of prostate cancer, namely nuclear factor kappa enhancer binding protein (NF-κB), transforming growth factor β (TGFβ), phosphoinositide 3ʹ-kinase/AKT (PI3K/AKT) and Src kinase pathways. However, the detailed mechanisms by which TGFβ activates these pathways to contribute in tumorigenesis and invasive behavior of prostate cancer cells have not been elucidated. We have demonstrated (paper I) that the E3 ligase activity of TRAF6 is crucial for recruitment of the regulatory subunit of PI3K, p85α, to TβRI and for TGFβ-induced Lys63-linked polyubiquitination of p85α. TRAF6 is required for the TGFβ-induced recruitment of AKT to the complex of PI3K and TβRI, where the polyubiquitination and activation of AKT occurs. When activated, AKT promotes TGFβ-induced cell migration which is dependent on p85 and PI3K activity, as well as on TRAF6, but not on TβRI kinase activity. Thus, TGFβ-induced activation of PI3K/AKT induces cell motility contributing to the progression of cancer. We have demonstrated (paper II) a pivotal role of TAK1 polyubiquitination in three different pathways, including TNFR, IL-1R, and TLR4 signaling. Lys63-linked polyubiquitination of TAK1 at Lys34 is essential for downstream signaling to NF-κB-mediated target gene expression in both cancer and immune cells. These findings are of importance for the understanding of the mechanism of activation of NF-κB in inflammation and may aid in the development of new therapeutic strategies to treat chronic inflammation and cancer. We have also shown (paper III) that TGFβ activates the tyrosine kinase Src via formation of a complex between TβRI and Src. The E3 ligase TRAF6 promotes the formation of the complex in a manner not dependent on its ubiquitin ligase activity, suggesting that TRAF6 acts as an adaptor. Moreover, the activation of Src is not dependent on the kinase activity of TβRI. On a functional level, Src activity was found to be necessary for TGFβ-induced chemotaxis. In conclusion, we have elucidated molecular mechanisms whereby TGFβ activates non-Smad pathways, i.e. PI3K and Src. Our findings shed light on the pro-tumorigenesis mechanisms of TGFβ. In addition, we have demonstrated how the activation of TAK1, an important component of the TGFβ non-Smad pathway, by TGFβ and other stimuli leads to the activation of NF-κB and thereby induction of inflammation which likely contributes to prostate cancer progression

Molecular mechanisms for activation of non-canonical TGFβ pathways and their importance during prostate cancer progression

Prostate cancer is the most common invasive cancer diagnosed in men and a major and growing health problem in Western countries. Deregulation of different pathways has been implicated in progression of prostate cancer, namely nuclear factor kappa enhancer binding protein (NF-κB), transforming growth factor β (TGFβ), phosphoinositide 3ʹ-kinase/AKT (PI3K/AKT) and Src kinase pathways. However, the detailed mechanisms by which TGFβ activates these pathways to contribute in tumorigenesis and invasive behavior of prostate cancer cells have not been elucidated. We have demonstrated (paper I) that the E3 ligase activity of TRAF6 is crucial for recruitment of the regulatory subunit of PI3K, p85α, to TβRI and for TGFβ-induced Lys63-linked polyubiquitination of p85α. TRAF6 is required for the TGFβ-induced recruitment of AKT to the complex of PI3K and TβRI, where the polyubiquitination and activation of AKT occurs. When activated, AKT promotes TGFβ-induced cell migration which is dependent on p85 and PI3K activity, as well as on TRAF6, but not on TβRI kinase activity. Thus, TGFβ-induced activation of PI3K/AKT induces cell motility contributing to the progression of cancer. We have demonstrated (paper II) a pivotal role of TAK1 polyubiquitination in three different pathways, including TNFR, IL-1R, and TLR4 signaling. Lys63-linked polyubiquitination of TAK1 at Lys34 is essential for downstream signaling to NF-κB-mediated target gene expression in both cancer and immune cells. These findings are of importance for the understanding of the mechanism of activation of NF-κB in inflammation and may aid in the development of new therapeutic strategies to treat chronic inflammation and cancer. We have also shown (paper III) that TGFβ activates the tyrosine kinase Src via formation of a complex between TβRI and Src. The E3 ligase TRAF6 promotes the formation of the complex in a manner not dependent on its ubiquitin ligase activity, suggesting that TRAF6 acts as an adaptor. Moreover, the activation of Src is not dependent on the kinase activity of TβRI. On a functional level, Src activity was found to be necessary for TGFβ-induced chemotaxis. In conclusion, we have elucidated molecular mechanisms whereby TGFβ activates non-Smad pathways, i.e. PI3K and Src. Our findings shed light on the pro-tumorigenesis mechanisms of TGFβ. In addition, we have demonstrated how the activation of TAK1, an important component of the TGFβ non-Smad pathway, by TGFβ and other stimuli leads to the activation of NF-κB and thereby induction of inflammation which likely contributes to prostate cancer progression

