Artículos de revistas: "Mark 7:24-30"

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Sun, Poling. "Naming the Dog: Another Asian Reading of Mark 7:24–30." Review & Expositor 107, no. 3 (2010): 381–94. http://dx.doi.org/10.1177/003463731010700310.

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Sayles, Guy. "Jesus and the challenging gift of the other: An expository article on Mark 7:24–30." Review & Expositor 114, no. 1 (2017): 110–17. http://dx.doi.org/10.1177/0034637316688036.

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Mark 7:24–30 tells the story of Jesus’ surprising encounter and sharp verbal exchange with a Syrophoenician woman who sought healing for her demon-oppressed daughter. The woman embodies otherness in many dimensions: religious, ethnic, status, and gender. Jesus’ initial response to her request, expressed in a harsh-sounding parabolic proverb, is resistance and reluctance. This article explores possible reasons for that reluctance and suggests that Jesus initially understood that the Reign of God would be realized first among Jews and only later among Gentiles. The woman’s clever response to Jesus, as well as her insistence on the inclusiveness of divine mercy, served to change Jesus’ mind about the order and timing of the fulfillment of God’s in-breaking rule and reign. This article takes the view that Jesus’ change of mind can serve as a model for contemporary followers of Jesus who sometimes struggle to receive the challenging gifts of otherness. It also affirms that “the others” often have both insights and courage which may be catalytic for the growth of those who encounter them.

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Weaks, Dawn Darwin. "Navigating need: Mark 6:30–44." Review & Expositor 116, no. 3 (2019): 347–50. http://dx.doi.org/10.1177/0034637319867089.

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In society’s 24/7 news cycle, caring people can easily become overwhelmed with the needs of this world, in addition to the needs of family, friends, and self. This sermon explores one of the most-told stories of the New Testament, the miraculous feeding of thousands, specifically the account in Mark 6:30–44. It outlines three potential responses to meeting needs: engorging, exhausting oneself, and engaging. The sermon celebrates the radically alternative way of Jesus to meet needs miraculously, as it offers a hopeful word about how Christians can navigate need faithfully, responsively, and expectantly.

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Smith, Julien C. H. "The Construction of Identity in Mark 7:24-30: The Syrophoenician Woman and the Problem of Ethnicity." Biblical Interpretation 20, no. 4-5 (2012): 458–81. http://dx.doi.org/10.1163/156851512x643832.

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Hart, Lawrence D. "The Canaanite Woman: Meeting Jesus as Sage and Lord: Matthew 15:21-28 & Mark 7:24-30." Expository Times 122, no. 1 (2010): 20–25. http://dx.doi.org/10.1177/0014524610377043.

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Zamoryonov, Mihail, Vadim Kopp, Yuriy Rapatsky, Daria Zamoryonova, and Victoria Lipka. "Process analysis of technological complex operation with different kinds of depreciating failures by path methods." Science intensive technologies in mechanical engineering 2020, no. 7 (2020): 24–30. http://dx.doi.org/10.30987/2223-4608-2020-7-24-30.

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The application of a path method allowing the simulation of the process of semi-mark system operation is considered. There is shown a sample of the technological complex during the operation of which various failures are possible. The simulation of the technological complex taking into account depreciating failures is carried out; the accuracy of the path method is confirmed.

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McLoughlin, John Grant. "Solutions to Calendar." Mathematics Teacher 90, no. 7 (1997): 562–63. http://dx.doi.org/10.5951/mt.90.7.0562.

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Problems 1, 6, 26, and 27 were contributed by Harry Simon, 701 Viola Street, Eunice, LA 70535-4339. Problems 2, 7–11, 18, 19, 22, 25 and 31 were prepared by Bob Tex Kenney, P. 0. Box 454, Saipan, MP 96950. Problems 3, 4, 5, 21, and 23 were adapted from Mathematical Quickies by Charles W. Trigg (Mineola, NY: Dover Publications, 1985). Problems 12–14 and 20 were offered by Morris Jack DeLeon, Florida Atlantic University, Boca Raton, FL 33431. Problem 15 was submitted by Enrico Uva, Outreach Schools, 1741 de Biencourt, Montreal, PQ H4E 1T4. Problems 16, 17, and 24 were adapted from The Moscow Puzzles: 359 Mathematical Recreations by Bons A. Kordemsky (Mineola, NY: Dover Publications, 1992). Problems 29 and 30 were contributed by Mark Harbison, 5737 College Avenue, #23, San Diego, CA 92120.

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Parovichnikova, Elena N., Vera V. Troitskaya, Andrey N. Sokolov, et al. "No Differences in the Treatment Outcome in T-Cell Acute Lymphoblastic Leukemia/Lymphoma Regarding the Initial Bone Marrow Blasts Count: Results of the Russian Acute Lymphoblastic Leukemia (RALL) Study Group." Blood 128, no. 22 (2016): 5149. http://dx.doi.org/10.1182/blood.v128.22.5149.5149.

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Abstract Introduction T-cell acute lymphoblastic leukemia (T-ALL) and lymphoma (T-LBL) originate from the common T-cell precursors and are formally differentiated by bone marrow blast count with less than 25% considered as T-LBL. ALL treatment protocols are successfully applied with quite similar long-term results in both entities. Dose intense chemotherapy is proposed to be the best option. RALL is conducting a prospective multicenter trial in the treatment of Ph-negative adult ALL patients based on the opposite approach - non-intensive but non-interruptive treatment (NCT01193933). T-LBL pts were included in the study.So we decided to define whether the difference in response rate and long-term results exists in T-ALL and T-LBL patients treated according to RALL-2009 protocol. Patients and Methods The therapy was unified for all Ph-negative ALL pts, but in T-cell ALL/LBL autologous hematopoietic stem cell transplantation (auto-HSCT) after non-myeloablative BEAM conditioning was scheduled as late intensification (+3-4 mo of CR) followed by prolonged 2 years maintenance. From Jan 2009, till Jul 2016, 30 centers enrolled 107 T-ALL/LBL pts. Median age was 28 years (15-54 y), 34 f / 73 m; early T-cell (TI/II) phenotype was verified in 56 (52.3%), mature (T-IV) - in 10 (9.4%), thymic (TIII, CD1a+) ALL - in 41 pts (38.3%). T-lymphoblastic lymphoma (T-LBL= <25% b/m blasts) was diagnosed in 22 pts (20,5%). We divided the analyzed population into 3 groups: < 5% b/m blasts, with 5-24%, ≥25%. Pts' characteristics according to the b/m involvement are depicted in Table 1. Autologous HSCT was performed in 35, allogeneic-in 7 pts. The analysis was performed in July 2016. Results As it's shown in Table 1 the patients with T-LBL disregarding the % of blasts cells (<5% or 5-24%) have much less initial WBC and LDH levels, more frequent mediastinum involvement, less frequent CNS disease in comparison with T-ALL patients. There were no patients with pro-T-subtype (T1) T-LBL comparing with 42% of patients with pro-T-ALL. Mature T-subtype was slightly more frequent (4/22 vs 6/85) (p=0,1) in T-LBL. Total CR rate in 97 available for analysis patients was 87,6% (n=85), induction death was registered in 5,1% (n=5), resistance-in 7,2% (n=7). All induction deaths occurred in T-ALL patients, resistant cases were registered much more frequently (p=0,01) in T-LBL with less than 5% of blast cells than in T-ALL (3/10 vs 4/85). Only 35 of 85 (41,2%) CR pts underwent autologous HSCT due to logistics problems and refusals. Auto-HSCT was done at a median time of 6 mo from CR and pts proceeded to further maintenance. We compared 5-y disease-free survival (DFS) and probability of relapse (RP) in transplanted pts and those who survived in CR ≥ 6 months (land-mark) receiving only chemotherapy. This analysis was carried out in 2 cohorts of patients: T-LBL (<5%; 5-24%) and T-ALL (≥25%). Land-mark analysis demonstrated the essential benefit of auto-HSCT only for T-ALL patients: DFS from time of transplantation was 95% and from land-mark for chemotherapy group - 61% (p=0,005), RP-5% vs 30% (p=0,02). But in T-LBL pts there were no benefit of autologous HSCT over chemotherapy (DFS -100% vs 86%, RP-0% vs 14%, p=0,3). At 5 years overall survival (OS) for the whole T-ALL/T-LBL group constituted-66%, DFS-76%. There were no differences in OS (77% vs 66%, p=0,8) and in DFS (87% vs 74%, p=0,7) in T-LBL and T-ALL. Conclusions Our data demonstrate that non-intensive, but non-interruptive treatment approach is effective as in T-ALL so in T-LBL. T-LBL patients had no induction mortality but more frequently were reported as having resistant disease on RALL-2009 protocol. Auto-HSCT after BEAM conditioning followed by maintenance provided substantial benefit only for patients with T-ALL, but not T-LBL. Table 1 Clinical characteristics and treatment outcome in T-ALL and T-LBL patients Table 1. Clinical characteristics and treatment outcome in T-ALL and T-LBL patients Disclosures No relevant conflicts of interest to declare.

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Lee, J. H., Y. W. Jeung, S. H. Hyun, E. S. Lee, and E. B. Jeung. "212 EFFECT OF OVULATION STATUS ON PREGNANCY RATES IN RECIPIENT GILTS TRANSFERRED WITH CLONED EMBRYO TRANSFER." Reproduction, Fertility and Development 19, no. 1 (2007): 223. http://dx.doi.org/10.1071/rdv19n1ab212.

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This study was conducted to determine the optimal stage of the estrus cycle to achieve the highest pregnancy rates in surrogate recipient gilts receiving somatic cell nuclear transfer (SCNT) embryos. Potential surrogate gilts over 7 months of age were checked at Day 21 of their estrus cycle for their estrous status by observing external signs: vaginal fluid, vulva redness, vulva swelling, and standing response to back pressure. Viscosity of vaginal fluid was evaluated and classified as none, medium, and strong. Vulva redness and swelling were respectively assessed as none or shrink, medium, and strong. Back pressure was estimated by an immediate move, standing less than 10 s, and standing over 10 s. Ovulation status was observed when surrogates had SCNT embryos transferred into their oviducts, and then ovulation status of each surrogate was classified depending on the follicular diameter, as follows: preovulation (PO – 17 surrogates; follicular diameter of PO was 3 to 5 mm), just prior to ovulation (JPO – 20 surrogates; follicular diameter of JPO was 6 to 8 mm), ovulating (IO – 12 surrogates; ovulation mark with JPO follicles), just after ovulation (JAO – 14 surrogates; ovulation mark without follicles), and after ovulation (AO – 24 surrogates; ovaries showed only corpora lutea). Real-time ultrasonograpy was used for pregnancy diagnosis by observing amniotic vesicles. All data were subjected to analysis of variance (ANOVA) and protected least significant difference (LSD) test using general linear models in a statistical analysis system (SAS Institute, Inc., Cary, NC, USA) program to determine differences among experimental groups. The first pregnancy diagnosis was done on Day 30 after ET and then repeated in 2-week intervals until Day 114. SCNT embryos transferred into JPO surrogates gave better pregnancy rates (9/20, 45%) than others (4% to 11%) on Day 30 after ET (P &lt; 0.05). These results suggest that ovulation status of surrogate gilts is an important critical factor for pregnancy. This information indicates that surrogate gilts implanted with SCNT pig embryos just prior to ovulation can achieve optimal pregnancy rates. In conclusion, the JPO surrogate selected should strongly show all parameters (vaginal fluid, vulva redness, vulva swelling, and standing response to back pressure) for the preparation of surrogates. This study was supported by the bio-organ production research grant (No.06020602) of the NLRI.

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Gal-Or, Benjamin. "Jet Engines – The New Masters of Advanced Flight Control." International Journal of Turbo & Jet-Engines 35, no. 2 (2018): 95–99. http://dx.doi.org/10.1515/tjj-2018-9010.

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Abstract ANTICIPATED UNITED STATES CONGRESS ACT should lead to reversing a neglected duty to the people by supporting FAA induced bill to civilize classified military air combat technology to maximize flight safety of airliners and cargo jet transports, in addition to FAA certifying pilots to master Jet-Engine Steering (“JES”) as automatic or pilot recovery when Traditional Aerodynamic-only Flight Control (“TAFC”) fails to prevent a crash and other related damages [1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42]. Replacement of propeller driven air vehicles with jet engines marks the first jet-engine historical revolution. Yet designers of TAFC still a priori arrest jet engines to provide only brute force forward – a practice leading to wrong freezing of wings, tails, canards, landing gear, airframe and avionics prior to selection of off-the-shelf jet engine to fit that non-integrated design. A second jet-engine revolution is currently in. It originated by failures of TAFC to function and prevent catastrophes especially in post-stall flight domains, takeoff and landing, which mark the JES-Revolution. Full scale JES implementation started in 1986 in the U.S. by YF-22 design [24, 31, 32, 33, 34]. Three years later the YF-22 prototype was selected over the YF-23 that lacked IPA-78402 JES Technologies [31] like 60+ to 1 kill-ratio advantage during WVR air combat – a revolution gradually followed by RUSSIA, CHINA, INDIA, JAPAN and South KOREA [20, 21, 28]. Civilizing JES to maximize future passengers flight safety by preventing various airlines catastrophes [8] had been successfully first flight tested by a subscale JES-Boeing-727 under U.S. FAA support [8, 25]. Pro and cons of military vs. civil JES-technologies are presented by this editorial.

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Hiwase, Devendra K., Deepak Singhal, Rakchha Chhetri, et al. "Inclusion of RBC-Transfusion Dependency Can Improve the Prognostic Value of Revised-IPSS in MDS Patients." Blood 124, no. 21 (2014): 1923. http://dx.doi.org/10.1182/blood.v124.21.1923.1923.

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Abstract Background: The Revised International Prognostic Scoring System (R-IPSS) stratifies MDS patients better than the original IPSS scoring system. Although RBC-transfusion dependency (RBC-TD) is associated with poor prognosis, it is not included in the R-IPSS. Another limitation of R-IPSS is that it is designed to assess the prognosis of patients only at the time of diagnosis; it does not provide prognostic guidance during the disease course. We hypothesise that the use of RBC-transfusion dependency status as a time-varying covariate improves R-IPSS. Aim: To assess the impact of RBC-TD as a time-varying covariate in addition to R-IPSS in predicting survival outcome of MDS patients. Materials and Methods: To match the patient selection criteria as in R-IPSS, primary MDS patients, AML (blast 20-30%) and CMML (WBC≤12x109/L) not treated with disease modifying agents or stem cell transplantation were included. RBC-TD was defined as RBC transfusion of at least 1 unit/8 weeks for at least 4 months (Malcovati et al; JCO 2007). For the statistical analysis of overall survival (OS) measured in months since diagnosis, the Akaike Information Criterion (AIC) was used to assess the goodness-of-fit of a model. Landmark analyses at 6, 12 and 24 months after the diagnosis were also conducted; individuals who experienced the event (i.e. death) before the landmark time point were excluded. The remaining patients were then classified into two groups – RBC-TD noted at or before the landmark time point and transfusion independent at the landmark time point. Results: In our study, 295 patients met the inclusion criteria for analysis, their median age was 75 years (21-97 years) and 66% patients were male. The majority of patients were RCMD, RAEB1 and RAEB2. R-IPSS improved the risk stratification of MDS patients, predominantly for the IPSS-intermediate group (Table I). The median OS in R-IPSS Very Low, Low, Intermediate, High and Very High risk group was 87, 62, 28, 13 and 12 months respectively (p<0.001). Median OS was significantly inferior in male patients (42.4 vs. 63.9 months; p<0.001) compared to females and elderly patients (129, 51 and 33 months in patients <60, 60-80 and >80 years respectively). Of the 295 patients, 22 patients died and 1 lost-to-follow-up within four months of diagnosis; they did not complete the four months qualifying period for RBC-TD and hence were excluded from further analysis. Of the models tested, the four factor model which included R-IPSS, RBC-TD as a time-varying covariate, age and sex was best supported. RBC-TD (HR 5.5; P<0.001) was associated with poor survival, independent of the R-IPSS category, sex and age at diagnosis (Table 2). At each land mark analysis RBC-TD was associated with poor survival, independent of R-IPSS, age and gender. The median survival of patients who became RBC-TD by 6 months was significantly poorer than patients who remained RBC-transfusion independent (18 vs.64 months; p<0.001; Fig 1A). Similarly median OS was significantly poorer in patients who became RBC-TD by 12 months (26 vs.71 months; p<0.001; Fig 1B) and 24 months (40 vs. 87 months; Fig.1C) Conclusions: Majority of MDS patients become progressively cytopaenic and require RBC transfusion during the disease course. RBC-transfusion dependency is always associated with poor prognosis irrespective of time to become RBC-TD. Assessing RBC-TD status along with R-IPSS provides more precise prognostic information during the disease course. Table 1: Refinement of IPSS patient risk categories by R-IPSS scoring system R-IPSS IPSS Very Low Low Intermediate High Very High Low (n=126; 43%) 60 64 2 0 0 Intermediate1 (n=121; 41%) 8 54 45 14 0 Intermediate-2 (n=33; 11%) 0 0 7 16 10 High (n=15; 5%) 0 0 0 4 11 Total=295 68 23% 118 40% 54 18% 34 11.5% 21 7% Table 2: Factors Predicting Survival of Primary Untreated MDS Patients Factor Hazard Ratio P value (Chi Sq) Age at diagnosis (Unit = 1 year) 1.04 <0.001 Sex (Male) 1.99 <0.001 R-IPSS Low (Ref Level = Very Low) 1.46 0.106 R-IPSS Int 3.23 <0.001 R-IPSS High 4.03 <0.001 R-IPSS Very High 7.72 <0.001 Transfusion Dependency as a Time Varying Covariate 5.50 <0.001 Figure 1: Landmark analysis for OS according to RBC-transfusion dependency (RBC-TD): Patients were classified according to transfusion dependency at 6, 12 and 24 months. At all three land mark analysis time-points median OS of RBC-TD patients was significantly inferior compared to patients who remained independent Figure 1:. Landmark analysis for OS according to RBC-transfusion dependency (RBC-TD): Patients were classified according to transfusion dependency at 6, 12 and 24 months. At all three land mark analysis time-points median OS of RBC-TD patients was significantly inferior compared to patients who remained independent Disclosures Hiwase: Novartis pharmaceutical Ltd , Australia: Research Funding. Ross:Novartis: Honoraria, Research Funding; BMS: Honoraria. Reynolds:Novartis AG: Former Novartis AG employee and holder of Novartis AG stock Other.

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Simon, Louis. "Le Christ est né chez les païens. Prédication de Louis Simon (Matthieu 15/21-28 et Marc 7/24-30)." Autres Temps. Les cahiers du christianisme social 15, no. 1 (1987): 99–102. http://dx.doi.org/10.3406/chris.1987.1181.

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ملكاوي, أسماء حسين. "عروض مختصرة". الفكر الإسلامي المعاصر (إسلامية المعرفة سابقا) 15, № 59 (2010): 200–189. http://dx.doi.org/10.35632/citj.v15i59.2647.

