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Post-translational removal of α-DG-N is important for early stage endometrial cancer development
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Abstracts / Placenta 57 (2017) 225e335
cases the cause is difficult to identify. In low-income countries up to10-25% of SB are caused by infectious diseases. In order to define the relationship between infections and SB, maternal, placental and neonatal samples were examined in cases of SB which occurred at Maggiore Hospital. Methods and results: According to WHO recommendation, SB is defined as babies or fetuses with no signs of life born after 22 weeks of gestation or weighing > 500g. 27 consecutive cases of SB between April 2014 and October 2016 were investigated according to the Regional Emilia-Romagna Still Birth Committee Multidisciplinary Protocol and discussed in a multidisciplinary audit. The microbiological investigation showed a positive result for bacteria and fungi in 8 vaginal swabs, 17 placental swabs, 9 fetal blood culture and 2 fetal throat swabs. Upon pathological findings in fetus and/or placenta, PCR on placental biopsies was performed in 3 cases. Discussion: We assumed that a SB was strictly related to infection when both histological evidence of fetal organ damage and positive fetal microbiological findings were found. Ascending bacterial infection seems to be the most prevalent infectious cause. The multidisciplinary approach allowed us to identify a definite association between SB and infection in 2 cases in which was identified group B streptococcus (GBS): vaginal swab, placenta and fetal samples were positive. Histology showed chorionamnionitis and fetal pneumonitis. Conclusion: Fetal blood cultures and neonatal throat swabs seem to be sufficient to guide the diagnostic workup. Placental biopsies are useful for subsequent virological analysis in cases of suspicious histological features. http://dx.doi.org/10.1016/j.placenta.2017.07.194
P1.109. POST-TRANSLATIONAL REMOVAL OF a-DG-N IS IMPORTANT FOR EARLY STAGE ENDOMETRIAL CANCER DEVELOPMENT Evans 1, 2, Lois Salamonsen 1, 2, Tom Sophea Heng 1, 2, Jemma Jobling 3, 4, Guiying Nie 1, 2. 1 Centre of Reproductive Health, Hudson Institute of Medical Research, Melbourne, Victoria, Australia; 2 Department of Molecular and Translational Sciences, Monash University, Melbourne, Victoria, Australia; 3 Department of Obstetrics and Gynaecology, Monash University, Melbourne, Victoria, Australia; 4 Epworth Research Institute, Epworth Health Care, Melbourne, Victoria, Australia Objectives: Endometrial cancer is one of the most common gynecological malignancies affecting post-menopausal women, yet the underlying mechanisms are not well understood. Dystroglycan (DG) is a large glycoprotein, consisting of a- and b-subunits, which are derived from a single gene. While b-DG is anchored to the plasma membrane, a-DG is noncovalently associated to the extracellular N-terminus of b-DG. Posttranslational removal of the N-terminus of a-DG a-DG-N) by a furin-like enzyme has been linked to a variety of cancers. However, the functional significance of a-DG-N removal is unknown. Previous studies in our laboratory have demonstrated that furin is significantly up-regulated in endometrial cancer of post-menopausal women. However, it is unknown whether a-DG-N removal occurs in endometrial cancer. In this study we investigated a-DG expression and the importance of a-DG-N removal in post-menopausal endometrial cancer. Methods and Results: We demonstrated by immunohistochemical analysis that a-DG-N removal occurred predominantly in early stage endometrial cancer tissues. We further found by ELISA that the cleaved a-DG-N was significantly elevated in the uterine lavage of early grade endometrial cancer patients. Functionally, a-DG-N removal significantly decreased the tight junction integrity and polarity of the endometrial epithelial cells, promoting the loss of polarity markers scribble and atypical protein kinase C (aPKC) and reducing the trans-epithelial electrical resistance. In addition, the removal of a-DG-N sensitized the cells for estrogen-dependent proliferation. Conclusion: Our results suggest that a-DG-N removal plays an important role in early stage development of endometrial cancer, and that the elevated levels of a-DG-N in uterine fluid may provide a biomarker for early detection of endometrial cancer. http://dx.doi.org/10.1016/j.placenta.2017.07.195