Molecular mechanisms for activation of non-canonical TGFβ pathways and their importance during prostate cancer progression

Prostate cancer is the most common invasive cancer diagnosed in men and a major and growing health problem in Western countries. Deregulation of different pathways has been implicated in progression of prostate cancer, namely nuclear factor kappa enhancer binding protein (NF-κB), transforming growth factor β (TGFβ), phosphoinositide 3ʹ-kinase/AKT (PI3K/AKT) and Src kinase pathways. However, the detailed mechanisms by which TGFβ activates these pathways to contribute in tumorigenesis and invasive behavior of prostate cancer cells have not been elucidated. We have demonstrated (paper I) that the E3 ligase activity of TRAF6 is crucial for recruitment of the regulatory subunit of PI3K, p85α, to TβRI and for TGFβ-induced Lys63-linked polyubiquitination of p85α. TRAF6 is required for the TGFβ-induced recruitment of AKT to the complex of PI3K and TβRI, where the polyubiquitination and activation of AKT occurs. When activated, AKT promotes TGFβ-induced cell migration which is dependent on p85 and PI3K activity, as well as on TRAF6, but not on TβRI kinase activity. Thus, TGFβ-induced activation of PI3K/AKT induces cell motility contributing to the progression of cancer. We have demonstrated (paper II) a pivotal role of TAK1 polyubiquitination in three different pathways, including TNFR, IL-1R, and TLR4 signaling. Lys63-linked polyubiquitination of TAK1 at Lys34 is essential for downstream signaling to NF-κB-mediated target gene expression in both cancer and immune cells. These findings are of importance for the understanding of the mechanism of activation of NF-κB in inflammation and may aid in the development of new therapeutic strategies to treat chronic inflammation and cancer. We have also shown (paper III) that TGFβ activates the tyrosine kinase Src via formation of a complex between TβRI and Src. The E3 ligase TRAF6 promotes the formation of the complex in a manner not dependent on its ubiquitin ligase activity, suggesting that TRAF6 acts as an adaptor. Moreover, the activation of Src is not dependent on the kinase activity of TβRI. On a functional level, Src activity was found to be necessary for TGFβ-induced chemotaxis. In conclusion, we have elucidated molecular mechanisms whereby TGFβ activates non-Smad pathways, i.e. PI3K and Src. Our findings shed light on the pro-tumorigenesis mechanisms of TGFβ. In addition, we have demonstrated how the activation of TAK1, an important component of the TGFβ non-Smad pathway, by TGFβ and other stimuli leads to the activation of NF-κB and thereby induction of inflammation which likely contributes to prostate cancer progression