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 القرآن الكريم والقراءة الحداثية دراسة تحليلية نقدية لإشكالية النص عند محمد أركون، الحسن العباقي، دمشق: صفحات للدراسات والنشر، 2009م، 320 صفحة. أزمة الحضارة العربية المترددة، أبو يعرب المرزوقي، الدوحة: الدار العربية للعلوم ناشرون، مركز الجزيرة للدراسات، 2009م، 71 صفحة. العولمة وأزمة الليبرالية الجديدة - الكتاب الثاني، محمد عابد الجابري، بيروت: الشبكة العربية للأبحاث والنشر، 2009م، 392 صفحة. أزمة القيم من مأزق الأخلاقيات إلى جماليات الوجود، جمال مفرج، بيروت: الدار العربية للعلوم ناشرون، 2009م، 95 صفحة. التعليم وأزمة الهوية الثقافية، محمد عبد الرؤوف عطية، القاهرة: مؤسسة طيبة للنشر والتوزيع، 2009م، 334 صفحة. Media, Religion and Conflict, By Lee Marsden, and Heather Savigny, London: Ashgate Publishing; Har/Ele edition (October 30, 2009), 184 pages. Muslims and Media Images: News versus Views, By Ather Farouqui, Oxford University Press, New York: USA (October 11, 2009), 368 Arab News and Conflict: A Multidisciplinary Discourse Study (Discourse Approaches to Politics, Society and Culture),By Samia Bazzi, John Benjamins Pub Co (October 15, 2009), 240 pages. Terror Post 9/11 and the Media (Global Crises and the Media), By David L. Altheide, Peter Lang Publishing; First printing edition (July 15, 2009), 232 pages. Al-Ghazali, Averroes and the Interpretation of the Qur'an: Common Sense and Philosophy in Islam (Culture and Civilization in the Middle East), By Avital Wohlman, Routledge; 1 edition (December 25, 2009), 130 pages. Al- Ghazali's Philosophical Theology, By Frank Griffel, New York: Oxford University Press, USA (May 28, 2009), 424 pages. The Qur'an in Its Time (So as Middle East Issues), By Werner Daum, Al Saqi (September 24, 2009), 224 pages. The East-West dichotomy, By Thorsten Pattberg, New York: LoD Press, (August 18, 2009), 276 pages. Understanding Muslim Identity: Rethinking Fundamentalism, By Gabriele Marranci, Palgrave Macmillan; 1 edition (February 17, 2009), 242 pages. God's Continent: Christianity, Islam, and Europe's Religious Crisis (The Future of Christianity), By Philip Jenkins, Oxford University Press, USA; Reprint edition (April 6, 2009), 352 pages. Was Jesus a Muslim?: Questioning Categories in the Study of Religion, By Robert F. Shedinger, Fortress Press (May 1, 2009), 192 pages. A Deadly Misunderstanding: A Congressman's Quest to Bridge the Muslim-Christian Divide, By Mark D. Siljander, HarperOne; 1 edition, (October 7, 2008), 272 pages.  للحصول على كامل المقالة مجانا يرجى النّقر على ملف ال PDF في اعلى يمين الصفحة.

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Raje, Noopur, Robert Vescio, Charles W. Montgomery, et al. "Bone Marker-Directed Dosing of Zoledronic Acid for the Prevention of Skeletal Complications in Patients with Multiple Myeloma: Final Results of the Z-MARK Study." Blood 120, no. 21 (2012): 4077. http://dx.doi.org/10.1182/blood.v120.21.4077.4077.

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Abstract Abstract 4077 Introduction: Treatment with zoledronic acid (ZOL, 4mg) has proven effective for reducing the risk of skeletal-related events (SREs) in patients (pts) with multiple myeloma (MM), with a SRE incidence rate as low as 27% after 3.7 years' median follow-up (Morgan G, et al. Lancet Oncology 2011;12:743-52). Pts with normal bone metabolism may not require as intense a treatment schedule as pts with accelerated bone turnover. The Z-MARK study evaluated if pts with 1–2 years of prior intravenous (IV) bisphosphonate (BP) therapy can be treated safely long-term with less-frequent ZOL dosing based on bone turnover markers. Methods: MM pts (N=121) who started IVBP therapy (ZOL or pamidronate) 1–2 years before enrollment and received ≥4 prior doses, with baseline calculated creatinine clearance (CrCl) of ≥30 mL/min, were enrolled. Pts received 4mg IV ZOL every (q) 4 or 12 weeks (wk) based on their most recent urinary N-telopeptide of type I collagen (uNTX) levels (q4 wk if uNTX ≥50 nmol/mmol Cr, q12 wk if uNTX <50 nmol/mmol Cr). Pts who developed a SRE or had disease progression requiring a change in MM therapy on study were treated q4 wk thereafter regardless of uNTX levels. The study's primary endpoint was the proportion of pts who experienced ≥1 SRE during study Year 1. Group A (ZOL q12 wk only, N=79) is compared with Group B (all others, N=42). Results: Of 121 pts enrolled, 52 discontinued early: 29 (36.7%) in A and 23 (54.8%) in B. Median time to discontinuation was ∼20 months (mo) in A and ∼24 mo in B. Median time on ZOL on study was 22.5 mo for A and 20.8 mo for B. The mean age was 63.8 years (range, 34–90) with approximately 1:1 male:female ratio. By International Staging System criteria, 81.0% in A and 69.1% in B were Stage I/II, while 15.2% and 19.0% were Stage III. Median time from initial MM diagnosis to enrollment was 18.4 mo in A and 18.6 mo in B. A majority of pts in both groups had ≥1 osteolytic lesions at enrollment (A, 65.8%; B, 76.2%). The median duration of prior IVBP therapy was 13.8 mo in A and 14.4 mo in B. At enrollment, 72.2% in A and 78.6% in B had ≥1 SRE. The baseline mean (standard deviation) for uNTX and calculated CrCl was 19.88 (8.8) nmol/mmol Cr, and 85.1 (31.8) mL/min in A and 24.1 (15.6) nmol/mmol Cr and 84.3 (40.0) mL/min in B. Four pts started ZOL at q4 wk vs 117 pts at q12 wk based on uNTX at study entry. Of 117 pts assigned to q12-wk dosing, 79 stayed on schedule throughout the study; 38 pts switched to q4 wk (14 for increased uNTX, 4 for SREs, and 20 for disease progression). Only 7 pts (5.8%; all in A) had a SRE in study Year 1 (3 pathologic fractures, 3 spinal cord compressions, 4 radiation to bone, 1 surgery to bone, 1 hypercalcemia of malignancy). In Year 2, only 5 pts (4.1%) had a SRE (1 pathologic fracture, 4 radiation to bone). Baseline uNTX (low: <28, high: ≥28) was predictive of SREs (hazard ratio=3.1, P=.06). Treatment was well-tolerated. The most common AEs were fatigue (26.4%), upper respiratory tract infection (24%), diarrhea (21.5%), pneumonia (21.5%), cough (20.7%), pyrexia (18.2%), arthralgia (17.4%), and nausea (17.4%); none were attributed to ZOL. Except for arthralgia, the incidence of these AEs was higher in B vs A. Serious AEs were reported in 29.1% in A and 59.5% in B. Overall, 19.8% of pts (15.2% A, 28.6% B) had an AE leading to ZOL discontinuation. At 48 wk, the median percentage change in uNTX was –13.3% in A and 0% in B. No change in the median serum Cr was observed in either group at 48 wk. Four deaths (2 from progression of MM, 1 from pneumonia, 1 unknown) were reported on study (not suspected to be related to ZOL). Four reports of osteonecrosis of the jaw (ONJ) were suspected to be related to ZOL (all in A, q12-wk dosing) at 22.2 mo median follow-up. Conclusions: The final Z-MARK results show that bone marker-directed dosing is feasible and safe in pts with 1–2 years of prior IVBP therapy. The low incidence of SREs on study shows that less-frequent IVBP dosing beyond 1–2 years continues to reduce the SRE risk and may reflect changing treatment patterns for MM that include therapies with bone protective effects. Baseline uNTX (≥28 nmol/mmol Cr) trended toward significance for predicting SREs. Finally, this study, which prospectively evaluated ONJ beyond 3 years, demonstrated an incidence rate of 3.3%. Further studies and additional follow-up are needed to determine the potential predictive value and long-term benefits of bone marker-directed ZOL dosing in MM pts after standard IVBP treatment. Disclosures: Raje: Amgen: Research Funding; Acetylon: Research Funding; Millenium: Consultancy; Celgene: Consultancy; Onyx: Consultancy; Eli-Lilly: Research Funding; Novartis: Consultancy. Off Label Use: Zoledronic acid (4 mg every 3–4 weeks) is indicated for the treatment of patients with multiple myeloma and patients with bone metastases from solid tumors. Vescio:Novartis Pharmaceuticals Corporation: Speakers Bureau. Hadala:Novartis Pharmaceuticals Corporation: Employment. Warsi:Novartis: Equity Ownership; Novartis: Employment. Ericson:Novartis Pharmaceuticals Corporation: Employment, Stocks Other. Anderson:Novartis Pharmaceuticals Corporation: Consultancy.

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Kapadia, M., T. Pannellini, C. Moezinia, et al. "FRI0403 CLINICAL FEATURES OF PROSTHETIC JOINT INFECTIONS DIFFER IN PATIENTS WITH INFLAMMATORY ARTHRITIS AND OSTEOARTHRITIS." Annals of the Rheumatic Diseases 79, Suppl 1 (2020): 799.2–800. http://dx.doi.org/10.1136/annrheumdis-2020-eular.4777.

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Background:Inflammatory arthritis (IA) patients are at increased risk for prosthetic joint infections (PJI). However, because active IA patients without infections can have elevated inflammatory markers that mimic joint infection, PJI diagnosis is challenging in this population.Objectives:We used an institutional PJI registry to identify and compare the clinical, microbiologic, and histopathologic features of culture positive (CP) and culture negative (CN) total hip and knee PJI in IA and OA patients. We also evaluated the relationship between culture positivity, IA, and clinical outcomes.Methods:A retrospective cohort of THA/TKA PJIs, from 2009 to 2016, were identified by ICD codes, and confirmed by chart review. IA diagnosis was also confirmed by use of IA-specific medications. CN cases were defined as PJIs with no evidence of microbial growth in intraoperative cultures and CP PJI cases were defined by positive microbial growth in intraoperative cultures. Treatment failure was defined as subsequent surgical treatment for infection after the initial infection surgery. H&E slides of OA and IA PJI cases matched by age (+/-5) sex, and culture status were reviewed by a pathologist for evidence of the histopathologic features listed in Table 2. Fisher’s exact test, chi-square test, and Kaplan-Meier estimates were used.TABLE 1.Patient characteristics in IA and OA PJIsIAOAN%/SDN%/SDp-valueTotal36771Age58.511.466.812<.001BMI30.26.7306.70.861Female2877.833243.1<.001CCI2.81.71.72.10.002Smoking411.18611.20.792Glucorticoids1027.8395.1<.001Culture Negative1027.810914.10.024Treatment Success at 2 years1952.8509660.146IA- inflammatory arthritis; OA – osteoarthritis; PJI -prosthetic joint infection; CCI – Charlson Comorbidity IndexTABLE 2.Histopathology and clinical presentation in IA and OA PJIsOA (N=57)IA (N= 31)CP-IA (N=23)CN-IA (N=8)N (%)p-valueN (%)p-valuePathology Review>10 PMN per HPF42 (74)22 (71)0.80620 (87)2 (25)0.003Chronic Inflammation13 (23)23 (74)0.00118 (78)5 (63)0.393Necrosis17 (30)9 (29)18 (35)1 (13)0.38Clinical PresentationMSIS50 (88)26 (84)0.74722 (96)4 (50)0.009Sinus Tract7 (12)7 (23)0.2335 (22)2 (25)1Elevated ESR or CRP41 (72)24 (77)0.62217 (74)7 (88)1Elevated Synovial WBC33 (58)19 (61)0.82313 (57)6 (75)1Elevated Synovial %PMN31 (54)20 (65)0.37714 (61)6 (75)0.333OA – osteoarthritis; IA – inflammatory arthritis; CP – culture positive; CN – culture negative; MSIS – meets Musculoskeletal Infection Society diagnostic criteriaResults:807 PJI cases were identified including 36 IA (33 RA and 3 SLE) and 771 OA. A higher proportion of IA PJI were CN (N=10, 27%) vs. OA PJI (N=109, 14%, p=0.02). IA-PJI were younger, female, on glucocorticoids, and with more comorbidities. Type of surgical treatment did not differ significantly between IA and OA groups. Comparing CN-IA vs. CP-IA, no difference was observed in age, smoking, diabetes, surgical treatment, IA-specific meds or Charlson comorbidities. One-year survivorship of CN-IA and CN-OA were 66% and 87% (p>0.05). Across all CP cases, 57% were staphylococcal, with no differences between groups. Treatment failure was more frequent for CP-IA (42%) compared to CP-OA (30%), (p=0.2).Histopathology of 88 PJIs (31 IA and 57 OA) was reviewed. The IA cohort presented with more chronic inflammation (p=0.001) than the OA cohort. Within the IA cohort, a higher proportion of CP-IA had >10PMN per HPF (p= 0.003) and met MSIS criteria (p=0.009). Comparing CP-OA and CN-OA, there were no significant differences in histopathology findings or number of patients meeting MSIS criteria.Conclusion:IA PJIs are more likely to be culture negative than OA PJIs. Although our analysis was limited by our cohort size, our findings including differences in histopathology, and better clinical outcomes suggest the presence of biologic differences between CN and CP PJI that require further study.Disclosure of Interests:Milan Kapadia: None declared, Tania Pannellini: None declared, Carine Moezinia: None declared, Andy Miller: None declared, Mark Figgie: None declared, Peter Sculco: None declared, Michael Cross: None declared, Michael Henry: None declared, Linda Russell: None declared, Laura Donlin Consultant of: Consultant – Genentech/Roche, Allina Nocon: None declared, Susan Goodman Shareholder of: Reginosine- Investment, Grant/research support from: Novartis, Horizon, Consultant of: Novartis, Celgene, UCB

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Alam, Arif, Sabir Hussain, Amar Lal, Donna Lee, and Jorgen Kristensen. "Molecular Response to Tyrosine Kinase Inhibitors (TKIs) for Chronic Myeloid Leukemia (CML). an Update on Experience at Tawam Hospital, Abudhabi, UAE in the Light of ELN Guidelines." Blood 124, no. 21 (2014): 5526. http://dx.doi.org/10.1182/blood.v124.21.5526.5526.

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Abstract Background Chronic Myeloid Leukemia (CML) is a clonal myeloproliferative disorder characterized by the presence of a balanced reciprocal translocation involving the long arms of chromosomes 9 and 22. The fusion gene that is created by this translocation (BCR-ABL1) encodes for a constitutively active protein tyrosine kinase that is primarily responsible for the leukemic phenotype. Targeted therapy with Tyrosine Kinase Inhibitors (TKIs) has become the recommended first-line treatment for patients with CML. Commercially available TKIs include Imatinib, Nilotinib, Dasatinib, Ponatinib and Bosutinib. The first three drugs are approved for first line therapy while the later 2 are for resistant disease. Monitoring of the response to therapy is done with quantification of the BCR-ABL transcripts by RQ-PCR–based molecular technique. Methods Retrospective review of charts of patients diagnosed with CML between January 2010 and June 2014. Data points were measured at 3, 6, 12, and 24 months post initiation of therapy and results were documented as per ELN guidelines. Results 56 patients were diagnosed with CML. The median age was 33 years (range 19-73 years). Male to female ratio was 4:1. Sokal score was calculated for 53 patients (data for 3 patients was incomplete) 21 were low risk, 24 were intermediate risk and 8 were high risk. 7 patients were lost from follow up after diagnosis and are excluded from analysis. 1 patient has not reached the 3 month mark and is also excluded from analysis. 13 patients were started on initial treatment with Imatinib 400 mg while 35 with second generation TKIs (Dasatinib 100 mg daily or Nilotinib 300 mg BID) daily as upfront therapy. With a median follow up of 27 months (range 3 month to 51 months) 4/13 (30%) patients on Imatinib as first line therapy were able to achieve optimal repsone (one at a dose of 600 mg daily). 8 patients were switched to second line therapy and 7/8 patients have achieved MMR (1 patient remains in full cytogenetic relapse due to non-compliance). 35 patients were treated with 2ndgeneration TKIs as first line therapy. 22 out of 35 (62 %) patients have achieved optimal results within 18 months of front line therapy . Second line therapy was initiated in patients achieving suboptimal results or intolerance in 11 patients. 5 of these patients subsequently achieved MMR while 5 remain with suboptimal results. 1 patient had disease progression while one was lost to follow-up after achieving a partial cytogenetic response at 6 months. Interestingly 12 (25%) patients achieved MMR/CMR within 6 months of starting TKIs. Of these only 1 was on Imatinib while the rest were on 2ndgeneration TKIs. MMR 4.5 or undetectable levels of bcr-abl transcript have been documented in 10 patients (20 %) for the whole cohort. 4 patients had disease progression on TKI (treatment failure rate of 8 %). One patient had disease progression to accelerated and then blast crisis (lymphoid and myeloid) while the other 3 patients are alive with only CHR with one resistant to all TKIs, one with intolerance of all TKIs and one secondary to noncompliance. Conclusion We have previously reported on our experience with CML. We have now updated our report with a larger cohort of patients. The median age remains much lower as compared to Western countries, just reflecting differences in the age distribution of the population in the UAE with 80% being below the age of 65 years. MMR report from Enestnd trial is 67-71% in favor of Nilotinib as compared to Imatinib 44%, while the Dasision trial reported a MMR of 44 % in favor of Dasatinib with faster rate to response. Our results mirror the results of these phase 3 randomized trial with optimal response of 62 % with second generation TKIs% as compared to 30 % with Imatinib as front line therapy. Expatriates accounts for approximately 80% of the population in the UAE and many are temporary employed, having limited health care coverage, limited financial means as well as limited possibilities to attend regular follow-ups. This leads to compliance problems, loss from follow-up and suboptimal management and monitoring of their disease. These factors also complicate any chance of treatment free period for patients who achieve undetectable levels of bcr-abl transcripts. Additionally absence of technology for mutational analysis makes it impossible to determine underlying reasons for suboptimal response with accuracy. Disclosures Alam: BMS: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Hussain:BMS: Honoraria; Novartis: Honoraria. Lal:BMS: Honoraria; novartis: Honoraria.

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Werth, V., J. Merrill, R. Furie, et al. "OP0132 EFFECT OF IBERDOMIDE ON CUTANEOUS MANIFESTATIONS IN SYSTEMIC LUPUS ERYTHEMATOSUS: RESULTS OF A 24-WEEK, PLACEBO-CONTROLLED, PHASE 2 STUDY." Annals of the Rheumatic Diseases 80, Suppl 1 (2021): 76–77. http://dx.doi.org/10.1136/annrheumdis-2021-eular.2181.

