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Journal articles on the topic '379.2/4/0941'

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Published: 29 July 2024

Last updated: 31 July 2024

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1

Sarker, D., R. Kristeleit, K. E. Mazina, J. A. Ware, Y. Yan, M. Dresser, M. K. Derynck, and J. De-Bono. "A phase I study evaluating the pharmacokinetics (PK) and pharmacodynamics (PD) of the oral pan-phosphoinositide-3 kinase (PI3K) inhibitor GDC-0941." Journal of Clinical Oncology 27, no. 15_suppl (May 20, 2009): 3538. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.3538.

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3538 Background: The PI3K-PTEN-AKT signaling pathway is deregulated in a wide variety of cancers. GDC-0941 is a potent and selective oral inhibitor of class I PI3K and demonstrates activity in a broad range of preclinical models (breast, ovarian, lung, and prostate). Methods: Patients (pts) with histologically confirmed advanced solid tumors and ECOG PS 0–1 were treated with GDC-0941 using a 3+3 escalation design at a single institution. Treatment was a single dose with 1wk washout, followed by GDC-0941 qd on a 3wk on, 1wk off schedule. Objectives were to determine MTD and DLT, evaluate PD endpoints in surrogate (pAKT in platelet rich plasma) and tumor (pAKT and pS6 in paired tumor biopsies and FDG uptake via PET imaging) tissues, and describe anti-tumor activity. Results: Thirteen patients have been enrolled in 4 successive cohorts (15–60 mg qd). GDC-0941 was generally well-tolerated with no drug related Grade 3 or 4 AEs or DLTs to date. Grade 1 diarrhea, nausea, dysgeusia, peripheral sensory neuropathy, dry mouth, thrombocytopenia, and increased aspartate aminotransferase have been observed. Preliminary PK data suggest dose-proportional increases in fasting mean Cmax and AUC. Preliminary PD data show decreased levels of pAKT in platelet rich plasma correlated with GDC-0941 plasma concentrations. GDC-0941 effects on FDG-PET imaging is being assessed, with 1 patient with HER2+ metastatic breast cancer showing a reduction in FDG uptake and improvement of a chest wall lesion (dose level 60 mg qd). Evaluation of PI3K pathway modulation from paired tumor biopsies is underway. Conclusions: GDC-0941 is generally well tolerated when administered qd at doses associated with inhibition of pAKT in surrogate tissues. Evidence of PD activity in tumor tissue has also been observed. Dose-escalation continues and updated PK/PD data will be presented. [Table: see text]

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LoRusso, Patricia, Geoffrey Shapiro, Shuchi Sumant Pandya, Eunice Lee Kwak, Cheryl Jones, Marcia Belvin, Luna C. Musib, et al. "A first-in-human phase Ib study to evaluate the MEK inhibitor GDC-0973, combined with the pan-PI3K inhibitor GDC-0941, in patients with advanced solid tumors." Journal of Clinical Oncology 30, no. 15_suppl (May 20, 2012): 2566. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.2566.

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2566 Background: Both RAS/RAF/MEK and PI3K/Akt signaling pathways are deregulated in many tumor types. Targeting both pathways may be more efficacious than targeting either pathway alone. In preclinical models, concurrent administration of GDC‑0973, a potent, selective, MEK1/2 inhibitor and GDC-0941, a potent class I PI3K inhibitor, shows improved efficacy compared to either agent alone dosed continuously or intermittently. Methods: A phase Ib dose-escalation study with 3+3 design was initiated in patients (pts) with advanced solid tumors to evaluate the safety and pharmacokinetics (PK) of oral dosing of GDC-0973 and GDC-0941. Pts received: concurrent GDC-0973 + GDC-0941 once daily (qd) on a 21 day on/7 day off (21/7) schedule; intermittent GDC-0973 on Days 1, 4, 8, 11, 15, 18 of a 28 day cycle + GDC-0941 qd on a 21/7 schedule (MEK int); or GDC-0973 + GDC-0941 qd on a 7 day on /7 day off schedule (7/7). Starting doses were 20 mg GDC-0973 + 80 mg GDC-0941 (21/7), 100 mg GDC-0973 + 130 mg GDC-0941 (MEK int); 40 mg GDC-0973 + 130 mg GDC-0941 (7/7). Serial plasma PK samples, FDG-PET, and CT scans were obtained. Results: 78 pts have enrolled. DLTs were G3 lipase (n=1), G4 CPK elevation (n=1). Compared to the 21/7 MTD of 40 mg GDC-0973 + 100 mg GDC-0941, higher doses of GDC-0973 + GDC-0941 were tolerated on the MEK int schedule. Overall, adverse events related to the study drug combination in ≥ 20% pts were diarrhea, rash, nausea, fatigue, vomiting, decreased appetite, dysgeusia, and elevated CPK. Preliminary analysis indicated PK of GDC-0973 and GDC-0941 are not altered when dosed in combination. Of 46 evaluable pts, 26 had an FDG-PET partial metabolic response (≥ 20% decrease in mean SUVmax from baseline) at ≥1 time points. Partial responses were observed in 3 pts (mBRAF melanoma, mBRAF pancreatic ca, mKRAS endometrioid ca); 5 pts had stable disease ≥ 5 months. Conclusions: Combination dosing of GDC‑0973 and GDC-0941 is generally well tolerated, with toxicities similar to those observed in single agent GDC-0973 and GDC-0941 phase 1 trials. There are early signs of anti-tumor activity. Dose escalation on MEK int and 7/7 schedules continues and updated data will be presented.