A Case of Cushing’s Syndrome in Pregnancy

Cushing’s syndrome (CS) occurs rarely during pregnancy. CS can be caused by prolonged abnormal exposure to excess glucocorticoids leading to special and significant signs and symptoms. It is often difficult to diagnose pathological hypercortisolism in pregnant women since some symptoms of the disease might be due to a complicated pregnancy, including preeclampsia or gestational diabetes. In this study, we report the case of a 29-year-old female who referred to our institution with hypertension, weakness, steria, and truncal obesity. Physical examination revealed cushingoid characteristic. She was also found to be 27 weeks pregnant. CS was diagnosed on the basis of abnormal serum cortisol and adrenocorticotropin hormone (ACTH) levels, as well as radiologic findings. She eventually gave birth to a preterm infant via vaginal delivery. A right adrenal adenoma was diagnosed and was subsequently treated with surgical resection. The patient’s condition remained stable after the surgery

The type II TGF-β receptor phosphorylates Tyr 182 in the type I receptor to activate downstream Src signaling

Transforming growth factor–β (TGF-β) signaling has important roles during embryonic development and in tissue homeostasis. TGF-β ligands exert cellular effects by binding to type I (TβRI) and type II (TβRII) receptors and induce both SMAD-dependent as well as SMAD-independent intracellular signaling pathways. Activation of the tyrosine kinase Src is one such SMAD-independent consequence of TGF-β signaling. We investigated the mechanism by which TGF-β stimulation activates Src in human and mouse cells. Before TGF-β stimulation, inactive Src was present in a complex with TβRII. Upon TGF-β1 stimulation, which induces the formation of a complex of TβRI and TβRII, TβRII phosphorylated TβRI on serine and threonine residues, which promotes TβRI kinase activity, and on Tyr182. The SH2 domain of Src bound to phosphporylated Tyr182, leading to activation of Src kinase activity. Interaction of the Src SH3 domain with a proline-rich region in TβRI also contributed to binding. TGF-β1–induced Src activation depended on the kinase activity of TβRII but not on that of TβRI, indicating that binding to TβRI activated Src through a non-enzymatic mechanism. Activated Src then phosphorylated TβRI on several tyrosine residues, which may stabilize Src binding to the receptor. In functional assays, Src activation was required for the TGF-β–induced production of fibronectin and for migration in human breast carcinoma cells and for the induction of α-smooth muscle actin (α-SMA) and actin reorganization in mouse fibroblasts. Thus, TGF-β induces Src activation by stimulating a direct interaction with TβRI that depends on tyrosine phosphorylation of TβRI by TβRII.

Molar twin pregnancy with a live coexisting triple X fetus: case report

Background: Complete molar twin pregnancy with coexisting fetus is a rare and important diagnosis in obstetrics. Preeclampsia, preterm labor and life-threatening vaginal bleeding are the serious complications of this type of pregnancy. Gestational trophoblastic neoplasia should be ruled out after termination of pregnancy. In this study we reviewed a molar twin pregnancy with a live coexisting triple x fetus which has not been reported till now. Case Presentation: Our case was a 22-year-old primigravida woman and 17-18th week of pregnancy, who referred to an University Hospital in Mashhad, Iran with complaint of vaginal bleeding On October 2016. Her first trimester ultrasonography in 13th week of gestational age, reported a live single fetus with an anterior great placenta and cystic formation regarding molar pregnancy. According to above-report, Amniocentesis was done in 15th weeks of pregnancy and its result was triple X. After severe and life-threatening vaginal bleeding, she underwent an emergent hysterotomy. A fetus with no obvious anomaly and a great hydropic and vesicular placenta delivered. Episodic crisis of her blood pressure was best controlled with anti-hypertensive drugs. In our case, chemotherapy with methotrexate was started after poor decline of βHCG titration and definite diagnosis of gestational trophoblastic neoplasia. Remission was completely achieved after four courses of chemotherapy. Conclusion: Differentiation between complete molar pregnancy with live fetus and partial mole is always challenging in obstetrics. Serious complications as preeclampsia and severe vaginal bleeding may become life-threatening. Coexisting molar pregnancy should be ruled out in a pregnancy associated with frequent and unexpectant vaginal bleeding. Amniocentesis and an expert radiologist can help to differentiate them. Following these patients is very important to reveal any trophoblastic neoplasia

SUMOylation of PDGF receptor α affects signaling via PLCγ and STAT3, and cell proliferation