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Background:Iberdomide is a high-affinity cereblon ligand that promotes proteasomal degradation of Ikaros (IKZF1) and Aiolos (IKZF3), transcription factors involved in innate and adaptive immune cell development and homeostasis, and linked to the genetic risk for systemic lupus erythematosus (SLE). A phase 2, placebo-controlled study evaluated the efficacy and safety of iberdomide in patients (pts) with moderate to severe SLE.Objectives:To examine the effect of iberdomide on cutaneous manifestations in SLE pts.Methods:Adult autoantibody-positive SLE pts with a SLE Disease Activity Index 2000 (SLEDAI 2K) score ≥6 were randomized (2:2:1:2) to oral iberdomide (0.45, 0.3, 0.15 mg) or placebo once daily (QD) for 24 weeks while continuing standard background lupus medications. The Cutaneous Lupus Area and Severity Index Activity score (CLASI-A) was assessed every 4 weeks through week 24. As prespecified, exploratory analyses, change from baseline and the proportion of pts who achieved ≥50% reduction from baseline (CLASI-50) were evaluated for all pts, pts with baseline CLASI-A ≥8, and by cutaneous lupus subtypes (acute [ACLE], subacute [SCLE], chronic [CCLE]). CLASI-A outcomes were also evaluated post hoc for subgroups with high baseline expression of IKZF3 or the type 1 interferon (IFN) gene signatures in the blood.Results:Of 288 randomized pts, the mean and median (range) baseline CLASI-A scores were 6.9 and 5.0 (0-49), with 28% of pts having a score ≥8. 56% of pts had ACLE, 29% CCLE, and 16% SCLE. CLASI-50 responses were not significantly different comparing iberdomide to placebo in all pts and pts with baseline CLASI-A ≥8 at week 24, where high placebo response rates were observed (Table). Numerically greater mean improvement from baseline in CLASI-A scores in pts with baseline CLASI-A ≥8 was observed for iberdomide 0.45 mg vs placebo beginning at week 4, with continuous improvement through week 24. For pts with SCLE or CCLE, CLASI-50 response rates were significantly higher with iberdomide 0.45 mg vs placebo (P<0.04; Table). SCLE pts had significantly greater mean change and median percent improvement in CLASI-A from baseline with iberdomide 0.45 mg vs placebo at week 24 (P<0.03). Treatment differences in CLASI-A between iberdomide 0.45 mg and placebo were larger for SCLE and CCLE subgroups with high baseline IKZF3 or type 1 IFN gene signatures, with statistical significance achieved for SCLE pts but not CCLE pts (Figure).Table 1.CLASI-50 Response Rates by Subgroups at Week 240.15 mg QD0.3 mg QD0.45 mg QD(n=42)(n=82)(n=81)PlaceboSubgroup(n=83)0.15 mg QD vs Placebo0.3 mg QD vs Placebo0.45 mg QD vs Placebon/m (%)n/m (%)Str Diff in % (95% CI)P valuen/m (%)Str Diff in % (95% CI)P valuen/m (%)Str Diff in % (95% CI)P valueAll pts37/83 (44.6)19/42 (45.2)0.4 (-17.33, 18.55) P=0.96141/82 (50.0)5.3 (-9.93, 20.11) P=0.49945/81 (55.6)10.9 (-4.30, 25.51) P=0.163CLASI-A ≥810/20 (50.0)8/13 (61.5)15.9 (-17.42, 45.45) P=0.39913/24 (54.2)12.1 (-17.57, 39.97) P=0.45816/24 (66.7)15.1 (-15.51, 42.49) P=0.368ACLE23/50 (46.0)15/30 (50.0)4.8 (-17.22, 26.31) P=0.66220/43 (46.5)-3.3 (-22.95, 16.67) P=0.73817/38 (44.7)-3.0 (-23.20, 17.65) P=0.782SCLE9/17 (52.9)5/9 (55.6)2.6a (-33.04, 36.33) P=0.9663/9 (33.3)-6.6 (-38.98, 31.86) P>0.99911/12 (91.7)38.7a(4.54, 61.75) P=0.035CCLE5/18 (27.8)7/14 (50.0)22.2a (-10.51, 50.00) P=0.19810/23 (43.5)23.8 (-6.89, 48.88) P=0.12918/29 (62.1)34.1 (4.43, 56.16) P=0.029CI, confidence interval; Str Diff, stratified difference.aUnstratified difference.Conclusion:Iberdomide showed beneficial effects on skin manifestations in pts with SLE. Efficacy appears to be more pronounced in pts with SCLE and CCLE skin subtypes, and in pts with high IKZF3 or IFN gene expression signatures.Δ, treatment difference of adjusted means; CCLE, chronic cutaneous lupus erythematosus; CLASI-A, Cutaneous Lupus Erythematosus Disease Area and Severity Index-activity score; IFN, interferon; SCLE, subacute cutaneous lupus erythematosus.Acknowledgements:This study was sponsored by Bristol Myers Squibb. Professional medical writing assistance was provided by Peloton Advantage, LLC, an OPEN Health company, and funded by Bristol Myers Squibb.Disclosure of Interests:Victoria Werth Consultant of: Bristol Myers Squibb, Grant/research support from: Bristol Myers Squibb, Joan Merrill Consultant of: UCB, GlaxoSmithKline, AbbVie, EMD Serono, Remegen, Celgene/Bristol Myers Squibb, AstraZeneca, Lilly, Immupharma, Amgen, Janssen, Resolve, Alpine, Aurinia, Astellas, Alexion, and Provention, Grant/research support from: GlaxoSmithKline and AstraZeneca, Richard Furie Consultant of: Bristol Myers Squibb, Grant/research support from: Bristol Myers Squibb, Thomas Dörner Consultant of: support for clinical studies and honoraria for scientific advice: AbbVie, Bristol Myers Squibb Company, Celgene, Eli Lilly, Janssen, Novartis, Roche, Employee of: Charite Universitätsmedizin, Berlin and DRFZ Berlin, Germany, Ronald van Vollenhoven Speakers bureau: UCB, AbbVie, Galapagos, Janssen, Pfizer, Paid instructor for: support for educational programs: Pfizer, Roche, Consultant of: AstraZeneca, Biogen, Biotest, Celgene, Gilead, Servier, UCB, AbbVie, Galapagos, Janssen, Pfizer, Grant/research support from: Bristol Myers Squibb, GlaxoSmithKline, Eli Lilly, UCB, Peter Lipsky Employee of: RILITE Foundation, Michael Weiswasser Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb, Shimon Korish Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb, Peter Schafer Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb, Mark Stern Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb, Zhaohui Liu Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb, Shaojun Tang Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb, Nikolay Delev Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb

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Li, Yingbo, Guimei Guo, Longhua Zhou, et al. "Transcriptome Analysis Identifies Candidate Genes and Functional Pathways Controlling the Response of Two Contrasting Barley Varieties to Powdery Mildew Infection." International Journal of Molecular Sciences 21, no. 1 (2019): 151. http://dx.doi.org/10.3390/ijms21010151.

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Powdery mildew caused by Blumeria graminis f. sp. hordei (Bgh) is one of the most serious diseases in barley. The numerous barley varieties across China provide valuable genetic resources to screen the resistant germplasm and to discover the primary genes of resistance to powdery mildew. In this study, Chinese barley variety Feng 7 was identified as a highly resistant genotype which limited Bgh colonization by cell apoptosis using leaf staining assay, while another variety Hua 30 showed high susceptibility. The performance of high resistance to Bgh in F1 plants from the two varieties suggested dominant gene(s) controlled the resistance to powdery mildew in Feng 7. To understand the host transcriptional response to Bgh infection, these two barley varieties Feng 7 and Hua 30 were inoculated with Bgh, and their transcriptional profiling using RNA sequencing (RNA-seq) at four time points (12 h post-inoculation (hpi), 24 hpi, 48 hpi, and 72 hpi) were compared. 4318 differentially expressed genes (DEGs), including 2244 upregulated and 2074 downregulated genes, were detected in Feng 7, compared with Hua 30 at 12 hpi. 4907 DEGs (2488 upregulated and 2419 downregulated) were detected at 24 hpi. 4758 DEGs (2295 upregulated and 2463 downregulated) were detected at 48 hpi. 3817 DEGs (2036 upregulated and 1781 downregulated) were detected at 72 hpi. The results showed the number of DEGs between two varieties peaked at 24 hpi (for the upregulated) or 48 hpi (for the downregulated), which is matched with the processing of Bgh infection. In addition, the number of upregulated DEGs involved in the functional pathways of plant defense (mitogen-activated protein kinase (MAPK) pathway and plant hormone signal transduction) is elevated remarkably at 24 hpi. Six candidate genes (PR13, glutaredoxin, alcohol dehydrogenase, and cytochrome P450) were identified in Feng 7. All of them present continuous expression at higher levels upon Bgh infection, compared with the performance in Hua 30, which revealed the potential contribution to Feng 7 mediate resistance to Bgh. In conclusion, the candidate genes and relevant pathways provided key information towards understanding the defense of barley to Bgh attack and the molecular mechanisms of different genetic resistance to powdery mildew.

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Abramova, Anastasia V., Elena A. Mikhaylova, Zalina T. Fidarova, et al. "Oligoclonal Expansion and T-Cells Subpopulations in Patients with Aplastic Anemia at Different Stages of the Disease." Blood 132, Supplement 1 (2018): 3864. http://dx.doi.org/10.1182/blood-2018-99-119414.

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Abstract Background. The main mechanism of the bone marrow (BM) failure in idiopathic aplastic anemia (AA) has an immunomediated character. Researching the T-cell clone's effect in the AA pathogenesis is very relevant at the present time. Oligoclonal expansion of T cells is frequent in AA and the identification of immunodominant T-cell clones can correlate with the disease activity and may possibly serve as response predictor to immunosuppressive therapy (IST). The aim. To identify T-cells subpopulations, expression of PD-1 and PD-L1 on T-cells and TCR-Vβ repertoires by flow cytometry in different groups of AA patients. Methods. Thirty AA patients (pts) with median age of 30.5 (19-71), m/f ratio 1:1,3 were divided in 3 groups: pts with newly diagnosed (ND) AA (n=13), pts with overall response to IST (OR) (n=10), non-response pts (NR) for 2 and more lines of IST (n=7). Flow cytometry was performed with BD FACS Canto II. We used commercial kit (IOTest® Beta Mark TCR Vb Repertoire) for evaluation of TCR-Vβ repertoire in the bone marrow (BM) of these patients. We performed analysis of BM samples from healthy donors as a control group (n=8). Due to low amount of donor samples the maximal value each of the 24 subclones (for CD4+ (T-helpers - Th) and CD8+ cells (T-cytotoxic cells - TCL)) was accepted as threshold. We concluded the presence of clonal expansion if TCR subclone exceeded this threshold. We identified different T-cell subpopulations in all 3 groups of AA and healthy donors by flow cytometry: double positive T-cells (CD3+CD4+CD8+), double negative T-cells (CD3+CD4- CD8-), Th (CD3+CD4+), TCL (CD3+CD8+), NK-T-cells (CD3+CD56+) out of CD3+ cells. Among Th and TCL cells was determined naive T-cells (CD28+CD95-), effector T-cells (CD28-CD95+), memory T-cells (CD28+CD95+), regulatory T-cells (CD4+CD127-CD25high) and subpopulations Th and TCL co-expressed PD-1 and PD-L1. Multiple comparisons were assessed by ANOVA or Kruskal Wallis test by GraphPad Prism software. Results. In our study all 30 AA patients had an immunodominant TCR-Vβ clones among Th and/or TCL cells. We identified the most common clonotypes in comparison with healthy donors - Vβ1, Vβ2, Vβ3 among the Th cells and Vβ3, Vβ9, Vβ13.1 among the TCL cells. In ND group Vβ1 was highly expanded in 5 (38.5%), Vβ3 - in 7 (53.8%) pts among Th, and Vβ3 - in 3 (23.1%) and Vβ9 - in 4 (30.8%) out of 13 pts among TCL. In OR group Vβ2 expansion was in 4 (40%) and Vβ3 - in 5 (50%) pts among Th; Vβ3 in 6 (60%) and Vβ9 in 6 (60%) out of 10 pts among TCL. In NR group the most frequent was Vβ13.1 clone in TCL - in 3 (42.9%) out of 7 pts. In NR group in overall clonal expansion was less frequent than in ND and OR groups. We also analyzed the previously mentioned subpopulations of T-cells in patients with AA in three groups (ND, OR, NR) compared to healthy donors (table 1). We obtained significant differences in the count of naive Th and TCL cells, memory T-cells in all three groups of AA patients compared to donors: proportion of naive Th and TCL cells was significantly higher and proportion of memory Th cells was lower in the donor group than in AA pts. The percent of TCL effectors was higher in ND AA pts compare to donors. We also found that cell count of activated Th (CD4+CD25+) was higher in the group of refractory pts. In OR pts proportion of PD-1-positive Th was higher than in donors. In NR pts Th and TCL co-expressed with PD-L1 were lower compare to donors (table 1). Conclusions. In our study we found immunodominant clonotypes in different AA pts and depletion of the pool of naive T cells. Dynamic observation of changes in the most common clonotypes in AA pts during treatment will provide suitable therapy tactics (allogenic bone marrow transplantation or IST). Disclosures No relevant conflicts of interest to declare.

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Mark, Tomer, Megan C. Manco, Maureen Lane, et al. "The Effect of Bortezomib, Cyclophosphamide, and Filgrastim On Complete Remission Rates and CD34+ Stem Cell Collections in Multiple Myeloma." Blood 114, no. 22 (2009): 4349. http://dx.doi.org/10.1182/blood.v114.22.4349.4349.

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Abstract Abstract 4349 Background The combination of lenalidomide (Len, Revlimid®), bortezomib (Bz, Velcade®), and dexamethasone (dex; RVD) has shown excellent efficacy in relapsed/refractory multiple myeloma (MM) patients, with overall response rates (ORR) of 69%, including 26% complete/near complete responses (CR/nCR), and manageable toxicities (Anderson et al. ASCO 2009). The phase I portion of the study (Richardson et al. IMW 2009) found the maximum tolerated dose (MTD) of this combination in newly diagnosed MM patients to be Len 25 mg/day, Bz 1.3 mg/m2, and dex 20 mg. In all phase I patients, the ORR (PR or better) was 100%, including 31% CR, 9% nCR, and 75% ≥very good partial response (VGPR). Results reported here are for patients treated in the phase II portion of the study. Methods Patients were treated with Len 25 mg/day (days 1–14), Bz 1.3 mg/m2 (days 1, 4, 8, 11), and dex 20 mg (cycles 1–4) and 10 mg (cycles 5–8) on the day of and day after Bzfor up to eight 21-day cycles. Patients received prophylactic anticoagulants. Responses were assessed by modified EBMT and Uniform criteria to include nCR and VGPR. Patients with at least partial response (≥PR) could proceed to ASCT after ≥4 cycles; responding patients who did not go on to ASCT could continue therapy at their physician's discretion. Patients with ≥grade 2 peripheral neuropathy (PNY) by CTCAE v3 were excluded. Thirty five patients were enrolled in the phase II portion of this study and were evaluable for both efficacy and safety. Results Median age was 59 years (range 22-86), 54% were men, 34% / 54% / 11% were ISS Stage I / II / III, and 57% / 31% had IgG / IgA MM, respectively. Patients received a median of 8 cycles of Bz and dex and 11 cycles of Len; 11 (31%) patients remain on therapy. Among the 24 patients who have gone off therapy, 5 (21%) completed treatment per protocol, 8 (33%) proceeded to ASCT, 3 (13%) had progressive disease (all during cycle 14 or later), 1 (4%) withdrew due to toxicities, 1 (4%) received non-protocol therapy, and the remaining (n=6; 25%) withdrew consent or stopped treatment due to physician decision. All patients (100%) had a best confirmed pre-ASCT response of ≥PR, with 54% CR/nCR and 69% ≥VGPR (Table). Response rates in the 31 and 24 patients who completed 4 and 8 cycles, respectively, are shown in the Table. Among the 24 patients without CR at cycle 4, response improved between cycles 4 and 8 in 16 (67%) patients. Fifteen of the 35 (43%) patients were mobilized for ASCT, with a median stem cell yield of 4.4 × 106 (2.3–6.6 × 106) CD34+ cells/kg. After median follow-up of 19.3 months, median time to progression (TTP), progression-free survival (PFS), and overall survival (OS) have not been reached; the estimated 1-year TTP and PFS are 76% and the estimated OS is 100%. Treatment-emergent grade 3 and 4 adverse events that occurred in >1 patient included lymphopenia (n=7; 20%), hypokalemia (n=3; 9%), and fatigue and neutropenia (n=2; 6% each). Sensory PNY of any grade occurred in 27 (77%) patients, which was grade 1 (n=18; 67%) and grade 2 (n=8; 30%) in the majority of patients; only one patient had grade 3 sensory PNY. Neuropathic pain and motor PNY were reported in 10 (29%; all grade 1 and 2) and 6 (17%; 1 grade 3) patients, respectively, with no grade 3 PNY seen. Importantly, PNY was reversible with dose reduction, supportive care, and/or completion of therapy. Thrombosis/thromboembolism was reported in just 2 (6%) patients. No treatment-related mortality was seen. Conclusion These phase II results suggest that RVD is a highly effective combination, with a pre-ASCT ORR of 100% and high rates of CR/nCR, and encouraging time-to-event analyses to date. RVD was well tolerated, with limited rates of grade 3 PNY and DVT/PE despite prolonged use of Bz and Len. Data from patients treated at the MTD in phase I and the impact of adverse risk factors (including advanced stage and high-risk cytogenetics) on outcome, as well as following ASCT, will be reported at the meeting. Based upon these promising results, phase II/III studies of RVD and RVD-based combinations are either planned or ongoing. Disclosures: Mark: Celgene: Research Funding, Speakers Bureau. Skerrett:Angioblast Systems, Inc.: Consultancy, Equity Ownership; Mesoblast Ltd: Consultancy, Equity Ownership; Council of Human Blood and Transfusion Services for NYS DOH: Membership on an entity's Board of Directors or advisory committees. Schuster:Celgene: Speakers Bureau; Genzyme: Membership on an entity's Board of Directors or advisory committees; Millennium Pharmaceuticals, Inc.: Speakers Bureau. Shore:Millennium: Membership on an entity's Board of Directors or advisory committees. Zafar:Celgene Corp: Speakers Bureau; Millenium: Speakers Bureau. Niesvizky:Celgene: Consultancy, Research Funding, Speakers Bureau; Millennium Pharmaceuticals, Inc.: Consultancy, Research Funding, Speakers Bureau; Proteolix: Consultancy, Research Funding.

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Choi, Y. H., J. Ritthaler, and K. Hinrichs. "33 PRODUCTION OF A CLONED FOAL USING MITOCHONDRIAL DNA-IDENTICAL OOCYTES." Reproduction, Fertility and Development 26, no. 1 (2014): 131. http://dx.doi.org/10.1071/rdv26n1ab33.

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Recently we reported the birth of a viable foal produced by nuclear transfer (NT) using oocytes recovered from immature follicles of live mares by transvaginal ultrasound-guided aspiration (TVA; 2013 Theriogenology 79, 791–796). This procedure opens the door for production of mitochondrial DNA-identical cloned foals; typically, use of heteroplastic oocytes results in cloned offspring that have different mitochondrial DNA from that of the donor. We selected 2 mares (BL and SM) from the maternal line of the donor, a 23-year old stallion. Genetic analysis confirmed that the mares’ mitochondrial genotype was identical to that of the donor. Oocytes were obtained from the mares by TVA of all follicles ≥5 mm diameter, and were matured in vitro for 20 to 26 h. Donor fibroblasts were treated with 15 μM roscovitine for 24 h, then were directly injected into enucleated oocytes using a Piezo drill. Reconstructed oocytes were activated with 5 μM ionomycin for 4 min followed by injection with sperm extract, then incubation in 2 mM 6-dimethylaminopurine for 4 h. Oocytes from mare SM were assigned to treatment with either Scriptaid (500 nM) or Scriptaid plus vitamin C (50 μg mL–1) for 14 to 16 h, starting at the onset of 6-dimethylaminopurine exposure; mare BL did not provide sufficient oocytes for treatment grouping. Presumptive zygotes were cultured in vitro for 7 to 11 days and blastocysts were shipped for transfer to recipient mares, 1 embryo per mare. In mare BL, 10 aspiration sessions were conducted, 78 follicles were aspirated and 45 oocytes were collected, of which 4 were degenerating. After in vitro maturation, 12/40 (30%) oocytes were mature. Five of 12 oocytes lysed during manipulation; the remaining 7 were cultured and 1 blastocyst (14%) was obtained, which did not yield a pregnancy. In mare SM, 3 aspiration sessions were conducted and 53 oocytes were recovered from 81 follicles. After in vitro maturation, 31/53 (58%) were mature. Four oocytes were lysed during manipulation, 27 were cultured, and 4 blastocysts (15%) were produced, 2 from scriptaid treatment and 2 from scriptaid plus vitamin C. Transfer of these blastocysts yielded one pregnancy (scriptaid treatment); the mare delivered a healthy foal at 328 days of gestation. These results indicate that NT can be successful using low numbers of immature oocytes from selected mares. However, the individual mare may greatly affect the outcome in terms of oocyte number and quality; in this case, mare BL not only yielded fewer oocytes per aspiration session (4.5 v. 17.7 for mare SM; P < 0.001, t-test), but also fewer reconstructed oocytes per oocyte recovered (7/45 v. 27/53, respectively; P < 0.001, Fisher's exact test). Efficiency (14 to 15% blastocysts per reconstructed oocyte cultured; 1 foal from 5 embryos transferred) was similar to that achieved previously in our laboratory using heteroplastic oocytes. This work was supported by the Link Equine Research Endowment Fund, Texas A&M University, by Kit Knotts, and by Jack Waggoner.

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Mark, Tomer M., John N. Allan, Geoffrey Marano, et al. "Car-Bird [Carfilzomib, Clarithromycin(Biaxin(R)), Lenalidomide/(Revlimid(R)), Dexamethasone) For Newly-Diagnosed Multiple Myeloma." Blood 122, no. 21 (2013): 3216. http://dx.doi.org/10.1182/blood.v122.21.3216.3216.