P1.110. PLACENTAL CHORIONIC ARTERY THROMBOSIS: AN IDENTIFIABLE MARKER ON THE CHORIONIC PLATE OF FETAL SYSTEMIC THROMBOEMBOLISM Sarah Clancy 2, Des Butler 2, Patrycja Siofra McDermott 1, Abrumcjuk 2, John Gray 2, Louise Sutton 2, Lisa Hogan 2, John E. Gillan 3, Peter Kelehan 2, 4. 1 University of Limerick Medical School, Limerick, Ireland; 2 Bon Secours Hospital at Barringtons Limerick, Limerick, Ireland; 3 University Hospital Galway, Galway, Ireland; 4 National Maternity Hospital Dublin, Dublin, Ireland Placental chorionic fetal artery thrombosis has, traditionally and most commonly, been identified by histological recognition of avascular villi, with apical vascular occlusion of associated stem villi within the parenchymal disk. We suggest, and will illustrate, that thrombosis of a fetal artery can also be identified on the chorionic plate as a pale, firm, nodular dilation of a thin cord like vessel. As this is commonly seen at a bifurcation of the vessel, we hypothesise that instead of representing a primary intravascular thrombosis at this site, it is an impacted thromboembolus. A shower of fibrin emboli can only reach this site of impaction by traversing the umbilical cord arteries from the fetal aorta. When a large thrombus occludes at the level of the ileal bifurcation, and/or in the right or left hypogastric artery at the umbilical ring, the result is a proximal umbilical artery thrombosis. If Hyrtl’s anastomosis is not present and functioning, this can result in acute fetal vascular malperfusion. If the baby survives the acute event, which can be recognized clinically as dramatic changes in Doppler studies, extensive multifocal avascular villi will be seen on histology. In many cases where the characteristic lesion of chorionic artery thromboembolus is seen on the chorionic plate, there is also evidence of thrombosis of the chorionic veins, sometimes both acute and chronic and sometimes also propagating into the umbilical vein, identified grossly and microscopically as Fetal Thrombotic Vasculopathy/Fetal Vascular Malperfusion. Chorionic vein thrombosis is a potent cause of thromboembolism of the fetal systemic circulation and, with renal vein/inferior vena cava thrombosis, intra cardiac thrombosis, thrombosis of the ductus arteriosus and intrahepatic/ductus venosus thrombosis, it can be associated with cerebral infarction and peripheral limb ischaemia - all associated with a fetal hypercoagulable state. http://dx.doi.org/10.1016/j.placenta.2017.07.196
P1.111. EFFECTS OF HYDROXYCHLOROQUINE ON HUMAN PLACENTAL TISSUE A SYSTEMATIC REVIEW AND PRELIMINARY FUNCTIONAL STUDIES Rebecca Scott, Susan Greenwood, Rebecca Jones, Alexander Heazell. Maternal and Fetal Health Research Centre, University of Manchester, Manchester, UK Objectives: Stillbirth affects ~1:220 pregnancies in high income countries; this risk dramatically increases in antiphospholipid syndrome, lupus and chronic histiocytic intervillositis. Hydroxychloroquine (HCQ) is commonly used to treat these conditions with incomplete information regarding its efficacy or safety profile. This study aimed to collate current knowledge of the placental effects of HCQ. Further to this, we aimed to examine effects of HCQ on amino acid transport and human chorionic gonadotrophin (hCG) secretion in term placental villous explants. Methods: A systematic review of literature was performed using Medline in November 2016. All relevant studies of the effects of HCQ on human placenta were included. Placental villous explants from normal term pregnancies (n¼4) were maintained in culture for 7 days and treated with HCQ for 48hrs from day 5 (250, 750 and 1500ng/ml, representing subtherapeutic, therapeutic and supra-therapeutic levels). Taurine transporter (TauT) activity was measured as the Na+-dependent uptake of 3H-taurine (30-90min) at day 7. Conditioned medium was collected daily for analysis of hCG.