Abstract Background The platelet-derived growth factor (PDGF) family of ligands exerts their cellular effects by binding to α- and β-tyrosine kinase receptors (PDGFRα and PDGFRβ, respectively). SUMOylation is an important posttranslational modification (PTM) which regulates protein stability, localization, activation and protein interactions. A mass spectrometry screen has demonstrated SUMOylation of PDGFRα. However, the functional role of SUMOylation of PDGFRα has remained unknown. Results In the present study, we validated that PDGFRα is SUMOylated on lysine residue 917 as was previously reported using a mass spectrometry approach. Mutation of lysine residue 917 to arginine (K917R) in PDGFRα substantially decreased SUMOylation, indicating that this amino acid residue is a major SUMOylation site. Whereas no difference in the stability of wild-type and mutant receptor was observed, the K917R mutant PDGFRα was less ubiquitinated than wild-type PDGFRα. The internalization and trafficking of the receptor to early and late endosomes were not affected by the mutation, neither was the localization of the PDGFRα to Golgi. However, the K917R mutant PDGFRα showed delayed activation of PLC-γ and enhanced activation of STAT3. Functional assays showed that the mutation of K917 of PDGFRα decreased cell proliferation in response to PDGF-BB stimulation. Conclusions SUMOylation of PDGFRα decreases ubiquitination of the receptor and affects ligand-induced signaling and cell proliferation

Single-centre retrospective analysis of growth hormone supplementation in IVF patients classified as poor-prognosis

Background Patients undergoing in vitro fertilisation (IVF) receive various adjuvant therapies in order to enhance success rates, but the true benefit is actively debated. Growth hormone (GH) supplementation was assessed in poor-prognosis women undergoing fresh IVF transfer cycles. Methods Data were retrospectively analysed from 400 IVF cycles, where 161 women received GH and 239 did not. Results Clinical pregnancy, live birth rates and corresponding ORs and CIs were significantly greater with GH, despite patients being significantly older with lower ovarian reserve. Patient's age, quality of transferred embryo and GH were the only significant independent predictors of clinical pregnancy (OR: 0.90, 5.00 and 2.49, p < 0.002, respectively) and live birth chance (OR: 0.91, 3.90 and 4.75, p < 0.014, respectively). GH increased clinical pregnancy chance by 3.42-fold (95% CI 1.82 to 6.44, p < 0.0005) and live birth chance by 6.16-fold (95% CI 2.83 to 13.39, p < 0.0005) after adjustment for maternal age, antral follicle count and transferred embryo quality. Conclusion These data provided further evidence to indicate that GH may support more live births, particularly in younger women. It also appears that embryos generated under GH have a better implantation potential, but whether the biological mechanism is embryo-mediated or endometrium-mediated is unclear. © Article author(s) 2017

Multi Centric Paget’s Disease and Review of Literature

Introduction: Paget’s disease of the vulva (PDV) is a very rare malignancy originating in vulvar apocrinegland-bearing skin cells. Based on multi centric nature of Paget’s disease, it’s a chronic and relapsing course. The aim of this report is to introduce a case of multi centric Paget’s disease and review of literature.Case report: A 62-year-old woman with complaints of vulvar pruritus, painful vulvar lesion for 4 years was referred to oncology department of Ghaem hospital, Mashhad University of Medical Sciences in 2016. Pathological results of erythematous and exfoliated lesion of the major and minor labia extend to anus was reported as PDV with full-thickness involvement. In investigations, she had persistent hematuria. Pelvis and abdomen investigation revealed irregularity in the posterior wall of the bladder and biopsy detected urothelial carcinoma in the bladder. Radical cystectomy was performed subsequently. In addition, complete response of vulvar lesion to imiquimod cream was seen after 6 weeks of therapy. The patient is free of disease and now she is under serial follow-up.&nbsp;Conclusion: Generally standard treatment modality in patients who experienced multicenteric Paget’s disease is surgical resection, also topical 5% imiquimod cream may be considered as an alternative option in setting metastatic vulvar Paget.</p