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Abstract Background Carfilzomib (Cfz) synergizes with lenalidomide and dexamethasone (Len-dex) to provide impressive response rates as upfront treatment of multiple myeloma (MM) (Jakubowiak et al 2012). The addition of clarithromycin to Len-dex has shown superior time to progression compared to Len-dex alone (Gay et al 2010). We hypothesized that sequential treatment with Cfz-dex and BiRD would lead to enhanced efficacy, response duration, and tolerability. We thus tested a sequential approach of upfront carfilzomib / dexamethasone, consolidation with BiRd, and lenalidomide maintenance to evaluate overall response and safety as first line therapy for MM. Methods Twenty-four patients (pts) with symptomatic untreated MM were enrolled in a single institution study to evaluate the efficacy and tolerability of Car-BiRd. Car-BiRd therapy is: Cfz IV over 30 minutes on Days 1, 2, 8, 9, 15, 16 of a 28-day cycle at a dose of 20mg/m2 on days 1, 2 of the 1st cycle only and 45mg/m2 for each successive dose thereafter and dex 40mg on D1, 8, 15, 22. Cfz-dex was continued until plateau in disease response defined as unchanged M-protein for 2 cycles. Elective autologous stem cell collection was then performed per physician and patient discretion and consolidation with BiRd initiated. Transplant ineligible pts proceeded directly to BiRd. BiRd is: Clarithromycin 500mg BID, lenalidomide 25mg daily on D1-21, and dex 40mg daily D1, 8, 15, 22 of 28-day cycle. Therapy was continued until a 2nd plateau in disease response after which lenalidomide maintenance at a dose of 10mg daily D1-21 of 28 day cycle was continued until disease progression or intolerability. Results 24 pts have currently been enrolled; 23 have completed at least 1 cycle of therapy and were evaluable for response. Sixteen pts (67%) harbored high-risk cytogenetics, as defined by the presence of one or more of the following on iFISH: del 17p, gain 1q, del 1p, t(4;14), t(14;16), or complex karyotypic abnormalities. Median study follow-up was 30.8 weeks (range 4.5-62.2). Response to the Car-BiRD regimen was: overall response rate (ORR) 87%, stringent complete response (sCR) 13%, very good partial response (VGPR) 48%, partial response (PR) 26%, stable disease (SD) 13%. Maximum response to the Cfz-dex induction was: ORR 87%, sCR 9%, VGPR 39%, PR 35%, SD 13%. Median time to PR and maximum response with Cfz-dex was 2 cycles (range 1-2) and 4 cycles (range 1-5) respectively. Median M-spike percentage decrease with Cfz-dex was 92% (range 13-100%). Twelve pts thereafter received BiRD consolidation with 5 pts (41%) further decreasing the M-spike by a median of 8% (range 1-45%). A median of 3 cycles (range 2-7) of BiRD was given until a 2nd response plateau was achieved. Seven pts subsequently received lenalidomide and all have maintained their response after a median of 5 cycles (range 1-8) of follow-up. Seven pts (30%) have come off study, 2 (8%) secondary to disease progression (1 during Car-Dex and 1 during BiRD) and 5 pts (22%) due to toxicity (2 pts due to Grade III renal failure, both attributable to Cfz, and 2 pts due to Grade III CHF during Cfz-Dex, 1 attributable to Cfz; 1 pt with Grade III Thromboembolic event during BiRD, attributable to Len-dex). Discussion This is the first prospective study evaluating the response to induction Cfz/Dex in treatment-naïve MM. Cfz/Dex therapy appears safe and effective in newly diagnosed myeloma patients. Responses deepen with subsequent IMiD(R)-based consolidation and maintenance. Toxicities due to each component of the regimen were manageable. The ORR of 87% and rate of VGPR or better of 61% in group with a high percentage of unfavorable cytogenetics compares favorably to similar studies using 1st generation proteasome inhibitor combinations, and may continue to improve with longer study follow-up. Disclosures: Mark: Onyx: Research Funding, Speakers Bureau; Millennium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Off Label Use: Carfilzomib is not approved for front line use in myeloma. Rossi:Celgene: Speakers Bureau. Zafar:Onyx: Speakers Bureau; Millennium: Speakers Bureau; Celgene: Speakers Bureau. Pekle:Millennium: Speakers Bureau; Celgene: Speakers Bureau. Niesvizky:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Onyx: Consultancy, Honoraria, Research Funding, Speakers Bureau; Millennium: The Takeda Oncology Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

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GENOVESE, MARK C., STANLEY B. COHEN, DAVID WOFSY, et al. "A 24-Week, Randomized, Double-Blind, Placebo-Controlled, Parallel Group Study of the Efficacy of Oral SCIO-469, a p38 Mitogen-activated Protein Kinase Inhibitor, in Patients with Active Rheumatoid Arthritis." Journal of Rheumatology 38, no. 5 (2011): 846–54. http://dx.doi.org/10.3899/jrheum.100602.

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Objective.To evaluate the efficacy, safety, and tolerability of oral SCIO-469, a p38 MAPK inhibitor that blocks tumor necrosis factor-α, interleukin-1ß, and cyclooxygenase-2 synthesis in patients with active rheumatoid arthritis (RA).Methods.Patients were randomized to receive SCIO-469 at either 30 or 60 mg three times daily in an immediate-release (IR) formulation or at 100 mg once daily in an extended-release (ER) formulation, or placebo for 24 weeks. The primary endpoint was American College of Rheumatology (ACR)20 response at Week 12. Safety was monitored through Week 26.Results.Overall, 302 patients were randomized: 76 to placebo, 75 to 30 mg IR, 73 to 60 mg IR, and 78 to 100 mg ER. There were no significant differences in ACR20 responses at Week 12 between SCIO-469 and placebo. Declines in C-reactive protein and erythrocyte sedimentation rate during early treatment did not persist to Week 12 and were not a consequence of decreased SCIO-469 plasma levels. The 60 mg IR regimen showed a dose-limiting toxicity manifested by elevations in alanine aminotransferase. Adverse events were common in all groups (79.7% and 86.7% through 13 and 26 weeks, respectively). Twenty-one patients reported 28 serious adverse events (SAE). SAE were more common with IR SCIO-469 than with placebo (7% vs 4%) but were not reported with ER SCIO-469.Conclusion.In all regimens tested, SCIO-469 showed no greater efficacy compared to placebo in patients with RA. The transient effect of SCIO-469 on acute-phase reactants suggests a complex role of p38 MAPK in inflammation.

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Stipesevic, Bojan, Miro Stosic, Bojana Teodorovic, et al. "Comparison of different side-dressings on winter wheat yield." Journal of Agricultural Sciences, Belgrade 54, no. 3 (2009): 189–96. http://dx.doi.org/10.2298/jas0903189s.

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The trial with different side-dressing fertilizations for winter wheat has been conducted at Vetovo site, Croatia, in vegetation seasons 2007/08 and 2008/09. The five side-dressing fertilizations has been tested (Control - no sidedressing, KAN - 100 kg KAN ha-1 in tillering and jointing stages; M1 - 8 l of foliar NPK fertilizer 'Profert Mara' ha-1; M2 - 16 l ha-1 of foliar fertilizer, and; M3 - 24 ha-1 of foliar fertilizer) at four winter wheat cultivars (Anika, Fiesta, Gabi and Rapsodija), with previously applied 400 kg NPK 7:20:30 ha-1 for all treatments. Results showed that all foliar side-dressing treatments gave winter wheat grain yield higher than the control, and that M1 treatment showed equal in comparison with KAN side-dressing. Treatments M2 and M3 had, in comparison with the control, KAN and M1 treatments, higher yields which leads toward conclusion that foliar treatments can be recommended for side-dressing for given agroecological conditions.

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Mark, Tomer M., Sujitha Yadlapati, Lyubov Neglyad, et al. "High-Dose Carfilzomib and Dexamethasone As First-Line Treatment in Symptomatic Multiple Myeloma." Blood 126, no. 23 (2015): 4258. http://dx.doi.org/10.1182/blood.v126.23.4258.4258.

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Abstract Background: Carfilzomib (Cfz) is approved for use in relapsed and refractory multiple myeloma (RRMM) at a dose of 27mg/m2 after escalation from 20mg/m2. The response rate for Cfz and dexamethasone (dex) as first-line therapy in multiple myeloma (MM) is unknown. Higher doses of Cfz have been shown to enhance overall response in RRMM (Lendvai 2014); the presence of a dose-response relationship of Cfz for first-line therapy in untreated MM has not been evaluated. A protocol of Cfz-Dex induction at two dosing levels, followed by BiRd (Clarithromycin 500mg PO BID, Lenalidomide (Len) 25mg for 21/28 days, Dex 40mg weekly) consolidation, and thereafter Len (10mg 12/28 days) maintenance, evaluated response and safety by Cfz dose level in patients (pts) with newly diagnosed symptomatic MM. The ORR and safety data for Cfz-Dex induction stratified by Cfz dose is reported. Methods: 70 patients with untreated MM were enrolled in a phase 2 study of Cfz-dex. Cfz-dex is: Cfz IV on D1, 2, 8, 9, 15, 16 of a 28-day cycle at a dose of 20mg/m2 on days 1, 2 of cycle 1 and 45mg/m2 thereafter and Dex 40mg on D1, 8, 15, 22. After the first 26 pts were enrolled, the protocol was amended to increase the Cfz from 45 to 56mg/m2. Screening echocardiogram and pulmonary function testing were performed. Brain natriuretic peptide (BNP) was measured with each cycle. Cfz-dex was continued until plateau in disease response (unchanged M-protein for 2 cycles). Elective stem cell collection was then performed in transplant eligible pts. This was followed by BiRd until 2nd response plateau, and then by LEN maintenance. Disease response evaluation was performed monthly with serum and urine protein electrophoresis, immunofixation, and free light chain analysis; bone marrow biopsy with skeletal imaging was used to confirm MM progression or complete response (CR). Cytogenetic testing was performed on CD138-selected cells. Results: 25 pts received Cfz-Dex at 45 mg/m2 and 44 (out of 45 enrolled) pts at 56 mg/m2 for at least 1 cycle and were evaluable for response. 56% of pts were ISS II/III and 64% had high-risk cytogenetics as per IMWG definition. Pts received a median of 5 cycles of Cfz-dex in both the 45 mg/m2 (range 1-10) and 56 mg/m2 groups (range 1-14). Maximum response to Cfz-dex is shown in Table 1. There was no difference in response between the 45 and 56mg/m2 groups (P = 0.20). Median time to PR and maximum response for the 45 and 56 mg/m2 cohorts were both 2 and 3 cycles, respectively. 42 pts had stem cell harvest. All collected stem cells to support at least two transplants (> 5 x 10^6 CD34/kg) in one mobilization attempt using G-CSF, with mean yield of 13.74x10^6 CD34/kg (range 5.94-32.14). 79% collected in 1 apheresis session. Adverse events (AEs) were notable for renal failure in 3 pts (2 Grade 2, 1 grade 3) and congestive heart failure in 1 pt (grade 3). Two of the 3 cases of renal failure occurred in the 56 mg/m2 cohort, all other AEs occurred in the 45mg/m2 cohort. All AEs resolved after stopping Cfz. There was no correlation with TTE, PFTs or serial BNPs and development of cardiac or pulmonary toxicity. Discussion: This is the first prospective study evaluating induction responses to Cfz-dex in MM. Cfz-dex is safe and active in induction at both 45 and 56 mg/m2, with an ORR of 93% and rate of >= VGPR of 68% despite a primarily high risk population. Specific dose did not correlate with response. Higher dose of Cfz did not lead to more toxicity. Cfz-dex induction led to successful stem cell collection in all attempts. Cfz-dex is a highly active and well-tolerated induction regimen. Transitioning to IMiD-based therapy after maximum response led to deeper responses with a remarkable 97% rate of VGPR or better. Table 1. Maximum Response with Cfz-Dex, followed by BiRD consolidation and lenalidomide maintenance: Response Category Cfz-Dex 45 mg/m2 Cfz-Dex 56 mg/m2 Overall Cfz-Dex phase BiRD phase Lenalidomide maintenance phase N = 25 (%) N = 44 (%) N = 69 (%) N = 44 (%) N = 33 (%) >= PR 22 (88) 42 (95) 65 (93) 44 (100) 33 (100) >= VGPR 16 (72) 31 (70) 45 (68) 42 (95) 32 (97) >= CR 3 (12) 2 (5) 5 (7) 12 (27) 15 (45) SCR 3 (12) 2 (5) 5 (7) 9 (20) 13 (39) CR 0 (0) 0 (0) 0 (0) 3 (7) 2 (6) VGPR 13 (52) 29 (66) 42 (61) 30 (68) 17 (52) PR 6 (24) 11 (25) 17 (25) 2 (5) 1 (3) SD 3 (12) 2 (5) 5 (7) 0 0 Disclosures Mark: Calgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Off Label Use: Carfilzomib as first line therapy in myeloma.. Rossi:Amgen: Speakers Bureau; Takeda: Speakers Bureau; Celgene: Speakers Bureau. Pearse:Celegen: Consultancy. Perry:Takeda: Speakers Bureau; Celgene: Speakers Bureau. Pekle:Celgene: Speakers Bureau; Takeda: Speakers Bureau. Huang:Celgene: Research Funding. Coleman:Celgene: Speakers Bureau; Takeda: Speakers Bureau. Chen-Kiang:Celgene: Consultancy. Niesvizky:Celgene: Consultancy, Speakers Bureau.

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Tan, Yan, Florence N. Hutchison, and Ayad A. Jaffa. "Mechanisms of angiotensin II-induced expression of B2 kinin receptors." American Journal of Physiology-Heart and Circulatory Physiology 286, no. 3 (2004): H926—H932. http://dx.doi.org/10.1152/ajpheart.00757.2003.

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Although the primary roles of the kallikreinkinin system and the renin-angiotensin system are quite divergent, they are often intertwined under pathophysiological conditions. We examined the effect of ANG II on regulation of B2 kinin receptors (B2KR) in vascular cells. Vascular smooth muscle cells (VSMC) were treated with ANG II in a concentration (10—9-10—6 M)- and time (0–24 h)-dependent manner, and B2KR protein and mRNA levels were measured by Western blots and PCR, respectively. A threefold increase in B2KR protein levels was observed as early as 6 h, with a peak response at 10—7 M. ANG II (10—7 M) also increased B2KR mRNA levels twofold 4 h after stimulation. Actinomycin D suppressed the increase in B2KR mRNA and protein levels induced by ANG II. To elucidate the receptor subtype involved in mediating this regulation, VSMC were pretreated with losartan (AT1 receptor antagonist) and/or PD-123319 (AT2 receptor antagonist) at 10 μM for 30 min, followed by ANG II (10—7 M) stimulation. Losartan completely blocked the ANG II-induced B2KR increase, whereas PD-123319 had no effect. In addition, expression of B2KR mRNA levels was decreased in AT1A receptor knockout mice. Finally, to determine whether ANG II stimulates B2KR expression via activation of the MAPK pathway, VSMC were pretreated with an inhibitor of p42/p44mapk (PD-98059) and/or an inhibitor of p38mapk (SB-202190), followed by ANG II (10—7 M) for 24 h. Selective inhibition of the p42/p44mapk pathway significantly blocked the ANG II-induced increase in B2KR expression. These findings demonstrate that ANG II regulates expression of B2KR in VSMC and provide a rationale for studying the interaction between ANG II and bradykinin in the pathogenesis of vascular dysfunction.

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Morschhauser, Franck, Herve Tilly, Aristeidis Chaidos, et al. "Phase 2 Multicenter Study of Tazemetostat, an EZH2 Inhibitor, in Patients with Relapsed or Refractory Follicular Lymphoma." Blood 134, Supplement_1 (2019): 123. http://dx.doi.org/10.1182/blood-2019-128096.

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Introduction: Relapsed/refractory (R/R) follicular lymphoma (FL) remains a difficult-to-treat condition, with limited treatment options. New, tolerable treatments with unique mechanisms of action are needed, especially for high-risk patients whose disease progresses within 24 months of diagnosis (POD24). The epigenetic regulator EZH2 catalyzes the histone 3 lysine 27 trimethylation (H3K27m3) gene suppressive mark, which is essential for BCL6-driven germinal center (GC) formation. Conversely, a reduction in EZH2 catalytic activity is required for centroblast differentiation and initiation of the GC exit program. Activating mutations (MT) in EZH2, present in ~20% of FL patients, and enhanced H3K27me3 prevent GC exit, resulting in GC hyperplasia and lymphomagenesis. Tazemetostat, an investigational, selective, oral EZH2 inhibitor, has demonstrated durable, single-agent, antitumor activity in R/R FL patients with MT or wild-type (WT) EZH2. Herein, we report newly emerging interim efficacy and safety data from the MT and WT cohorts and the POD24 subgroup. Methods: This open-label, multicenter, phase 2 study (NCT01897571) evaluated tazemetostat 800 mg administered orally twice daily in patients with MT or WT EZH2 R/R FL (Grade 1-3b). Key inclusion criteria included age ≥18 years, Eastern Cooperative Oncology Group performance status of 0-2, ≥2 prior treatment regimens, and measurable disease per 2007 IWG-NHL criteria. The primary endpoint was objective response rate (complete response + partial response). Secondary endpoints included progression-free survival and safety. The POD24 subgroup was composed of patients experiencing disease progression or relapse within 24 months of diagnosis or the start of frontline treatment with immunochemotherapy. Results: As of June 7, 2019, interim data were available for 99 patients (MT EZH2, n=45 [POD24, n=17; 38%]; WT EZH2, n=54 [POD24, n=30; 56%]). Of the 33 patients in the MT cohort with an objective response, 15 (45%) had a response at ≥6 months, 7 (21%) at ≥12 months, and 4 (12%) at ≥16 months. Of the 18 patients in the WT cohort with an objective response, 15 (83%) had a response at ≥6 months, 9 (50%) at ≥12 months, and 6 (33%) at ≥16 months. Data from the MT cohort continue to mature, with 11 (24%) patients enrolled in the past year and 17 (38%) patients still on treatment. Updated data from the fully enrolled MT cohort, and sub-group analyses from both WT and MT cohort, will be presented. Interim efficacy data from the response-evaluable population and POD24 subgroup of the MT and WT cohorts are presented in Table 1. These results demonstrate the potent, antitumor activity of tazemetostat regardless of the prognostic category of patients. Treatment-related Grade ≥3 adverse events (AEs) were reported in 17% of all patients and 15% of patients in the POD24 subgroup. The most frequently reported AEs were similar across the total population and the POD24 subgroup and included thrombocytopenia (3%), anemia (2%), asthenia (2%), vomiting (1%), and fatigue (1%). Five percent of all patients discontinued treatment, and 9% had dose reductions due to treatment-related AEs. No treatment-related Grade 5 AE and deaths were reported. Conclusion: Tazemetostat was generally well tolerated, with a low incidence of treatment-related AEs. Tazemetostat demonstrated clinically meaningful, durable, single-agent activity across a spectrum of patients with FL, including the POD24 subgroup, and pronounced responses in patients with EZH2 activating mutations. Disclosures Morschhauser: BMS: Honoraria; Roche/Genentech: Consultancy; Servier: Consultancy; Janssen: Honoraria; Celgene: Honoraria; Gilead: Consultancy. Tilly:servier: Honoraria; merck: Honoraria; roche: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; Gilead: Honoraria; BMS: Honoraria; Karyopharm: Consultancy; Roche: Consultancy; Celgene: Consultancy, Research Funding; Astra-Zeneca: Consultancy. Phillips:Bayer: Consultancy; Incyte: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy; Seattle Genetics: Consultancy; Gilead: Consultancy; Abbvie: Research Funding; Pharmacyclics: Consultancy, Research Funding. Ribrag:Servier: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Epizyme: Consultancy, Research Funding; ArgenX: Research Funding; MSD: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Infinity: Membership on an entity's Board of Directors or advisory committees; AZ: Membership on an entity's Board of Directors or advisory committees; Nanostring: Membership on an entity's Board of Directors or advisory committees; Roche: Other: Travel, accommodations, and expenses ; BMS: Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodations, and expenses . Campbell:Janssen: Honoraria, Research Funding, Speakers Bureau. Jurczak:Servier: Research Funding; Loxo: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk: Research Funding; Takeda: Research Funding; Bayer: Research Funding; Celgene: Research Funding; Roche: Research Funding; Morphosys: Research Funding; TG Therapeutics: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celtrion: Research Funding; Sandoz: Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; Gilead: Research Funding; AstraZeneca/Acerta: Membership on an entity's Board of Directors or advisory committees, Research Funding. McKay:Epizyme: Consultancy, Honoraria. Opat:Celgene: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Mundipharma: Consultancy, Honoraria. Radford:GSK: Equity Ownership; ADC Therapeutics: Consultancy, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria; AstraZeneca: Equity Ownership, Research Funding; Novartis: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria. Whalen:Epizyme: Employment, Equity Ownership. Rajarethinam:Epizyme: Employment, Equity Ownership. Navia:Epizyme: Employment, Equity Ownership. Adib:Epizyme: Employment, Equity Ownership. Salles:Amgen: Honoraria, Other: Educational events; Autolus: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria; Epizyme: Consultancy, Honoraria; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis, Servier, AbbVie, Karyopharm, Kite, MorphoSys: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Roche, Janssen, Gilead, Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events.

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Saunthararajah, Yogen, Reda Z. Mahfouz, Ricki Englehaupt, et al. "A Proof of Principle Clinical Trial in Myelodysplastic Syndromes of Non-Cytotoxic Differentiation Therapy with Decitabine,." Blood 118, no. 21 (2011): 3830. http://dx.doi.org/10.1182/blood.v118.21.3830.3830.

