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International audience; Objectives: To validate a model predicting the risk of threatened preterm delivery and to establish the optimal threshold for this risk scoring system. Materials and methods: Two cohorts were studied: one of singleton pregnancies without preterm premature rupture of membranes (PPROM) and no cervical cerclage (cohort 1) and one of twin pregnancies without PPROM and no cervical cerclage (cohort 2). Patients were included from January 1st 2013 until December 31st 2013 by the Regional Perinatal Network of Ile de France with patients transferred because of threatened preterm delivery at 22 to 32 weeks of gestation. The individual probability of delivery within 48 hours of admission was calculated using the nomogram for every patient. Discrimination and calibration of the nomogram as well as the optimal threshold were determined using R studio. Results: The nomogram accurately predicted obstetric outcome. Discrimination and calibration were excellent, with an area under the curve (AUC) of 0.88 (95% CI 0.86-0.90) for cohort 1 and 0.73 (95% CI 0.66-0.80) for cohort 2. The optimal threshold would be 15% for cohort 1 and 10% for cohort 2. Using these thresholds, the performance characteristics of the nomogram were: sensitivity 80% (cohort 1) and 69% (cohort 2), negative predictive value 94.8% (cohort 1) and 91.3% (cohort 2). Use of the nomogram would avoid 253 unnecessary transfers in cohort 1. Conclusions: The nomogram was efficient and clinically relevant in our high risk population. A threshold set at 15% would help minimize the risk of preterm deliveries in singleton pregnancies and should reduce unnecessary, costly and stressful in utero transfer.

To investigate and compare the views and experience of undergraduate medical students concerning two methods used in the teaching of pelvic and breast examinations: a video clip and a training model.Following the teaching sessions, the students (n=79; female 67%; median age 20; students' grade level: 2nd study year (87%) and 3rd study year (13%)) completed a satisfaction questionnaire, which included items related to the pedagogical value of these two different types of tool.Most of the students ranked their own satisfaction in each teaching session as either very satisfied or satisfied: the median rating was 3 or 4 for each item. For their satisfaction with the pedagogical tools, in terms of the degree to which they contributed toward practical knowledge of the examination procedures, the students rated the video clip with a higher degree of satisfaction than the training model, for both breast (very satisfied 73% vs. 40%, satisfied 27% vs. 43%, unsatisfied 0% vs. 7% (P0.001)) and pelvic examinations (very satisfied 57% vs. 33%, satisfied 39% vs. 66%, unsatisfied 4% vs. 1% (P0.004), respectively.Teaching sessions for pelvic and breast examination, which make combined use of videos and training models, are associated with a high degree of satisfaction from students in their 2nd or 3rd student's year.

A novel class of pan-Pim kinase inhibitors was designed by modifying the CK2 inhibitor CX-4945. Introduction of a triazole or secondary amide functionality on the C-7 position and 2'-halogenoanilines on C-5 resulted in potent inhibitors of the Pim-1 and Pim-2 isoforms, with many analogs active at single digit nanomolar concentrations. The molecules inhibited the phosphorylation at Serine 112 of the apoptosis effector BAD, and had potent antiproliferative effects on the AML cell line MV-4-11 (IC(50)