Abstracts / Placenta 57 (2017) 225e335
cases the cause is difficult to identify. In low-income countries up to10-25% of SB are caused by infectious diseases. In order to define the relationship between infections and SB, maternal, placental and neonatal samples were examined in cases of SB which occurred at Maggiore Hospital. Methods and results: According to WHO recommendation, SB is defined as babies or fetuses with no signs of life born after 22 weeks of gestation or weighing > 500g. 27 consecutive cases of SB between April 2014 and October 2016 were investigated according to the Regional Emilia-Romagna Still Birth Committee Multidisciplinary Protocol and discussed in a multidisciplinary audit. The microbiological investigation showed a positive result for bacteria and fungi in 8 vaginal swabs, 17 placental swabs, 9 fetal blood culture and 2 fetal throat swabs. Upon pathological findings in fetus and/or placenta, PCR on placental biopsies was performed in 3 cases. Discussion: We assumed that a SB was strictly related to infection when both histological evidence of fetal organ damage and positive fetal microbiological findings were found. Ascending bacterial infection seems to be the most prevalent infectious cause. The multidisciplinary approach allowed us to identify a definite association between SB and infection in 2 cases in which was identified group B streptococcus (GBS): vaginal swab, placenta and fetal samples were positive. Histology showed chorionamnionitis and fetal pneumonitis. Conclusion: Fetal blood cultures and neonatal throat swabs seem to be sufficient to guide the diagnostic workup. Placental biopsies are useful for subsequent virological analysis in cases of suspicious histological features. http://dx.doi.org/10.1016/j.placenta.2017.07.194
P1.109. POST-TRANSLATIONAL REMOVAL OF a-DG-N IS IMPORTANT FOR EARLY STAGE ENDOMETRIAL CANCER DEVELOPMENT Evans 1, 2, Lois Salamonsen 1, 2, Tom Sophea Heng 1, 2, Jemma Jobling 3, 4, Guiying Nie 1, 2. 1 Centre of Reproductive Health, Hudson Institute of Medical Research, Melbourne, Victoria, Australia; 2 Department of Molecular and Translational Sciences, Monash University, Melbourne, Victoria, Australia; 3 Department of Obstetrics and Gynaecology, Monash University, Melbourne, Victoria, Australia; 4 Epworth Research Institute, Epworth Health Care, Melbourne, Victoria, Australia Objectives: Endometrial cancer is one of the most common gynecological malignancies affecting post-menopausal women, yet the underlying mechanisms are not well understood. Dystroglycan (DG) is a large glycoprotein, consisting of a- and b-subunits, which are derived from a single gene. While b-DG is anchored to the plasma membrane, a-DG is noncovalently associated to the extracellular N-terminus of b-DG. Posttranslational removal of the N-terminus of a-DG a-DG-N) by a furin-like enzyme has been linked to a variety of cancers. However, the functional significance of a-DG-N removal is unknown. Previous studies in our laboratory have demonstrated that furin is significantly up-regulated in endometrial cancer of post-menopausal women. However, it is unknown whether a-DG-N removal occurs in endometrial cancer. In this study we investigated a-DG expression and the importance of a-DG-N removal in post-menopausal endometrial cancer. Methods and Results: We demonstrated by immunohistochemical analysis that a-DG-N removal occurred predominantly in early stage endometrial cancer tissues. We further found by ELISA that the cleaved a-DG-N was significantly elevated in the uterine lavage of early grade endometrial cancer patients. Functionally, a-DG-N removal significantly decreased the tight junction integrity and polarity of the endometrial epithelial cells, promoting the loss of polarity markers scribble and atypical protein kinase C (aPKC) and reducing the trans-epithelial electrical resistance. In addition, the removal of a-DG-N sensitized the cells for estrogen-dependent proliferation. Conclusion: Our results suggest that a-DG-N removal plays an important role in early stage development of endometrial cancer, and that the elevated levels of a-DG-N in uterine fluid may provide a biomarker for early detection of endometrial cancer. http://dx.doi.org/10.1016/j.placenta.2017.07.195