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Abstract Abstract 3830 In myeloid malignancies, genetic abnormalities in key apoptosis pathway genes (eg., p53) are associated with poor responses to conventional cytotoxic therapy. In pre-clinical models, non-cytotoxic, DNA methyltransferase 1 (DNMT1) depleting regimens of the deoxycytidine analogue decitabine relieve aberrant epigenetic repression of key late-differentiation genes and induce cell cycle exit by p53-independent differentiation pathways (CEBPE, MXD1, p27/CDKN1B) (Ng et al, Leukemia 2011). To translate these observations into practice, a clinical trial is being conducted in MDS, using decitabine at minimum doses required to deplete DNMT1 (0.1–0.2 mg/kg [5–10 mg/m2]), administered by the subcutaneous (SC) route to avoid high peak levels that cause apoptosis, and using a metronomic schedule (1-3X/week for ≥1y) to increase exposure time for S-phase specific depletion of DNMT1. To evaluate mechanism of action, correlative studies include quantification of pH2AX (DNA damage marker) and DNMT1 levels in bone marrow by flow-cytometry, and immunohistochemical evaluation by ImageQuant of p27/CDKN1B and KI67 expression, expected to vary directly and inversely respectively with terminal differentiation. A two-stage Simon design was used, and results from the first stage (n=15, patient characteristics table 1) are reported (median follow-up 330 days, range 142–180). Anti-emetics were not required, and there were no administration related adverse events. Neutropenic fever (NF) occurred in 11 patients, 7 of whom did not have NF prior to therapy (median time to nadir 40 days). By IWG criteria, complete hematologic and cytogenetic remissions (CR) with persistent dysplasia occurred in 2 subjects, hematologic improvement (HI) occurred in 4 subjects (overall response rate, ORR=40%), and stable disease in 7. Median response duration for HI/CR is 243 days, with 5 of 6 responses ongoing (range 74–292). Complete cytogenetic responses occurred even in patients with highly complex chromosome abnormalities (table 1). Bone marrow cell pH2AX expression decreased non-significantly from pre-treatment to week 6 to week 12 (median values 1.2, 0.5 and 0.4% respectively, p=0.27 Wilcoxon test), with a >3-fold reduction in mean percentage of cells expressing DNMT1 in the same period (Turkey-Kramer test p<0.001). Consistent with differentiation-mediated cell cycle exit, median p27/CDKN1B expression increased from 26.8 to 66.2 to 78.7% of bone marrow cells (p<0.001), with a concomitant decrease in median KI67 expression from 65.8 to 46.2 to 28.7% (p<0.001) (table 1). ORR of only 40% despite major p27 and cytogenetic responses and stable disease in almost all subjects (table 1), suggested that relief of cytopenia may require a threshold of normal stem cell reserve and a supportive marrow microenvironment. Accordingly, in HI/CR versus other subjects, median duration of disease was 855 versus 1350 days (p=0.15), and median pre-treatment bone marrow cellularity was 65 versus 30% (p=0.14). In conclusion, this study provides clinical proof of principle that a decitabine regimen rationalized for non-cytotoxic epigenetic-differentiation effects is active in myeloid malignancy, correlates with molecular markers of terminal differentiation, and has potentially important safety and efficacy advantages over cytotoxic therapy that warrant further evaluation and optimization. All subjects: baseline and response characteristics BM blasts: <5%/≥5%/≥10% Median Age (range) Prev. 5aza or lenali-domide (%) Prev. chemotx and XRT (%) Median disease duration (days) M/FM CR (%) HI (%) HI and CR (%) Cyto CR (%) Cyto PR (%) HI, CR and stable disease (%) 9/3/3 72 (46–83) 7 (46) 2 (13) 1080 (90–4680) 10/5 2/15 (13) 4/15 (26) 6/15 (40) 4/7 (57) 1/7 (14) 13/15 (87) Subjects with cytogenetic abnormalities pH2AX% KI67% p27 (CDKN1B) % Patient Number Pre-Tx Cyto. Abn. Best cyto Resp. Pre-Tx Wk 6 Wk 12 Pre-Tx Wk 6 Wk 12 Pre-Tx Wk 6 Wk 12 1 20q- 6/20 meta-phases Norm. 20/20 7 1 0.8 42 17 31 14 79 58 2 -7 19/20 meta. -7 6/20 0.2 0.2 0.2 71 65 36 30 57 78 8 del3, -5, -7, +22 4/20 meta. Norm. 20/20 3.4 1.8 0.2 66 50 24 44 69 71 9 +mar 2/20 meta. Norm. 20/20 0.7 1.6 0 74 39 27 13 55 88 11 -4,del5,-17,add19/45, add19),+19, +mar1/-6,+inv6,-7,-10,+del10, -14,+add14, -15,-22,t(15;22), +mar2 16/20 meta. Norm. 20/20 3.5 0.5 0.4 71 46 20 30 66 79 14 -Y 20/20 meta. -Y 16/20 4.3 0.2 0.2 70 54 47 86 15 -Y in 3/20 metaphases -Y 7/20 1.7 0.4 0.4 81 50 18 71 Disclosures: No relevant conflicts of interest to declare.

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Bhatia, Ankush, Vaios Hatzoglou, Gary Ulaner, et al. "Neurologic and oncologic features of Erdheim–Chester disease: a 30-patient series." Neuro-Oncology 22, no. 7 (2020): 979–92. http://dx.doi.org/10.1093/neuonc/noaa008.

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Abstract Background Erdheim–Chester disease (ECD) is a rare histiocytic neoplasm characterized by recurrent alterations in the MAPK (mitogen-activating protein kinase) pathway. The existing literature about the neuro-oncological spectrum of ECD is limited. Methods We present retrospective clinical, radiographic, pathologic, molecular, and treatment data from 30 patients with ECD neurohistiocytic involvement treated at a tertiary center. Results Median age was 52 years (range, 7–77), and 20 (67%) patients were male. Presenting symptoms included ataxia in 19 patients (63%), dysarthria in 14 (47%), diabetes insipidus in 12 (40%), cognitive impairment in 10 (33%), and bulbar affect in 9 (30%). Neurosurgical biopsy specimens in 8 patients demonstrated varied morphologic findings often uncharacteristic of typical ECD lesions. Molecular analysis revealed mutations in BRAF (18 patients), MAP2K1 (5), RAS isoforms (2), and 2 fusions involving BRAF and ALK. Conventional therapies (corticosteroids, immunosuppressants, interferon-alpha [IFN-α], cytotoxic chemotherapy) led to partial radiographic response in 8/40 patients (20%) by MRI with no complete responses, partial metabolic response in 4/16 (25%), and complete metabolic response in 1/16 (6%) by 18F-fluorodeoxyglucose (FDG)-PET scan. In comparison, targeted (kinase inhibitor) therapies yielded partial radiographic response in 10/27 (37%) and complete radiographic response in 14/27 (52%) by MRI, and partial metabolic response in 6/25 (24%) and complete metabolic response in 17/25 (68%) by FDG-PET scan. Conclusions These data highlight underrecognized symptomatology, heterogeneous neuropathology, and robust responses to targeted therapies across the mutational spectrum in ECD patients with neurological involvement, particularly when conventional therapies have failed.

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Lue, Jennifer Kimberly, Sathyen A. Prabhu, Yuxuan Liu, Owen A. O'Connor, and Jennifer E. Amengual. "Epigenetic Targeting with EZH2 and HDAC Inhibitors Is Synergistic in EZH2 Deregulated Lymphomas." Blood 128, no. 22 (2016): 839. http://dx.doi.org/10.1182/blood.v128.22.839.839.

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Abstract EZH2 is critical in a process known as the Germinal Center (GC) reaction during which B-cells undergo somatic hypermutation and isotype switching in order to develop a large antibody repertoire. EZH2 is a histone methyltransferase serving as the catalytic subunit of the Polycomb Repression Complex 2 (PRC2), which is responsible for tri-methylation of histone 3 lysine 27 (H3K27), a mark of transcriptional repression. EZH2 recruits HDAC1/2 and DNMTs through its cofactor EED to further inhibit transcription. Mutations in EZH2 are found in 7-12% of FL and 22% of GC-DLBCL. EZH2 overexpression secondary to MYC and miRNA dysfunction has also been described. EZH2 also plays a role in T-cell differentiation and has been found in various T-cell malignancies. Histone acetyltransferases (HAT), notably CBP and p300, have also been implicated in B- and T-cell lymphomas and are mutated/deleted in 39% of GC-DLBCL and 41% of FL. Given the presence of EZH2 and HAT dysregulation in lymphoma, we evaluated the potential synergy of EZH2 and HDAC inhibitors co-treatment. Single agent activity for GSK126, an EZH2 inhibitor, and romidepsin, a pan-HDAC inhibitor, was established in a panel of lymphoma cell lines (GC-DLBCL, Non-GC DLBCL, MCL and T-Cell lymphoma, n=21). Cell lines with known EZH2 dysregulation (GC-DLBCL and ATLL) were more sensitive to EZH2 inhibitors as exhibited by lower half maximal effective concentration (EC50) after 6 day exposure (EC50 0.01-16 µM). There was no association between HAT mutation/deletion and romidepsin sensitivity. A panel of lymphoma cell lines was treated for 72 hr with GSK126 and romidepsin using concentrations represented by their EC30-50 (0.5-4.0 µM), and EC20-40 (1.0-4.0 nM), respectively. Synergy was assessed by Excess over Bliss (EOB), where EOB > 10 represents synergy. Simultaneous exposure to GSK126 and romidepsin in GC-DLBCL cell lines demonstrated potent synergy as represented by EOB > 30. Synergy was also present in ATLL cell lines (EOB 28), which are known to have EZH2 dysregulation, as well as non-GC DLBCL cell lines (EOB 47). Although these cell lines do not have EZH2 mutations, some possess relative EZH2 over-expression compared to other lymphomas. Evaluation of drug schedule using GSK126 pretreatment prior to romidepsin exposure did not impact synergy. Compared to single agent activity, the combination of GSK126 (2 µM) and romidepsin (1-4 nM) led to a more pronounced decrease in H3K27 tri-, di-, and mono-methylation and increased acetylation in 4 GC-DLBCL cell lines (OCI-LY7, Pfeiffer, SU-DHL-6, SU-DHL-10) at 24 or 48 hrs. The impact of the combination on the function of the PRC2 complex was assessed via co-immunoprecipation in these cell lines. The combination demonstrated dissociation of the PRC2 complex (EZH2, SUZ12, EED, and RbAp46/48) as compared to single agent exposure. Treatment with the combination also induced dissociation of HDAC2 and DNMT3L. In addition, we observed decreased protein expression of PRC2 complex members and increased p21/CDKN1A, which was more notable in the combination treatment as compared to single agent. This may be due to the removal of HDACs from the p21 transcriptional start site through the disruption of the PRC2 complex and direct inhibition of HDACs, thus leading to increase expression of p21. The combination also led to decreased nuclear localization of EZH2 and its cofactors. Apoptosis was confirmed by caspase 3 and PARP cleavage, and was more potently cleaved after exposure to the combination. Based on the findingthat HDAC2 dissociated from PRC2 complex after treatment with GSK126 and romidepsin, a selective HDAC1/2 inhibitor, ACY-957 (Acetylon Pharmaceuticals), was combined with GSK126 which demonstrated potent synergy in 4 GC-DLBCL cell lines (EOB 37). This data suggests that concomitant inhibition of EZH2 and HDAC is highly synergistic and leads to the dissociation of PRC2 complex. By releasing transcriptional inhibition key tumor suppressors and cell cycle regulators may be re-expressed. Potency of this epigenetic combination may be predicted by gene expression signatures for which RNA-seq libraries are currently in production. Reversing transcriptional inhibition using a combination of EZH2 inhibitors and HDAC inhibitors may lead to a potent treatment option for lymphomas dependent upon EZH2 and HAT activity. Figure 1 Figure 1. Disclosures O'Connor: Seattle Genetics: Research Funding; Spectrum: Research Funding; Seattle Genetics: Research Funding; Spectrum: Research Funding; Mundipharma: Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Research Funding; Mundipharma: Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Research Funding; Bristol Myers Squibb: Research Funding; Bristol Myers Squibb: Research Funding; Celgene: Research Funding; Celgene: Research Funding. Amengual:Acetylon Pharmaceuticals: Research Funding; Bristol-Myers Squibb: Research Funding.

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Uy, Geoffrey L., Eric J. Duncavage, Gue Su Chang, et al. "Dynamic Changes in the Clonal Structure of MDS and AML in Response to Epigenetic Therapy." Blood 126, no. 23 (2015): 610. http://dx.doi.org/10.1182/blood.v126.23.610.610.

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Abstract Hematopoietic cells from patients with myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) contain gene mutations that are variably distributed between the founding clone and daughter subclone(s). Traditional response criteria in MDS and AML are based on bone marrow morphology and may not accurately reflect antitumor activity and clinical benefit in patients treated with hypomethylating agents. We used digital sequencing of serial bone marrow samples to monitor tumor burden and to characterize the changes in the clonal structure of MDS and AML that occur during treatment with epigenetic therapy. We hypothesized that digital sequencing may provide an alternative measure of antitumor activity and identify the persistence or emergence of resistant clones during treatment which mediate disease relapse. We conducted a phase I/II study in older adults (age ≥ 60) with advanced MDS (IPSS ≥ 1.5) or AML. Subjects received a combination of decitabine 20 mg/m2 on d1-5 with the histone deacetylase inhibitor, panobinostat 10-40 mg po 3x/week every 28 days for up to 12 cycles. Serial bone marrow samples were collected for digital sequencing at baseline, after every 2 cycles of treatment and at the time of relapse. A total of 52 patients, 14 with MDS and 38 with AML were enrolled in this study. For AML patients, 10% achieved a complete remission (CR+CRi) with an additional 18% of patients achieving a morphologic leukemia-free state (mLFS) using IWG response criteria. For patients with MDS, 14% achieved a CR and 21% achieved a marrow CR. We identified 9 MDS and 16 AML patients that had banked, paired bone marrow and skin (as a source of normal DNA) samples and a somatic mutation in at least 1 of 54 recurrently mutated MDS/ AML genes. DNA was enriched for 285 genes commonly mutated in MDS and AML (n=24 patients) or whole exome probes spiked-in with the 285 genes (enhanced exome sequencing; EES) (n=7 patients), and sequenced on a HiSeq2000 instrument with 2x101bp reads. We detected an average of 4.9 SNVs and indels per patient (range 1-15) when only the 285 gene panel was used, compared to 27.4 mutations per patient (range 9-43) using EES. Ten genes were mutated in at least 3 pre-study samples. The presence of a TP53 mutation (N=8) was associated with a trend towards achieving a response (p=0.09). We then analyzed variant allele frequencies (VAF) of mutations in serial samples. We observed five distinct patterns that were associated with different clinical responses, including i) AML patients achieving a CR+CRi (n=2): mutation VAFs were undetectable by cycle 2 using standard sequencing, ii) AML with mLFS (n=2): mutation VAFs remained detectable but decreased to <10%, iii) MDS with CR/cCR+mCR (n=3): mutation VAFs decreased to <10% and were intermittently below the level of detection, iv) MDS with stable disease (n=2): mutation VAFs decreased but some remained >10%, and v) AML with treatment failure (n=5): mutation VAFs were essentially unchanged and remained >30%. We observed responding patients can have persistent measurable clonal hematopoiesis for at least one year without disease progression. Sequencing also revealed selective AML subclone clearance in a patient with treatment failure, nominating a set of mutations that may mark super-responder clones. We observed that the blast percentage decreases prior to mutation VAFs in some patients, suggesting that the differentiation of blasts could falsely underestimate tumor burden. Finally, sequencing revealed that tumor burden can be measured even in patients achieving a CR. Using an ultra-sensitive barcode sequencing approach, we sequenced 1 MDS and 1 AML patient achieving a clinical and molecular CR (based on standard sequencing). We detected extremely rare TP53 mutations months to years prior to disease relapse (VAFs = 0.23% in MDS and 0.05% in AML during a CR - equivalent to a sensitivity of 1 in 2000 heterozygous mutant cells). While patients can live with persistent clonal hematopoiesis in a CR or stable disease, ultimately we find evidence that expansion of a rare subclone drives relapse or progression from MDS to secondary AML. Digital sequencing provides an alternative measure of disease response which may augment traditional clinical response criteria and should be explored in future clinical trials. Disclosures Uy: Novartis: Research Funding. Off Label Use: Panobinostat in MDS/AML. Duncavage:Cofactor Genomics: Consultancy; DI&P Consulting: Consultancy. Jacoby:Sunesis: Research Funding; Novo Nordisk: Consultancy. Abboud:Teva Phamaceutical: Research Funding.

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Maeda, Azusa, Atsushi Iwama, Koji Eto, et al. "Expression of Endomucin, a CD34-Like Sialomucin, Marks Definitive Hematopoietic Stem Cells throughout Development." Blood 104, no. 11 (2004): 563. http://dx.doi.org/10.1182/blood.v104.11.563.563.

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Abstract In order to identify cell surface molecules specific to hematopoietic stem cells (HSCs), a modified signal sequence trap was applied to mouse bone marrow (BM) CD34− c-Kit+ sca-1+ lineage− (CD34−KSL) cells which is highly enriched for HSCs. Among the identified genes, mRNA expression of Endomucin, an endothelium-specific gene encoding a CD34-like sialomucin, appeared highly specific to CD34-KSL HSCs. To further investigate the expression of Endomucin, we generated two rat anti-mouse Endomucin monoclonal antibodies that recognize different epitopes (AE2D4, AE7F2). Taking advantage of these and another monoclonal antibody, V7c7 (1999, Blood, 93; 1; 165), detailed expression analysis was performed. Endomucin expression was largely confined to lineage markers-negative (Lin−) cells. Approximately 7 % of Lin− cells were Endomucin-positive. Cells strongly expressing Endomucin represented 30% of c-kit+ sca-1+ cells. Gating out CD34+ cells from Lin− Endomucin+ population resulted in high yield of KSL cells. High correlation between Lin− Endomucin+CD34− cells and KSL cells was confirmed by in vivo bone marrow transplantation. When Lin− cells were fractionated by their expression of CD34 and Endomucin, only Lin− Endomucin+CD34− cells contributed to long-term repopulation (LTR), and as few as 100 cells were enough to obtain engraftment. Furthermore, the majority of CD34−KSL cells were Endomucin+, and again, only CD34−KSL-Endomucin+ cells had LTR activity. These data indicate two facts: 1) A single positive marker, Endomucin can substitute for c-kit+ sca-1+, 2) All LTR -HSCs express Endomucin. We then analyzed the expression of Endomucin during embryonic development of the hematopoietic system. Definitive HSCs arise from the hemogenic endothelium lining the wall of the dorsal aorta in embryonic aorta-gonads-mesonephros (AGM) region, then seed to the fetal liver. E10.5 AGM CD45− cells were segregated into subpopulations by their expression of Endomucin and CD41, an early marker of embryonic hematopoiesis. In vitro coculture system with a stromal cell line, OP9, was applied to detect the ability of hematopoietic potential. Hematopoietic activity was exclusively found in the CD41+Endomucin+ population, that represents 24% of CD41+ cells. Taken together, these data indicate that Endomucin marks both embryonic and adult HSCs, providing a novel useful cell surface marker for definitive HSCs throughout development. Figure Figure

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Siegel, David S., A. Krishnan, S. Lonial, et al. "Phase II Trial of SCIO-469 as Monotherapy (M) or in Combination with Bortezomib (MB) in Relapsed Refractory Multiple Myeloma (MM)." Blood 108, no. 11 (2006): 3580. http://dx.doi.org/10.1182/blood.v108.11.3580.3580.