The PIM family of serine/threonine kinases are pro-proliferative kinases activated by multiple cytokines and growth factor signaling. The Pim kinases are unusual in that they are regulated primarily by transcription and not by membrane recruitment or phosphorylation like other serine/threonine kinases. Activated cytokine receptors recruit JAKs to induce STAT-dependent transcription of the Pim genes. They are proto-oncogenes and have been implicated in the process of lymphomagenesis and malignant transformation. Pim overexpression has been reported in diffuse B cell lymphoma, chronic lymphocytic leukemia, FLT3-mediated acute myelogenous leukemia and prostate cancer. Pim-2 is over expressed in leukemias and lymphomas, whereas Pim-3 overexpression has been observed in melanoma, pancreatic and gastric tumors. The recent reports of elevated levels of Pim-1 expression in human prostate tumor biopsies implicate the Pim family of protein kinases in the progression of human prostate tumors. Further, in transgenic animal models, Pim-1 expression has been shown to be elevated in prostate tumors that are caused by overexpression of the c-myc oncogene. Recent evidence reveals the overlapping and compensatory nature of Pim-1 and Pim-2 phosphorylation and highlights the importance of inhibiting all isoforms. The emerging role of the PIM kinase family in hematological malignancies and solid tumors and the druggable nature of their ATP binding pocket make them attractive targets for anticancer drug development. Utilizing a highly distinct molecular scaffold, CX-6258 was developed as a selective and potent small molecule pan-PIM kinase inhibitor. CX-6258 inhibits Pims 1, 2 and 3 with IC50 values in the low nanomolar range and high selectivity as evidenced in a screening panel of over 100 kinases. CX-6258 demonstrates potent in vitro antiproliferative activity, particularly in leukemia derived cell lines expressing the FLT3-ITD. Moreover, CX-6258 inhibits the phosphorylation of BAD and 4EBP1, known substrates for PIMs 1, 2 and 3. When delivered orally, this pan-Pim inhibitor is well tolerated and demonstrates potent antitumor activity in murine xenograft models of PIM driven cancer. Using CX-6258 as our “path finder” molecule, we have created four additional unique chemical scaffolds as pan-Pim inhibitors, and certain molecules from these scaffolds can inhibit Pims 1, 2 and 3 in the picomolar range while exhibiting no inhibitory activity of the Flt3 protein kinase. The in vivo and in vitro profiles of these chemically diverse series are indicative of an effective and potent anti-cancer mechanism mediated through the selective inhibition of PIM kinase activity. Together, these findings exemplify that we have created multiple proprietary chemical series of pan-Pim inhibitors exhibiting picomolar potency and discerning selectivity. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A246.

Abstract 1726 Poster Board I-752 The PIM family of serine/threonine kinases are pro-proliferative kinases activated by multiple cytokines and growth factor signaling. The Pim kinases are unusual in that they are regulated primarily by transcription and not by membrane recruitment or phosphorylation like other serine/threonine kinases. Activated cytokine receptors recruit JAKs to induce STAT-dependent transcription of the Pim genes. They are proto-oncogenes and have been implicated in the process of lymphomagenesis and malignant transformation. Pim overexpression has been reported in diffuse B cell lymphoma, chronic lymphocytic leukemia, FLT3-mediated acute myelogenous leukemia and prostate cancer. Pim-2 is over expressed in leukemias and lymphomas, whereas Pim-3 overexpression has been observed in melanoma, pancreatic and gastric tumors. The recent reports of elevated levels of Pim-1 expression in human prostate tumor biopsies implicate the Pim family of protein kinases in the progression of human prostate tumors. Further, in transgenic animal models, Pim-1 expression has been shown to be elevated in prostate tumors that are caused by overexpression of the c-myc oncogene. Recent evidence reveals the overlapping and compensatory nature of Pim-1 and Pim-2 phosphorylation and highlights the importance of inhibiting all isoforms. The emerging role of the PIM kinase family in hematological malignancies and solid tumors and the druggable nature of their ATP binding pocket make them attractive targets for anticancer drug development Utilizing a highly distinct molecular scaffold, CX-6258 was developed as a selective and potent small molecule pan-PIM kinase inhibitor. CX-6258 inhibits Pims 1, 2 and 3 with IC50 values in the low nanomolar range and high selectivity as evidenced in a screening panel of over 100 kinases. CX-6258 demonstrates potent in vitro antiproliferative activity, particularly in leukemia derived cell lines expressing the FLT3-ITD. Moreover, CX-6258 inhibits the phosphorylation of BAD and 4EBP1, known substrates for PIMs 1, 2 and 3. When delivered orally, this pan-Pim inhibitor is well tolerated and demonstrates potent antitumor activity in murine xenograft models of PIM driven cancer. Using CX-6258 as our “path finder” molecule, we have created four additional unique chemical scaffolds as pan-Pim inhibitors, and certain of these scaffolds can inhibit Pims 1, 2 and 3 in the picomolar range while exhibiting no inhibitory activity of the Flt3 protein kinase. The in vivo and in vitro profiles of these chemically diverse series are indicative of an effective and potent anti-cancer mechanism mediated through the selective inhibition of PIM kinase activity. Together, these findings exemplify that we have created multiple proprietary chemical series of pan-Pim inhibitors exhibiting picomolar potency and high selectivity. Disclosures No relevant conflicts of interest to declare.