P1.110. PLACENTAL CHORIONIC ARTERY THROMBOSIS: AN IDENTIFIABLE MARKER ON THE CHORIONIC PLATE OF FETAL SYSTEMIC THROMBOEMBOLISM Sarah Clancy 2, Des Butler 2, Patrycja Siofra McDermott 1, Abrumcjuk 2, John Gray 2, Louise Sutton 2, Lisa Hogan 2, John E. Gillan 3, Peter Kelehan 2, 4. 1 University of Limerick Medical School, Limerick, Ireland; 2 Bon Secours Hospital at Barringtons Limerick, Limerick, Ireland; 3 University Hospital Galway, Galway, Ireland; 4 National Maternity Hospital Dublin, Dublin, Ireland Placental chorionic fetal artery thrombosis has, traditionally and most commonly, been identified by histological recognition of avascular villi, with apical vascular occlusion of associated stem villi within the parenchymal disk. We suggest, and will illustrate, that thrombosis of a fetal artery can also be identified on the chorionic plate as a pale, firm, nodular dilation of a thin cord like vessel. As this is commonly seen at a bifurcation of the vessel, we hypothesise that instead of representing a primary intravascular thrombosis at this site, it is an impacted thromboembolus. A shower of fibrin emboli can only reach this site of impaction by traversing the umbilical cord arteries from the fetal aorta. When a large thrombus occludes at the level of the ileal bifurcation, and/or in the right or left hypogastric artery at the umbilical ring, the result is a proximal umbilical artery thrombosis. If Hyrtl’s anastomosis is not present and functioning, this can result in acute fetal vascular malperfusion. If the baby survives the acute event, which can be recognized clinically as dramatic changes in Doppler studies, extensive multifocal avascular villi will be seen on histology. In many cases where the characteristic lesion of chorionic artery thromboembolus is seen on the chorionic plate, there is also evidence of thrombosis of the chorionic veins, sometimes both acute and chronic and sometimes also propagating into the umbilical vein, identified grossly and microscopically as Fetal Thrombotic Vasculopathy/Fetal Vascular Malperfusion. Chorionic vein thrombosis is a potent cause of thromboembolism of the fetal systemic circulation and, with renal vein/inferior vena cava thrombosis, intra cardiac thrombosis, thrombosis of the ductus arteriosus and intrahepatic/ductus venosus thrombosis, it can be associated with cerebral infarction and peripheral limb ischaemia - all associated with a fetal hypercoagulable state. http://dx.doi.org/10.1016/j.placenta.2017.07.196
P1.111. EFFECTS OF HYDROXYCHLOROQUINE ON HUMAN PLACENTAL TISSUE A SYSTEMATIC REVIEW AND PRELIMINARY FUNCTIONAL STUDIES Rebecca Scott, Susan Greenwood, Rebecca Jones, Alexander Heazell. Maternal and Fetal Health Research Centre, University of Manchester, Manchester, UK Objectives: Stillbirth affects ~1:220 pregnancies in high income countries; this risk dramatically increases in antiphospholipid syndrome, lupus and chronic histiocytic intervillositis. Hydroxychloroquine (HCQ) is commonly used to treat these conditions with incomplete information regarding its efficacy or safety profile. This study aimed to collate current knowledge of the placental effects of HCQ. Further to this, we aimed to examine effects of HCQ on amino acid transport and human chorionic gonadotrophin (hCG) secretion in term placental villous explants. Methods: A systematic review of literature was performed using Medline in November 2016. All relevant studies of the effects of HCQ on human placenta were included. Placental villous explants from normal term pregnancies (n¼4) were maintained in culture for 7 days and treated with HCQ for 48hrs from day 5 (250, 750 and 1500ng/ml, representing subtherapeutic, therapeutic and supra-therapeutic levels). Taurine transporter (TauT) activity was measured as the Na+-dependent uptake of 3H-taurine (30-90min) at day 7. Conditioned medium was collected daily for analysis of hCG.