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Abstract Background: p38a mitogen-activated protein kinase (MAPK) mediates production of proinflammatory cytokines and other factors including PGE-2 induced RANKL and IL-1 induced IL-6. SCIO-469 inhibits p38a MAPK blocking synthesis of Il-1ß, PGE2, VEGF, MIP-1α and TNFα thus reducing in vitro MM tumor growth and survival, and drug resistance. Objectives: Assess efficacy, safety, tolerability of SCIO-469 as M or MB in patients (pts) with relapsed and refractory multiple myeloma. Methods: Pts were treated with SCIO-469 alone (60 mg po tid)and assessed on Days 15, 30, 52 and 73. Bortezomib (1.0–1.3mg/m2 d 1,4,8,11 q21d) was added to M for PD or SD. Pts who had clinical benefit on either M or MB at Day 73 were allowed to continue on extension study for up to a total of 168 d, to further evaluate efficacy and saftey of M or MB. Results: 62 pts were enrolled: 39 M, 23 F, median age was 63 years (range 48–84), D-S stage at Dx: I (6%), II (32), III (60%%); median time from diagnosis to treatment 3.1 years; median # prior Rx = 5; including 29% with > 6; 71% prior transplant. 27 had received prior bortezomib and 17 were considered refractory. All 62 pts received study drug; 34 pts received MB at some time during the treatment period. 5 of the 28 (18%) pts treated with M and 25 of 34 (74%) pts treated with MB continued on the extension study. Median time on study was 77.5 d (range 7–304) for M and 180.5 d (range 34–275) for MB. Best response (EBMT; Blade 1998) to M was stable disease in 24% of pts; the best response to MB was 9/34 PR (26%), 2/34 MR (6%),3/34 SD (9%). Median time to progression (TTP) was 50 days for M compared to 140 days for MB. Safety/Tolerability: Adverse events on M were tabulated separately from those on MB. Neutropenia was minimal, < 3% with either regimen; anemia (47 vs 29%) and thrombocytopenia (26 vs 16%) were more prevalent with MB vs M, respectively. Epistaxis, fatigue and diarrhea were seen in > 15% of pts receiving M. Nausea, vomiting, diarrhea, constipation, abdominal pain, fatigue, pyrexia, anorexia, URI, arthralgia, muscle cramp, dizziness, peripheral neuropathy and headache occurred in > 15% pts receiving MB. 10 pts died on study, 9 during primary phase and 1 during extension phase. 3 deaths were the result of sepsis, the remaining 7 were due to progressive disease. Conclusions: SCIO-469, 60 mg tid, as monotherapy or in combination with Bortezomib was well tolerated. Although there were no objective responses in M (compared to 32% (11/34) in MB-including 4 patients who had failed prior bortezomib), 24% had stable disease at the end of monotherapy. Further studies to refine the dose of SCIO-469 as monotherapy and of SCIO-469 in combination with other agents are warranted.

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Gupta, P. S. P., S. Nandi, B. M. Ravindranatha, and P. V. Sarma. "Technical Report: Effect of commercially available PMSG on maturation, fertilization and embryo development of buffalo oocytes in vitro." Reproduction, Fertility and Development 13, no. 6 (2001): 355. http://dx.doi.org/10.1071/rd01026.

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In vitro fertilization (IVF) technology provides an opportunity to produce embryos for genetic manipulation, embryo transfer and basic research in developmental physiology, and can be exploited for emerging biotechnologies such as transgenesis and cloning. In the present study, the effects of different concentrations of commercially available pregnant mare serum gonadotrophin (PMSG) (Folligon; Intervet, International B.V., Boxmeer, Holland) in oocyte culture media, on maturation, fertilization and embryonic development of buffalo oocytes in vitro were investigated. Oocytes aspirated from abattoir-derived ovaries were cultured in media containing TCM-199 + PMSG at 0, 2.5, 20, 30, 40 and 50 IU mL–1 in presence or absence of steer serum (10%) for 24 h in a CO2 incubator. The maturation rate was assessed on the basis of degree of expansion of cumulus cells. The matured oocytes were inseminated with 9–10 x 106 spermatozoa mL–1 in Brackett and Oliphant medium and the cleavage rate was recorded 40–42 h after insemination. Uncleaved oocytes were stained with aceto-orcein for evaluation of fertilization rates. The cleaved embryos were further cultured in TCM-199 + 10% steer serum on buffalo oviducal cell monolayer for 7 days. Maturation, fertilization, cleavage and embryonic development were significantly higher (P<0.05) in oocytes cultured in TCM-199 + 10% steer serum supplemented with 40 and 50 IU PMSG mL–1. It is concluded that commercially available PMSG can effectively be used in place of pure follicle-stimulating hormone for in vitro maturation of buffalo oocytes, making it cost effective for IVF studies.

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Feldman, Rebecca, Sandeep K. Reddy, Zoran Gatalica, Joanne R. Mahanes, and Charles E. Myers. "Biomarker patterns of localized and metastatic prostate cancer." Journal of Clinical Oncology 33, no. 7_suppl (2015): 192. http://dx.doi.org/10.1200/jco.2015.33.7_suppl.192.

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192 Background: Presence or absence of metastases is a determining factor for prostate cancer prognosis. Common sites of metastasis include bone (B), lymph nodes (LN) or visceral organs (V). We sought to determine theranostic biomarker differences between primary (P) and metastatic (M) specimens, with subset analysis for differences between metastatic sites. Methods: 497 prostate cancer cases referred to Caris Life Sciences between 2009 thru 2014 were evaluated. Specific testing was performed and included a multiplatform approach: sequencing (Sanger, NGS), protein expression (IHC) and gene amplification (CISH/FISH). Results: 58% (287/497) were M specimens, of which 23% (66), 24% (68) and 52% (149) were from B, LN and V, respectively. Significant differences for EGFR amplification/overexpression, low MGMT expression, TOPO1/2A overexpression and higher PTEN mutation rate were found in the M subgroup. These alterations indicate a role for EGFR/PTEN in progression of prostate cancer, and potential role of MAPK/PAM-targeted therapies, alkylating agents and topoisomerase inhibitors in M disease. Mutational profiles of the M subgroup are more genetically unstable exhibiting mutations in 60% of genes tested (notable events include APC & β-Catenin, PTEN, TP53 and BRCA1/2) vs. 30% observed in the P subgroup (p=0.0067). In the subset analysis, EGFR amplification was higher in B (29%) and V (24%) compared to LN (13%); (not significant). Low TS expression was more frequent in B vs. LN (p=0.004), TOPO2A overexpression was higher in V vs. B (p=0.0001) and there was a trend for PD1 positive infiltrating lymphocytes being more abundant in LN vs B (p=0.09). Interestingly, cMET overexpression (7/230) and amplification (1/162) were rarely observed across the cohort, providing support for the surprising failure of cabozantinib in castration-resistant prostate cancer. Conclusions: Our data indicate a role for multiplatform profiling to identify therapeutic options that are appropriate for subsets of patients. Molecular changes associated with M disease including EGFR, PTEN, MGMT and TOPO1/2A, present opportunities for developing therapeutic strategies which may include a combination of targeted therapies, as well as traditional cytotoxic chemotherapies.

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Qun, Shen, and Ji Ou. "The Study On Apoptosis of the All-Trans-Retinoic Acid (ATRA)-Sensitive (NB4) Cells Induced by Puerariae Radix Flavones in Vitro." Blood 120, no. 21 (2012): 4922. http://dx.doi.org/10.1182/blood.v120.21.4922.4922.

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Abstract Abstract 4922 Background Puerariae radixis one of the main components of Xue-Fu-Kang, a Chinese native medicine group produced by Jiangsu Province Hospital of TCM, which has been the effective treatment in chronic myeloid leukemia and acute myeloid leukemia (AML). In the past five years, Prof. Shen Qun and her colleagues reported that four AML cells (Kasumi-1, HL-60, NB4 and U937) proliferations were inhibited by Puerariae radix flavones (PRF), an active component of Puerariae radix, but puerairin and Daidzin, the other two active components. The results showed that PRF can markedly inhibit the NB4 cells proliferation with arresting in S phase in vitro. PRF, acted synergy with ATO, could improve the life quality of Xenografts nude mice to some degrees in vivo. Objective To explore the effect of PRF±ATO on the proliferation and apoptosis in all-trans-retinoic acid (ATRA)-sensitive (NB4) cells, and the mechanism of PRF on retinoic receptor and the JNK signal pathway in the apoptosis of NB4 cells. Methods The cell vitality of NB4-R1 cells exposed with 0, 10, 30, 50μg/ml PRF±1μM ATRA for 24, 48, 72 hours and the proliferation of NB4 and NB4-R1 exposed with PRF±ATO for 24, 48, 72 hours were determined by MTT. Then, the NB4 and NB4-R1 cells were exposed with PRF group and PRF+ATO group for 48 hours. Cell apoptosis was determined by Wright's staining and confocal laser technique; cell cycle and apoptosis were analyzed by flow cytometry (FCM). JNK, TNFÁ, ERK and p38MAPK were examined by western blotting with interrupting or without interrupting JNK signaling pathway by pharmacological inhibitor (SP600125) for 48 hours in NB4 cells incubated with PRF. Results PRF (10, 30, 50μg/ml ± ATRA 1μM) inhibited the proliferation of NB4-R1 cells in time-dependent manners. There was no statistically difference in PRF IC50 between PRF group and PRF+ATRA group in 24, 48 and 72 hours (54. 25¡¢26. 68¡¢28. 55μg/ml, vs 59. 55¡¢28. 43¡¢26. 59μg/ml). PRF (10, 30, 50μg/ml ± ATO 1μM) inhibited the proliferation of NB4 and NB4-R1 cells in time- and dose-dependent manners. In NB4 cell line, PRF IC50 in 24¡¢48¡¢72h were 39. 82¡¢27. 45¡¢19. 27μg/ml, respectively; In the combined groups, IC50 were 29. 30¡¢21. 08¡¢7. 56μg/ml, respectively. In NB4-R1 cell line, PRF IC50 were 71. 66¡¢34. 29¡¢31. 44μg/ml, respectively; In the combined groups, IC50 were 38. 50¡¢24. 28¡¢16. 62μg/ml, respectively. The cells displayed distinct apoptotic characters by Wright's staining and confocal laser technique. Meanwhile, FITC-Annexin¢õ/PI double staining. The results indicated that PRF±ATO could induce NB4 and NB4-R1 cells to apoptosis, which presented dose dependent manner. Cell cycle process could be changed, with increasing cell in S phase and sub-diploid peak. The results in combined groups were more significantly. Interestingly, NB4-R1 cells treated with ATO 1μM group for 24h and 48h were proliferated, for 72h inhibited. PRF can induce apoptosis of NB4 cells accompanied by increased JNK1, JNK2/3, p38MAPK, ERK and TNFÁ. JNK inhibiting suppressed the activation of JNK1, JNK2/3 and p38MAPK, diminished ERK1/2 and TNFÁ expression in PRF 50μg/ml group, increased in 10μg/ml and 30μg/ml PRF groups. Conclusion These datas provide novel information on the PRF induced NB4 cells and NB4-R1 cells apoptosis. 0μg/ml to 50μg/ml PRF and also synergetic with 1μM ATO can induce the apoptosis of NB4 and NB4-R1 cells. PRF may evoke activation of MAPKs signaling pathway, by enhancing TNFÁ activation. JNK, ERK and p38MAPK, the three members of MAPK signaling pathway, but not retinoic receptor, may play an important role and influence each other in NB4 cells apoptosis induced by PRF. Disclosures: No relevant conflicts of interest to declare.

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Lopez Ruitti, Paula, Ruben Salanova, Julieta Nafissi, Guillermo Rabossi, Guillermo Bramuglia, and Yanina Powazniak. "Mutational status of KRAS and BRAF of an Argentinian population of colorectal tumors." Journal of Clinical Oncology 30, no. 15_suppl (2012): e14109-e14109. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.e14109.

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e14109 Background: Activating mutation of the KRAS oncogene is an established predictive biomarker for resistance to anti–epidermal growth factor receptor (anti-EGFR) therapies in advanced colorectal cancer (CRC). BRAF, another component of the EGFR-MAPK signal transduction pathway, is also subject to a common activating mutation in CRC. The aim of this report is to present the mutational status of KRAS, BRAF of an Argentinian population of CR tumors. Methods: Tumor blocks were obtained from 85 consenting patients of various public and private hospitals. We analyzed the presence of KRAS point mutations in codons 12 and 13, and the BRAF-V600E from formalin paraffin fixed sections with Polymerase Chain Reaction (PCR) amplification-sequencing. Results: From a total of 85 patients, 46% F and 54% M, with a median age of 64 years (range, 28-85), 72% (61) where found to be wild type, while the other 28% (24) showed the KRAS mutation in the following amino acids: G12V 30% (7), G12D 17% (4), G12C 17% (4), G12S 9% (2), G12A 4% (1), G13D 25% (6). We analyzed in 45 patients the mutational status of BRAF-V600E, 29 patients presented BRAF and KRAS wild type, 12 had a KRAS mutation while the BRAF was wild type, and 4 patients reveled a mutation of BRAF in the presence of a KRAS wild type. Conclusions: The type of mutation observed in this study corresponds to the findings of previous studies, where the most common KRAS mutation detected was G12V in codon 12 followed by G13D in codon 13. A preliminary report based in 146 patients from Argentine (Perazzo F, et al. 2009) revealed marked differences in KRAS mutation rates compared to our findings, showing the following percentage of mutations: G12V 62% vs. 30% , G12D 26% vs. 17% and G13R 1.7% vs. 0%, G13D 0% vs. 25%, respectively. BRAF mutational status was according to international and national reports.

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38

Gudasheva, T. A., P. Yu Povarnina, A. A. Volkova, S. V. Kruglov, T. A. Antipova, and S. B. Seredenin. "A Nerve Growth Factor Dipeptide Mimetic Stimulates Neurogenesis and Synaptogenesis in the Hippocampus and Striatum of Adult Rats with Focal Cerebral Ischemia." Acta Naturae 11, no. 3 (2019): 31–37. http://dx.doi.org/10.32607/20758251-2019-11-3-31-37.

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The nerve growth factor (NGF) and its mimetics, which have neuroprotective and neuroregenerative properties, are attractive candidates for developing new drugs for brain injury therapy. A dipeptide mimetic of NGF loop 4, bis(N-succinyl-L-glutamyl-L-lysine) hexamethylenediamide (GK-2), developed at the Zakusov Research Institute of Pharmacology, has the NGF-like ability to activate TrkA receptors, but unlike NGF, GK-2 activates mainly the PI3K/AKT pathway associated with neuroprotection and has no effect on the MAPK cascade associated with hyperalgesia, the main side effect of NGF. That GK-2 possesses neuroprotective activity has been observed in various models of cerebral ischemia. GK-2 was found to statistically significantly reduce the cerebral infarct volume in experimental stroke, even at treatment onset 24 h after injury. This suggests that GK-2 possesses neuroregenerative properties, which may be associated with the activation of neurogenesis and/or synaptogenesis. We studied the effect of GK-2 on neurogenesis and synaptogenesis in experimental ischemic stroke caused by transient occlusion of the middle cerebral artery in rats. GK-2 was administered 6 or 24 h after surgery and then once a day for 7 days. One day after the last administration, proliferative activity in the hippocampus and striatum of the affected hemisphere was assessed using Ki67 and synaptogenesis in the striatum was evaluated using synaptophysin and PSD-95. Ki67 immunoreactivity, both in the striatum and in the hippocampus of the ischemic rats, was found to have dropped by approximately 30% compared to that in the sham-operated controls. Synaptic markers - synaptophysin and PSD-95 - were also statistically significantly reduced, by 14 and 29%, respectively. GK-2 in both administration schedules completely restored the level of Ki67 immunoreactivity in the hippocampus and promoted its increase in the striatum. In addition, GK-2 restored the level of the postsynaptic marker PSD-95, with the therapeutic effect amounting to 70% at the start of its administration after 6 h, and promoted restoration of the level of this marker at the start of administration 24 h after an experimental stroke. GK-2 had no effect on the synaptophysin level. These findings suggest that the neurotrophin mimetic GK-2, which mainly activates one of the main Trk receptor signaling pathways PI3K/ AKT, has a stimulating effect on neurogenesis (and, probably, gliogenesis) and synaptogenesis in experimental cerebral ischemia. This effect may explain the protective effect observed at the start of dipeptide administration 24 h after stroke simulation.

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39

Khalessi Hosseini, Seyed Ali, Christy Morrissey, Takahiro Nakamura, and Daniel Jacob Becker. "Exploring the Cancer Genome Atlas (TCGA) for the molecular profile of young onset colorectal cancers." Journal of Clinical Oncology 38, no. 15_suppl (2020): 3548. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.3548.

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3548 Background: Colorectal cancer (CRC) incidence and mortality has been declining, in part due to increased implementation of screening, but the incidence among patients under 50 (young onset, YO) is increasing at a rate of 2% per year. The cause of this increasing incidence remains poorly understood, but differences in mutation profiles can help understand pathogenesis, prognosis, and identify targets for therapy. Methods: Genomic and clinical data for 488 TCGA CRC patients was used to evaluate differences in genetic alterations between YO and patients over 50. Chi-squared tests were used to determine differences in somatic mutation frequency in critical pathways implicated in CRC: DNA MMR, P53, WNT, RAS-MAPK, PI3K/AKT/mTOR, and TGF-B pathways. For 85 of the patients, proteomic data via RPPA was also available and analyzed. Results: The average age of included patients was 66 (SD 12.8). 76 (12.2%) were under 50 at time of diagnosis. When comparing YO with those over 50, there were no differences in microsatellite instability, histologic type (adeno or mucinous), location (colon or rectal), tumor size, or metastasis. YO patients were more likely to have nodal involvement (p = 0.007) and higher histological grade (p = 0.022). YO patients were more likely to have mutations in the MMR pathway (43% vs 23%, p = 0.002) and the PI3K/AKT/mTOR pathway (70% vs 54%, p = 0.024). Specifically, YO were more likely to have mutations in MSH2 (7% vs 1%, p = 0.001), MSH6 (24% vs 7%, p = 0.000); ATM (46% vs 30%, p = 0.015); FZD10 (7% vs 2%, p = 0.007); ERBB2 (15% vs 7%, p = 0.027); PIK3R1 (20% vs 9%, p = 0.014), PTEN (61% vs 35%, p = 0.000), and TGFBR2 (13% vs 4%, p = 0.004). When looking at proteomic data, YO were more likely to have decreased expression of MSH2 (p = 0.003) and MSH6 (p = 0.005). Conclusions: Patients with YO CRC are more likely to have somatic mutations in genes involved in the MMR pathway and the PI3K/AKT/mTOR pathway. Specifically, in MSH2, MSH6, ATM, FZD10, ERBB2, PIK3R1, PTEN and TGFBR2. When including proteomic data, significant differences were only seen in expression of MSH2/6. Some of these genes (e.g. ERBB2/HER2) are targets for existing therapies, and others are being actively investigated as potential therapeutic targets. Establishing differences in tumor genetic profiles is a first step towards understanding the increase in YO CRC, and simultaneously identifies targets for therapy. However, because of post-transcriptional changes (e.g. RNAi, methylation), genetic profiling alone cannot always reliably establish differences in protein expression, and thus therapy targets.

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40

Kavan, P., D. Melnychuk, A. Langleben, et al. "Phase I study of ECO-4601, a novel Ras pathway inhibitor." Journal of Clinical Oncology 25, no. 18_suppl (2007): 14128. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.14128.

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14128 Background: ECO-4601 is a structurally novel farnesylated dibenzodiazepinone with broad μM in vitro cytotoxic activity, and in vivo antitumor efficacy in rat glioma, hormone-independent human prostate, breast tumor xenograft tumor models. Preclinical data suggest ECO-4601 is a targeted anticancer drug with dual activity: selective binding to the peripheral benzodiazepine receptor (PBR), resulting in apoptosis, and inhibition of the Ras-MAPK pathway. Greatest efficacy was observed with continuous exposure, and a target plasma ECO-4601 efficacy concentration was determined. Preclinical toxicity studies did not demonstrate significant or dangerous side-effects. ECO-4601 is currently in phase I clinical trial testing to determine toxicity, pharmacologic profile and antitumor efficacy. Methods: ECO-4601 is administered as a 2-week continuous i.v. infusion (CIV), followed by 1 week off in repeated 21 day cycles. The trial includes dose- escalation and dose-extension portions, with comprehensive pharmacokinetics (PK) during the first cycle. Dose-escalation consists of increased doses in single pts until grade 3 toxicity is observed during cycle 1 of treatment, with up to five additional pts dosed to confirm dose-limiting toxicity (2/6 pts with grade 3 toxicities). The extension portion includes up to 15 pts at the dose determined in the first portion. Patients with a variety of cancers have been treated, including colorectal (10), ovarian (2), duodenal (1), and glioma (1). Results: ECO-4601 doses of 30, 60, 120, 180, 270, 360, and 480 mg/m2/day were evaluated in 14 patients. The number of cycles ranged from 1 to 8 with 7 pts completing at least 3 cycles of treatment. ECO-4601 is well tolerated and a maximum tolerated dose (MTD) has not been reached. Stable disease was observed in 6 of 7 evaluable pts; 4 colorectal, 1 ovarian, 1 duodenal. Preliminary PK shows steady state concentrations following 24 h CIV, dose proportionality, plasma concentrations above the preclinical efficacy threshold, rapid elimination post-infusion. Conclusions: ECO-4601 is a bifunctional targeting agent, against a novel combination of targets, that is well tolerated and demonstrates evidence of biological activity in an early phase clinical trial. The extension portion is currently ongoing. [Table: see text]

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41

Altermatt, J. L., T. K. Suh, J. E. Stokes, L. F. Campos-Chillon, and E. M. Carnevale. "271 EFFECT OF MARE AGE ON OOCYTE MORPHOLOGY AND DEVELOPMENTAL COMPETENCE AFTER INTRACYTOPLASMIC SPERM INJECTION." Reproduction, Fertility and Development 20, no. 1 (2008): 215. http://dx.doi.org/10.1071/rdv20n1ab271.

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Reduced fertility in aged mares is associated with delayed early embryo development and lower pregnancy rates, potentially related to oocyte developmental competence. Human oocyte morphology has been associated with developmental potential, although comparative evidence is lacking in the mare. Exogenous FSH may be beneficial in obtaining more oocytes; however, effects on oocyte morphology and competence are unknown. Objectives were to determine if zona pellucida thickness (ZPT), ooplasm volume (OV), and perivitelline space volume (PVSV) were related to mare age or FSH treatment and to cleavage, blastocyst, and pregnancy rates after intracytoplasmic sperm injection (ICSI). Cycles with and without eFSH treatment were alternated; eFSH treatments began in diestrus with a cohort of follicles ≥20 mm. Oocytes were collected by transvaginal aspiration from follicles >30 mm from young (4 to 9 years) and old (>20 years) mares at 20 to 24 h after administration of recombinant eLH. Oocytes were cultured for 18 h in TCM-199 at 38.5�C in 6% CO2 in air. Sperm were injected 40 � 1 h after eLH, using frozen sperm from a single ejaculate. Presumptive zygotes were incubated in Dulbecco's modified Eagle's medium/F12 + 10% fetal calf serum at 38.5�C in 5% CO2, 5%O2, and 90% N2. Cleavage (≥2 cells) was recorded 48 h after ICSI. Blastocysts considered viable (formation before 9 d and good quality) were transferred nonsurgically into recipients 3 to 7 days after ovulation. Only pregnancies of fetuses with heart beats were included. Morphological parameters of oocytes (old, n = 40; young, n = 37) were obtained from photographic images taken at ICSI and analyzed by computer-assisted measurement using digital calipers (Spot Software, Diagnostic Instruments, Inc., Sterling Heights, MI, USA). Zona pellucida thickness was averaged from 2 measurements 90� to 180� apart. Ooplasm volume was calculated (4/3πr3) from the average of 2 diameters of the ooplasm 90� apart; and PVSV was calculated as the difference of the vitelline membrane volume and that of the volume at the inner volume of the ZP calculated as an oblate spheroid (4/3πa2b) from the average of 2 diameters. Zona pellucida thickness, OV, and PVSV were analyzed using 2-way ANOVA for main effects of age and treatment and 3-way ANOVA by adding cleavage as a factor. Zona pellucida thickness was less (P = 0.007) for old compared with young (least squares mean SEM of 11.4 � 0.2 and 12.3 � 0.2 µm, respectively) with no effect on cleavage, blastocyst, or pregnancy rates. Ooplasm volume was not different (P = 0.14) between old and young (309 036 � 5373 and 320 544 � 5639 µm3, respectively) and did not affect cleavage, blastocyst, or pregnancy rates. The PVSV was greater (P = 0.001) in old compared with young (157 505 � 10 853 and 102 161 � 11 388 µm3, respectively) and may be related to the lower cleavage (P = 0.03), blastocyst (P = 0.02), and pregnancy (P = 0.05) rates. Treatment with FSH had no effect (P > 0.1) on morphology or embryo development. In this study, ZPT and PVSV differed with mare age and could be of predictive value for oocyte developmental competence.

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42

Kariminia, Amina, Sabine M. Ivison, Vivian Leung, Sandra E. Dunn, Aru Narendran, and Kirk R. Schultz. "YB-1 Is Activated by IL-7 and Is Overexpressed in Pediatric Pre-B Acute Lymphoblastic Leukemia." Blood 120, no. 21 (2012): 1468. http://dx.doi.org/10.1182/blood.v120.21.1468.1468.

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Abstract Abstract 1468 Background: Increased YB-1 expression correlates with poor prognosis, drug resistance and metastasis in several different cancers including B cell lymphoma. Phosphorylation and nuclear localization of YB-1 in response to growth factors leads to increased survival through expression of proteins such as survivin and multidrug resistance protein 1. Until now, its role in leukemia has not been investigated. We hypothesized that YB-1 expression is aberrantly regulated in pediatric pre-B acute lymphoblastic leukemia (pre-B ALL), and that YB-1 may be activated downstream of IL-7. This cytokine facilitates the differentiation and survival of pre-B cells and has been implicated in the drug resistance of pre-B ALL. Methods: YB-1 and IL-7Ra protein expression was investigated by flow cytometry in normal pre-B cells (CD19+CD10+CD20−), and mature B cells (CD19+CD10−CD20+) as well as diagnostic and relapsed pre-B ALL (CD19+CD10+/−). Cell surface and cytoplasmic expression was quantified by mean fluorescent intensity (MFI). Bone marrow from healthy donors was used as a source of normal pre-B cells, while mature B cells were derived from PBMCs; leukemic cells at presentation and relapse were obtained following local IRB approval and informed consent. Activation of YB-1 downstream of IL-7 stimulation (25 ng/ml) was examined in pre-B ALL cell lines or NSG (NOD scid gamma) mice-expanded pre-B ALL by Western blotting using anti-phosphoYB-1(S012). Pre-B ALL cell lines used in these experiments were 697, 380, RCH and RS-4;11. Signaling pathways were investigated by pre-treatment of cells with pharmacological inhibitors followed by Western analyses. For the transient overexpression of YB-1, pEGFP or a pEGFP/YB-1 fusion protein was electroporated into freshly isolated mature B cells (which have a low basal expression of YB-1) and YB-1 and IL-7Ra expression was assessed by flow cytometry after 24 h. Results: While intracellular YB-1 expression was significantly higher in leukemia samples at presentation compared to normal pre-B cells, the highest YB-1 levels were found in relapsed pre-B ALL (see figure, part A). All examined pre-B ALL cell lines had levels comparable to those of the relapse samples. Similarly, surface IL-7Ra (CD127) levels (MFI medians; upper-lower range) were increased in onset (221; 150–286), and relapsed (1840; 651–2030) ALL compared to normal pre-B cells (528; 333–2673). (normal pre-B vs. leukemia at presentation, p<0.001, Mann-Whitney). Overexpression of YB-1-GFP in normal mature B cells resulted in increased expression of IL-7Ra (see figure, part B), suggesting an link between the YB-1 and IL-7 signaling pathways. Activated YB-1 is phosphorylated on S102 and relocated to the nucleus. Addition of IL-7 to pre-B ALL cell lines led to phosphorylation of YB-1 within 30 min. Similar results were shown for patient-derived, NSG mice-expanded pre-B ALL samples. Intracellular immunostaining using Imagestream technology (Amnis) showed that IL-7 treatment of pre-B ALL cell lines increased nuclear YB-1 levels 4-fold. As PI3K and MEK1 are involved in signaling downstream of IL-7, we investigated their role in YB-1 signaling in both pre-B ALL cell lines and NSG-mouse expanded pre-B ALL using pharmacological inhibitors. Western analyses showed that inhibition of PI3K using LY294002 did not prevent IL-7-mediated phosphorylation of YB-1 but the MEK1 inhibitor U0126 did, indicating the involvement of MAPK (see figure, part C). Conclusion: We show that YB-1, which is highly expressed in pediatric pre-B ALL compared to normal pre-B cells, is expressed at even higher levels after relapse. We demonstrate a link between the YB-1 and IL-7 signaling pathways which could offer a novel target for the treatment of refractory leukemia. Disclosures: No relevant conflicts of interest to declare.

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43

Irvine, C. H. G., and S. L. Alexander. "The dynamics of gonadotrophin-releasing hormone, LH and FSH secretion during the spontaneous ovulatory surge of the mare as revealed by intensive sampling of pituitary venous blood." Journal of Endocrinology 140, no. 2 (1994): 283–95. http://dx.doi.org/10.1677/joe.0.1400283.

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Abstract Conflicting views exist on the mode of gonadotrophinreleasing hormone (GnRH) secretion during the ovulatory LH surge and the relative importance of changes in pituitary responsiveness to GnRH in generating the LH surge. This disagreement may stem from species differences and/or methodological problems. To provide data on the exact relationship between GnRH and gonadotrophin secretion during the spontaneous LH surge, we collected pituitary venous (PV) blood every 30 s for 3–4 h from eight mares and then assayed GnRH (in six of the mares), FSH and LH. Jugular blood was also collected from twelve mares without PV cannulae either thrice daily during the surge (n =8) or hourly for 24 h when close to ovulation (n=4) and assayed for LH. Hormone peaks in PV blood were detected by the Cluster program and PV hormone patterns were scanned for underlying periodicity using spectral analysis. Jugular LH concentrations rose slowly and steadily without abrupt increase during the prolonged ovulatory surge, suggesting that hormone secretory patterns seen during the periods of rapid sampling were typical of the surge. Jugular LH concentrations were similar in mares with and without PV cannulae. Intensive sampling of PV blood showed that GnRH, FSH and LH were secreted in frequent (two to five per h) brief (5–7 min) peaks. Secretion was not detectable in 24%, 28% and 57% of the total sampling time for GnRH, LH and FSH respectively. GnRH and LH peaks appeared to be irregular in time and amplitude in most mares. However, spectral analysis of the data revealed an underlying periodicity in the secretion of all three hormones, with the dominant period ranging from 20 to 65 min in individual mares. The spectra of GnRH, FSH and LH were highly coherent at this dominant frequency, and 90% of GnRH peaks were concurrent with LH peaks, which is consistent with the dogma that GnRH is the primary secretagogue for both FSH and LH. Although PV FSH and LH concentrations were closely correlated, PV GnRH and gonadotrophin concentrations were only weakly correlated, implying that there was no consistent relationship between the magnitudes of changes in GnRH and gonadotrophin secretion. When compared with our published mid-luteal phase values, the daily GnRH secretion rate during the LH surge was trebled, while the LH responsiveness to endogenous GnRH, as assessed by the between newly secreted LH and PV GnRH concentrations, was four times greater. We conclude that during the mare's ovulatory LH surge (1) GnRH, LH and FSH are secreted together, probably discontinuously, in frequent brief peaks, with the same underlying periodicity, which implies the existence of a pulse generator, (2) changes in pituitary responsiveness play an important role in generating the mare's LH surge, and (3) GnRH is the major signal for both FSH and LH secretion; however, other factors acutely modulate pituitary response to GnRH. Journal of Endocrinology (1994) 140, 283–295

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44

Shadman, Mazyar, Jeff P. Sharman, Moshe Y. Levy, et al. "Phase 2 Study of Zanubrutinib in Patients with Relapsed/Refractory B-Cell Malignancies Intolerant to Ibrutinib/Acalabrutinib." Blood 136, Supplement 1 (2020): 51–52. http://dx.doi.org/10.1182/blood-2020-134621.

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Background: Bruton tyrosine kinase (BTK) inhibitors (BTKi) have been shown to improve outcomes in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL); however, adverse events (AEs) were the most common reason for ibrutinib and acalabrutinib discontinuation (median time ≤6 mo; Mato et al, Haematologica 2018;103:874; Yazdy et al, Blood 2019; Supplement1: 4311). Off-target effects of ibrutinib have been implicated in BTKi-related AEs. Zanubrutinib, a BTKi approved for treatment of mantle cell lymphoma (MCL) and in development for other hematologic malignancies, was specifically engineered to optimize selectivity and maximize BTK occupancy. In the head-to-head ASPEN trial of zanubrutinib vs ibrutinib in patients with Waldenström macroglobulinemia (WM), zanubrutinib showed a lower rate of AEs leading to death, discontinuation, dose reduction, and dose holds (Dimopoulos et al, EHA 2020; Abstract S225). We conducted a prospective clinical trial of zanubrutinib in patients with relapsed/refractory B-cell malignancies who have become intolerant to prior BTKi (ibrutinib and/or acalabrutinib) therapy. Methods : In this ongoing phase 2, multicenter, US, single-arm, open-label study (NCT04116437; BGB-3111-215), the safety and efficacy of zanubrutinib monotherapy (160 mg twice daily or 320 mg once daily) is being evaluated in patients with B-cell malignancies who meet requirements for treatment and have become intolerant to prior BTKi therapy. An intolerant event was defined as an unacceptable toxicity where, in the opinion of the investigator (INV), treatment should be discontinued despite optimal supportive care as a result of 1 of the following: grade ≥2 nonhematologic toxicities for &gt;7 days (with or without treatment), grade ≥3 nonhematologic toxicity of any duration, grade 3 neutropenia with infection or fever, or grade 4 hematologic toxicity that persists to the point that the INV chose to stop therapy due to toxicity and not disease progression (PD). All enrolled patients must not have documented PD during prior BTKi therapy. Response assessment was evaluated by INV for CLL per modified International Workshop on CLL criteria (Hallek et al, Blood 2008;131:2745; Cheson et al, J Clin Oncol 2012;30:2820), for SLL, MCL, and marginal zone lymphoma per Lugano criteria (Cheson et al, J Clin Oncol 2014;32:3059), and for WM per modified 6th International Workshop on WM criteria (Owen et al, Br J Haemtol 2013;160:171). Disease parameters (imaging and laboratory parameters) performed at study entry were used as the baseline for response assessment. Results : As of 01 June 2020 (data cutoff), 17 patients with CLL/SLL were enrolled, received ≥1 dose of zanubrutinib, and were analyzed for safety. Median age was 70 years (range, 49-91) and median duration of treatment exposure was 3.02 mo (range, 0.56-7.59). The median number of prior regimens was 1 (range, 1-3). All patients had received ibrutinib. At data cut off, no patients had received acalabrutinib. At data cutoff, 16 patients remained on zanubrutinib treatment. One patient withdrew herself from the study following an AE (grade 3 syncope) unrelated, as per INV, to study treatment. Of the 31 BTKi-related AEs associated with intolerance (Table 1), 30 (96.8%) did not recur, and 1 event (3.2%; atrial fibrillation) recurred at a lower grade (grade 3 vs 2) and for a shorter duration (14 vs 3 days) vs the initial ibrutinib-intolerant event. Ten patients (58.8%) reported ≥1 AE. AEs reported in ≥10% of patients on zanubrutinib included dizziness (n=3; 17.6%) and cough (n=2; 11.8%). Grade ≥3 AEs were reported in 2 patients (11.8%): neutropenia and syncope (n=1 each; 5.9%). AEs of interest included hemorrhage and infections (n=3 each, 17.6%) and anemia, neutropenia, and atrial fibrillation (n=1 each; 5.9%). No AEs led to dose modification or treatment discontinuation. No serious AEs or deaths were reported. As of data cutoff, 10 patients were evaluable for efficacy with ≥1 response assessment. All 10 patients achieved at least stable disease, and 60% of these patients achieved a deepening of response since initiating zanubrutinib. Enrollment is ongoing and the presentation will include additional patients. Conclusions : Zanubrutinib demonstrated efficacy and tolerability in CLL/SLL patients who were intolerant to previous BTKi. These data suggest that zanubrutinib may provide a potential option after intolerance to other BTKi. Disclosures Shadman: Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; ADC Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Atara Biotherapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Cellectar: Consultancy, Membership on an entity's Board of Directors or advisory committees; Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol Meyers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; TG therapeutics: Research Funding; Sound Biologics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Mustang Bio: Research Funding; MophoSys: Consultancy, Membership on an entity's Board of Directors or advisory committees; Acerta Pharma: Ended employment in the past 24 months; Sunesis: Research Funding; Gilead: Research Funding. Sharman:Celgene: Consultancy, Research Funding; Bristol Meyers Squibb: Consultancy, Research Funding; BeiGene: Research Funding; Roche: Consultancy, Research Funding; Acerta: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding. Levy:Amgen: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding; Bristol Meyers Squibb: Consultancy, Honoraria, Research Funding; BeiGene: Consultancy, Research Funding, Speakers Bureau; AbbVie: Consultancy, Honoraria, Research Funding; Baylor University Med Center: Current Employment; Takeda: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding. Misleh:Medical Oncology Hematology Consultants (MOHC): Current Employment; High Mark Blue Cross: Membership on an entity's Board of Directors or advisory committees. Zafar:Bristol Meyers Squibb: Honoraria, Other: TRAVEL, ACCOMODATIONS, EXPENSES (paid by any for-profit health care company); AstraZeneca: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Karyopharm: Honoraria; Sarah Canon Research Institute: Research Funding; Florida Cancer Specialists and Research Institute: Current Employment. Freeman:Summit Medical Group: Current Employment. Burke:Kura: Consultancy; Celgene: Consultancy; Gilead: Consultancy; Adaptive: Consultancy; Morphosys: Consultancy; Bristol Myers Squibb: Consultancy; Roche: Consultancy; AbbVie: Consultancy; Bayer: Consultancy; Astra Zeneca: Consultancy; Verastem: Consultancy; Epizyme: Consultancy; Seattle Genetics: Speakers Bureau; Adaptive Biotechnologies: Consultancy. Cultrera:Amgen: Speakers Bureau; Florida Cancer Specialists + Research Institute: Current Employment; Celgene: Speakers Bureau; AcroTech: Speakers Bureau; Verastem: Speakers Bureau. Yimer:BeiGene: Other: TRAVEL, ACCOMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding, Speakers Bureau; Takeda: Speakers Bureau; Sanofi: Speakers Bureau; Epizyme: Consultancy, Divested equity in a private or publicly-traded company in the past 24 months; Texas Oncology: Current Employment; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Speakers Bureau; Karyopharm: Consultancy, Divested equity in a private or publicly-traded company in the past 24 months, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Speakers Bureau; TG Therapeutics: Consultancy; Janssen: Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding, Speakers Bureau; Celgene, a Bristol-Myers Squibb Company: Consultancy, Membership on an entity's Board of Directors or advisory committees. Chen:BeiGene: Current Employment, Current equity holder in publicly-traded company. Zhang:BeiGene: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months. Cohen:BeiGene: Current Employment, Current equity holder in publicly-traded company, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Ro:BeiGene: Current Employment, Current equity holder in publicly-traded company; Amgen: Current equity holder in publicly-traded company. Huang:BeiGene: Current Employment, Current equity holder in publicly-traded company, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Flinn:Iksuda Therapeutics: Consultancy; Loxo: Research Funding; Kite Pharma: Consultancy, Research Funding; Karyopharm Therapeutics: Research Funding; IGM Biosciences: Research Funding; Infinity Pharmaceuticals: Research Funding; Unum Therapeutics: Consultancy, Research Funding; Juno Therapeutics: Consultancy, Research Funding; Acerta Pharma: Research Funding; Incyte: Research Funding; Janssen: Consultancy, Research Funding; Great Point Partners: Consultancy; Genentech, Inc.: Research Funding; AstraZeneca: Consultancy, Research Funding; ArQule: Research Funding; Agios: Research Funding; Takeda: Consultancy, Research Funding; Forty Seven: Research Funding; Calithera Biosciences: Research Funding; BeiGene: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; Trillium Therapeutics: Research Funding; Triphase Research & Development Corp.: Research Funding; Verastem: Consultancy, Research Funding; Yingli Pharmaceuticals ≠: Consultancy, Research Funding; Rhizen Pharmaceuticals: Research Funding; Johnson & Johnson: Other; Roche: Consultancy, Research Funding; Vincera Pharma: Consultancy; Celgene: Research Funding; Merck: Research Funding; Constellation Pharmaceuticals: Research Funding; Curio Science: Consultancy; MorphoSys: Consultancy, Research Funding; Curis: Research Funding; AbbVie: Consultancy, Research Funding; Teva: Research Funding; Pfizer: Research Funding; Nurix Therapeutics: Consultancy; Novartis: Research Funding; Seattle Genetics: Consultancy, Research Funding; Portola Pharmaceuticals: Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; Forma Therapeutics: Research Funding; F. Hoffmann-La Roche: Research Funding; Gilead Sciences: Consultancy, Research Funding. OffLabel Disclosure: Zanubrutinib has not been approved for R/R CLL/SLL, MZL, and WM in the US

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De Roock, W., M. Janssens, B. Biesmans, et al. "DUSPs as markers of MEK/Erk activation in primary colorectal cancer." Journal of Clinical Oncology 27, no. 15_suppl (2009): 4064. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.4064.

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4064 Background: DUSPs dephosphorylate P-MAPK and are activated as a negative feedback loop upon RTK signaling. Higher expression of DUSP 4 & 6 is also found in cells with constitutive Erk activation like KRAS mutant (MUT) cells (Bild et al. Nature 2005). We correlated DUSP1, 4, 6 (isoforms a & b) & 8 mRNA expression level in FFPE primary colorectal cancer (CRC) of 186 chemorefractory patients treated with cetuximab (CTX) with KRAS MUT state and progression-free survival (PFS) and overall survival (OS). Methods: KRAS codon 12,13, 61&146, BRAF V600E and NRAS codon 12&13 MUT were analyzed with the Sequenom MALDI TOF MassArray system. The DUSPs and 3 housekeeping genes were quantified by qRT-PCR. TwoStep cluster analysis was performed. PFS and OS were estimated by the Kaplan-Meier method. Results: KRAS MUT was associated with increased DUSP4 (MWU;p=.0006) & 6a (p=.0067). DUSP6a dephosphorylates P-Erk, DUSP4 also dephosphorylates P-JNK & P-p38. DUSP1 & 8 primarily dephosphorylate P-JNK & P-p38 and were not associated with KRAS MUT. KRAS MUT clustered into 3 groups according to DUSP4 expression: 32 high, 38 median & 13 low (t- test;p<.0001). The low MUT expression was comparable to wild-type (WT) expression. KRAS WT clustered into 2 groups: 69 low & 24 high DUSP4 (ANOVA;p<.0001). 7/24 of high expressors were found to have a BRAF or NRAS MUT. The 32 MUT high expressors had a longer median PFS (log-rank;p=.015) and OS (p=.065) after CTX. The 17 KRAS/BRAF/NRAS WT high expressors had a shorter median OS (p=.026), but not PFS (p=.745). Conclusions: There is a significantly higher DUSP4 & 6a mRNA expression in the KRAS MUT compared to WT primary CRC. However, this is not a black and white observation. In the KRAS MUT there are 3 distinct clusters of DUSP4 expression. The high expressors (= supposed attenuated Erk signaling) have a longer PFS and OS after CTX. Adaptation to constitutive KRAS signaling with differential levels of MEK/Erk activation needs to be further investigated and will be of help in selecting patients for therapy with MEK inhibitors. It suggests not all KRAS MUT will be good candidates for MEK inhibitors. In the cluster of high DUSP4 expressing KRAS WT 30% are BRAF or NRAS MUT. This suggests DUSP expression of FFPE samples could be a more sensitive marker of MEK/Erk activation and resistance to EGFR inhibitors than KRAS MUT analysis alone. [Table: see text]

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Shin, Sang Joon, Jeeyun Lee, Tae Min Kim, et al. "A phase Ib trial of belvarafenib in combination with cobimetinib in patients with advanced solid tumors: Interim results of dose-escalation and patients with NRAS-mutant melanoma of dose-expansion." Journal of Clinical Oncology 39, no. 15_suppl (2021): 3007. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.3007.

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3007 Background: Belvarafenib, a potent, selective RAF dimer (type II) inhibitor, exhibits clinical activity in BRAFV600E- and NRAS-mutant (NRASm) melanoma patients. The combination of belvarafenib and cobimetinib more potently and durably suppressed MAPK pathway output and tumor growth than currently approved BRAF/MEK inhibitors in RAS- or RAF-mutant tumor xenograft models. This interim results of phase 1b trial evaluated the safety, tolerability, pharmacokinetics, and anti-tumor activity of belvarafenib in combination with cobimetinib in dose-escalation and NRASm melanoma patients among the 9 indication-specific expansion cohorts. Methods: Patients with locally advanced or metastatic solid tumors harboring RAS or RAF mutation were enrolled in the dose-escalation stage, and the recommended doses were explored in the indication-specific expansion stage. Patients in the dose-escalation stage were given belvarafenib (100–300mg BID) in combination with cobimetinib (20–40mg QD) and the dose of subsequent cohorts was decided by a traditional 3+3 design and safety profile. Primary objectives were to evaluate the safety and tolerability, to estimate the maximum tolerable dose, and to identify the RP2D of the combination. Results: A total of 32 patients enrolled were evaluated for safety analysis; 19 were enrolled in 4 cohorts in the dose-escalation stage and 13 NRASm melanoma patients were enrolled in the indication-specific expansion stage (cut-off date: 2020-7-24). There were 3 DLTs (G3 colitis, G3 diarrhoea, G3 nausea) in 2 patients at the starting dose of belvarafenib 200mg BID continuously and cobimetinib 40mg QD 21/7 schedule. Belvarafenib dose was escalated to 300mg BID with cobimetinib 20mg QD, which did not result in DLTs. The most common treatment-emergent adverse events that occurred in ≥30% of 32 patients were dermatitis acneiform, diarrhoea, constipation, and increase in blood creatine phosphokinase. Two combination doses were explored in the indication-specific expansion stage. Out of the 9 indication-specific expansion cohorts, NRASm melanoma patients exhibited promising efficacy signal; 5 patients reached partial responses (PRs) out of 13, giving a response rate of 38.5%. Among them, 11 had been previously treated with checkpoint inhibitors (CPIs), including 5 (45.5%) who achieved PR. The median PFS was 7.3 months and 5 patients remained on the treatment at the cut-off date. Conclusions: Belvarafenib in combination with cobimetinib showed acceptable tolerability and encouraging efficacy in NRASm melanoma, and in those with prior CPI treatment. Further research is ongoing in other cohorts (Clinicaltrial.gov, NCT03284502) and in NRASm melanoma (reference GO42273 by clinicaltrials.gov ID number). *S.J.S and J.L contributed equally to this work. Clinical trial information: NCT03284502.

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Wainberg, Zev A., Ulrik Niels Lassen, Elena Elez, et al. "Efficacy and safety of dabrafenib (D) and trametinib (T) in patients (pts) with BRAF V600E–mutated biliary tract cancer (BTC): A cohort of the ROAR basket trial." Journal of Clinical Oncology 37, no. 4_suppl (2019): 187. http://dx.doi.org/10.1200/jco.2019.37.4_suppl.187.

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187 Background: BTCs are rare, aggressive malignancies with poor prognoses. Treatment options and outcomes after first-line therapy are not well defined. Median progression-free survival (PFS) in second-line BTC is < 5 mo. Combined BRAF + MEK inhibition is efficacious in BRAF V600–mutated anaplastic thyroid cancer, melanoma, and lung cancer, but less so in BRAF V600E-mutated colorectal cancer. Activating BRAF V600E mutations have been reported in 0% to 20% of BTCs; thus, D (BRAF inhibitor) + T (MEK inhibitor) was evaluated as a treatment for pts with BRAF V600E–mutated BTC in the ROAR basket trial. Methods: In this phase II, open-label trial, pts with BRAF V600E mutations in 9 rare tumor types, including BTC, received D (150 mg BID) + T (2 mg QD) until unacceptable toxicity, disease progression, or death. Eligible pts had advanced or metastatic cancer and had been treated with ≥ 1 prior systemic therapy. The primary endpoint was investigator-assessed overall response rate (ORR). Secondary endpoints included duration of response (DOR), PFS, overall survival (OS), biomarker correlates, and safety. Results: Thirty-three pts with BTC had enrolled at data cutoff (January 3, 2018). BRAF V600E mutations were centrally confirmed in 30 of 33 pts with BTC (91%). Median age was 58 y, and 78% had received ≥ 2 prior lines of systemic therapy. 32 of 33 pts with BTC were evaluable. Investigator-assessed ORR was 41% (13/32; 95% CI, 24%-59%), with 6 of 13 responses ongoing at data cutoff, 7 of 13 pts (54%) had a DOR ≥ 6 mo. Median PFS was 7.2 mo (95% CI, 4.6-10.1 mo), and median OS was 11.3 mo (95% CI, 7.3-17.6 mo). Grade 3/4 adverse events in ≥ 3 pts were increased γ-glutamyltransferase (n = 3 [9%]) and decreased white blood cell count (n = 3 pts [9%]). Biomarker analyses demonstrate a heterogeneous genetic landscape, and suggest a higher baseline expression of MAPK pathway genes in the pts who did not respond to D + T. Conclusions: D + T demonstrated promising efficacy in pts with BTC, with a favorable safety profile. These pts should be considered for BRAF mutation analysis, and D + T should be considered for pts with BRAF V600E-mutated BTC. Clinical trial information: NCT02034110.

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Roubille, C., A. Coffy, N. Rincheval, et al. "OP0116 TEN-YEAR ANALYSIS OF VERY LOW-DOSE GLUCOCORTICOIDS IN EARLY RA (ESPOIR COHORT) SUPPORTS A TIME-DEPENDENT RISK OF SEVERE OUTCOMES." Annals of the Rheumatic Diseases 79, Suppl 1 (2020): 76.2–77. http://dx.doi.org/10.1136/annrheumdis-2020-eular.3917.

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Background:We previously failed to find any significant difference with regard to severe outcomes (death, severe infections, fractures, cardiovascular diseases [CVD]) between recent-onset RA patients taking or not low-dose GC treatment in a 7-year analysis of the ESPOIR cohort (1).Objectives:To explore the 10-year tolerability profile of GC use in patients with early RA.Methods:We analysed data from the early arthritis (less than 6 months disease duration) ESPOIR cohort. Patients were stratified in two groups, with or without GC treatment at least once during their follow-up (median 10 years IQR [9-10]). The primary outcome was a composite of death, CVD (including myocardial ischemia, cerebrovascular accident and heart failure), severe infection and fracture. In order to reduce the impact of treatment selection bias and potential confounding factors, the weighted Cox time-dependent analysis model was used with inverse probability of treatment weighting (IPTW) propensity score method.Results:Among the 608 RA patients (480 women, mean age of 47.5 ± 12.1 years), 397 patients (65%) received low-dose prednisone (median 1.9 mg/day [IQR 0.6-4.2], mainly during the first 6 months (70%). The mean duration of GC treatment was 44.6 months ± 40.1. Overall, 95 events were identified during follow-up: 10 deaths, 18 CVD, 32 fractures and 35 severe infections. Based on univariate analysis at 10 years, patients taking GC experienced significantly more events (n=71) than those without GC (n=24) (p=0.035), especially severe infections (n=30 with GC versus 5 without GC, p=0.009) (table 1), with a cumulative dose effect (p=0.007).On weighted Cox time-dependent analysis, using the IPTW propensity score method, the risk of events over time was significantly associated with GC treatment (p <0.001), age, history of hypertension and erythrocyte sedimentation rate. The risk associated with GC treatment, estimated by the hazard ratio (HR), increased between the first follow-up visit (HR at 6 months = 0.39, 95% CI 0.19-0.82) and 10 years (HR=6.83, 95% CI 2.29-20.35) (figure 1 and table 2).Table 1.Primary outcome and events at 10 years: univariate analysisTotal study population (n=608)Without GCWith CGP ValuePrimary outcome95 (15.6%)24 (11.4%)71 (17.9%)0.035Death10 (1.6%)1 (0.5%)9 (2.3%)0.103Cardiovascular diseases18 (3%)3 (1.4%)15 (3.8%)0.177Severe infections35 (5.8%)5 (2.4%)30 (7.6%)0.009Fractures32 (5.3%)15 (7.1%)17 (4.3%)0.137Table 2.Time-dependent relationship between glucocorticoids treatment and risk of eventsestimated by hazard ratioTime (Months)Hazard Ratio (95% CI)120.46 (0.23 - 0.90)240.62 (0.36 - 1.08)360.83 (0.52 - 1.33)481.12 (0.73 - 1.72)601.52 (0.96 - 2.40)722.05 (1.19 - 3.52)842.77 (1.44 - 5.34)963.74 (1.69 - 8.26)1085.05 (1.98 - 12.91)1206.83 (2.29 - 20.35)Figure 1.Time-dependent relationship between glucocorticoids treatment and risk of eventsestimated by hazard ratio (HR)Conclusion:This 10-year analysis of the ESPOIR cohort supports a dose and time-dependent impact of very low-dose GC treatment in early RA, with a long-term high risk of severe outcomes.Disclosure of Interests:Camille Roubille Consultant of: Servier, Pfizer, Novartis, Amandine Coffy: None declared, Nathalie Rincheval: None declared, Maxime Dougados Grant/research support from: AbbVie, Eli Lilly, Merck, Novartis, Pfizer and UCB Pharma, Consultant of: AbbVie, Eli Lilly, Merck, Novartis, Pfizer and UCB Pharma, Speakers bureau: AbbVie, Eli Lilly, Merck, Novartis, Pfizer and UCB Pharma, Rene-Marc Flipo Speakers bureau: Novartis, Janssen, Lilly, Jean-Pierre Daures: None declared, Bernard Combe Grant/research support from: Novartis, Pfizer, Roche-Chugai, Consultant of: AbbVie; Gilead Sciences, Inc.; Janssen; Eli Lilly and Company; Pfizer; Roche-Chugai; Sanofi, Speakers bureau: Bristol-Myers Squibb; Gilead Sciences, Inc.; Eli Lilly and Company; Merck Sharp & Dohme; Pfizer; Roche-Chugai; UCB

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Wang, Ying, Jianxun Lei, and Kalpna Gupta. "Targeting Central Mechanisms of Pain to Improve Acupuncture Analgesia in a Humanized Mouse Model of Sickle Cell Disease." Blood 132, Supplement 1 (2018): 1064. http://dx.doi.org/10.1182/blood-2018-99-115577.

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Abstract Background: Pain is one of the major comorbidities of sickle cell disease (SCD), which largely remains reliant on opioid use for analgesia. Side effects of opioids including, but not limited to fear of addiction, constipation, pruritus and opioid-induced hyperalgesia warrant the need for analgesic therapies devoid of side effects. Non-pharmacological strategies including acupuncture have been effective in pain treatment. A retrospective analysis (n=24 patients) showed that acupuncture reduced pain in a majority (75%) of SCD patients (Lu K et al., Clin J Pain. 2014). In a mouse model of SCD, electroacupuncture (EA) on conscious free-moving mice led to variable analgesic response ranging from high- (nociceptive threshold increase >200%), moderate- (threshold between 100~200%) to non-responders (threshold increase ≤100%) (Wang Y et al., Sci Rep. 2016). Substance P (SP), a proinflammatory vasoactive neuropeptide in the periphery and centrally and spinal activated p38 mitogen activated protein kinase (MAPK), critical mediators of chronic pain were significantly increased in sickle mice with moderate or no response to EA analgesia. Increased circulating SP has been reported in SCD patients at steady state and during chronic pain. We hypothesize that chronic pain in moderate- and non-responders is due to central sensitization mediated by SP-induced p38 MAPK phosphorylation; and that inhibiting the effect of SP and/or downstream p38 MAPK signaling would improve response to EA in moderate and non-responsive sickle mice. Methods: HbSS-BERK sickle mice expressing human sickle hemoglobin without any treatment and those showing moderate- (threshold between 100~200%) and no-response (threshold increase ≤100%); and HbAA-BERK control mice that express normal human hemoglobin A were used. All groups included mice of both genders at 5-7 months of age and were treated daily with 10 mg/kg, i.p. netupitant (antagonist of neurokinin 1 receptor, a receptor for SP), or SB203580, a p38MAPK inhibitor, with or without four sequential EA treatments (every 3rd day, frequency: 4 or 10 Hz, pulse width: 100 microsecond, duration: 30 min) at acupoint GB30. Hyperalgesia was evaluated daily before starting the inhibitor/EA treatment (baseline, BL) and after treatments throughout 12 days by determining the sensitivity to mechanical-, thermal- and deep tissue-stimuli using von Frey filaments, Hargreaves test, cold plate and grip force, respectively. Results: Sickle mice showing no- or moderate responsive to EA did not demonstrate a significant effect of netupitant or SB203580 without EA on hyperalgesia. However, co-treatment with netupitant and EA reduced mechanical, thermal and deep tissue hyperalgesia through the entire treatment, reaching significance at day 9 and/or day 12. Co-treatment with netupitant enhanced analgesia of EA by significantly decreasing mechanical hyperalgesia (p<0.05 vs untreated sickle or moderate-responder + netupitant) and heat sensitivity (p<0.05 vs BL) at day 9, cold sensitivity (p<0.05 vs BL) at day 12 for both moderate- and non-responders. Deep tissue hyperalgesia for co-treated moderate-responders (p<0.05 vs BL) was significantly reduced at day 9, while the reduction observed with co-treated non-responders (p<0.05 vs BL) only reached significance on day 12. These data suggest that SP mediates sustained chronic pain in SCD, which imparts resistance to EA analgesia. Co-treatment with SB203580 and EA together decreased heat sensitivity (p<0.05 vs BL) at day 9, mechanical hyperalgesia (p<0.05 vs BL or moderate-responder + EA) and cold sensitivity (p<0.05 vs BL) at day 12 and deep tissue hyperalgesia for moderate-responders (p<0.05 vs BL) at day 9 and 12 and non-responders (p<0.05 vs BL) at day 12. Therefore, central sensitization with increased p38MAPK phosphorylation perhaps mediated by high SP levels prevents the responsiveness to EA. Conclusion: Increased SP-induced spinal p38MAPK activation may underlie poor responsiveness to EA and perhaps other analgesic therapies in SCD. Therefore, inhibition of SP or p38 MAPK may improve analgesic outcomes with EA. Circulating SP levels may also be predictive of response to EA and/other analgesic therapies. Co-treatment strategies using acupuncture with mechanism-based targets of central sensitization may be potentially beneficial in treating pain and reducing opioid use in SCD. Disclosures Gupta: Tau tona: Consultancy; Novartis: Honoraria.

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Fine, Robert, Yoomi Lee, William H. Sherman, et al. "Prospective phase II trial of GTX in metastatic pancreatic cancer: Laboratory and clinical studies." Journal of Clinical Oncology 31, no. 4_suppl (2013): 209. http://dx.doi.org/10.1200/jco.2013.31.4_suppl.209.

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209 Background: We found that in pancreatic cancer (PC) cells, when gemcitabine, docetaxel, capecitabine (GTX) are given in a sequence and time specific manner, it 1) increased Bax, Bak, Fas and decreased Bcl-2 and Bcl-XL expression; 2) increased hENT-1 expression >8 fold, which increased intracellular gemcitabine accumulation by 220%; 3) specifically inhibited MEK to ERK phosphorylation (p-MEK) by >70%. Methods: From this pre-clinical data, we developed the GTX regimen utilizing: capecitabine 750 mg/m2/BID capped at 2500mg/day for days 1-14; on days 4 and 11 gemcitabine at 750mg/m2 given over 75mins (FDR), followed by docetaxel at 30mg/m2. Week 3 is off all drugs. Forty four patients with previously untreated metastatic PC were enrolled and followed until death. ECOG PS was: 0(2%), 1(63%), 2(35%), and median age was 60 (33-72). Over 85% of patients had >3 liver metastases. Results: Median response rate (RR) was 38% with 14% CR in metastatic or primary sites and 40% stable disease using RECIST 1.0 indices. Median PFS was 6.9 months and median OS was 14.5 months. After failing GTX, 80% of patients received our second line synergistic regimen called ICM (irinotecan 80mg/m2 and cisplatin 25mg/m2 on days 1 and 8, and mitomycin C 5mg/m2 on day 1 only, out of a 28 day cycle). The 6, 12, 18, 24, 30 and 36 month survival on GTX was 77, 59, 35, 16, 14 and 7%, respectively. Grade3/4 toxicities were: leukopenia (32%), neutropenia (29%), febrile neutropenia (3%), anemia (12%), thrombocytopenia (12%), diarrhea (5%), HFS (3%), fatigue (8%), and mucositis (8%). GTX inhibited MEK to ERK phosphorylation (P-MEK). We performed IHC (0-4+) for P-MEK in 16 patients and found high P-MEK (3-4+) correlated with an 85% RR while low P-MEK (0-1+) correlated with a 90% rate of PD to GTX. Conclusions: GTX is an effective regimen for metastatic PC with durable RR, PFS, OS rates, and acceptable toxicities. IHC for P-MEK seems to be a good biomarker to identify subsets of patients who will respond to GTX. GTX is a rationally designed regimen derived from lab studies. GTX increases pro-apoptotic and decreases anti-apoptotic proteins, inhibiting MEK to ERK in the MAPK pathway. Clinical trial information: NCT00996333.

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