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De, Pradip, Yuliang Sun, Lori Friedman, Nandini Dey, and Brian Leyland-Jones. "Effect of pan-PI3K and HER2 blockade on antitumor activity in preclinical models of breast cancer resistance to trastuzumab therapy." Journal of Clinical Oncology 31, no. 15_suppl (May 20, 2013): e13570-e13570. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.e13570.

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e13570 Background: PI3K-AKT-mTOR pathway signaling is important for the oncogenic function of HER2. Activating alterations of this pathway are frequently observed in HER2-enriched breast cancer and generally herald a poor response and resistance to trastuzumab (T). Targeting the PI3K-AKT-mTOR pathway is an attractive strategy in HER2+ breast cancer that is refractory to trastuzumab. The hypothesis is that the suppression of this pathway by pan-PI3K inhibitor, GDC-0941 may lead to overcome trastuzumab-resistance. Methods: The antiproliferative and HER2-mediated cellular signaling (pAKT, pP70S6K, pS6RP, p4EBP1 and p-ERK) effects of GDC-0941 alone and in combination with T were evaluated in HER2 amplified T-sensitive (BT474), T-resistant (BT474HR), and HER2 amplified/PIK3CA mutated (HCC1954, UACC893) BT cell lines by MTT assay and Western blots. Athymic mice bearing BT474 and BT474HR xenograft tumors were treated with GDC-0941 and T (alone and in combination). Results: (1) GDC-0941 exhibited in vitro cell killing activity in MTT assay with IC50’s ranging from 0.35 µM to 1 µm and potency was augmented by the addition of T, (2) inhibition of phosphorylation of AKT(S473, T308), P70S6K, S6RP, and 4EBP1(T37/46, T70) was observed following GDC-0941 treatment, and the combination of GDC-0941 and T more effectively blocked the PI3K-AKT-mTOR pathway, (4) GDC-0941 dose-dependently blocked 3D-ON-TOP clonogenic growth of HER2+ cells. This effect was potentiated in the presence of T and (5) xenograft data show that the combination of GDC-0941 and T has strongly enhanced anti-tumor effect in both sensitive (82%) and resistant models (79%), something that cannot be achieved by either monotherapy. Conclusions: Our data suggest that 1) therapeutic targeting of the PI3K-AKT-mTOR signaling should be effective in abrogating resistance to T therapy in HER2+ BT, and 2) targeting both the HER2 and the PI3K signaling pathways is an attractive strategy to enhance the clinical activity of T therapy, as well as to prevent or delay the development of resistance.

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Fouda, A. S., M. A. Ismail, A. S. Abousalem, and G. Y. Elewady. "Experimental and theoretical studies on corrosion inhibition of 4-amidinophenyl-2,2′-bifuran and its analogues in acidic media." RSC Adv. 7, no. 73 (2017): 46414–30. http://dx.doi.org/10.1039/c7ra08092a.

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Corrosion inhibition studies of carbon steel (CS) in 1 M HCl by newly synthesized bichalcophene compounds namely; 4-(2,2′-bifuran-5-yl)benzamidine (MA-0947) and 6-(2,2′-bifuran-5-yl)nicotinamidine (MA-0941) and 6-[5-(thiophen-2-yl)furan-2-yl]nicotinamidine (MA-0940).

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Iyengar, Sunil, Andrew J. Clear, Andrew Owen, Lenushka Maharaj, Janet Matthews, Maria Calaminici, Rebecca Auer, et al. "PI3K Inhibition with GDC-0941 Has Greater Efficacy Compared to p110δ-Selective Inhibition with CAL-101 in Mantle Cell Lymphoma and May Be Particularly Advantageous in Multiply Relapsed Patients." Blood 118, no. 21 (November 18, 2011): 1654. http://dx.doi.org/10.1182/blood.v118.21.1654.1654.

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Abstract Abstract 1654 Background: Mantle cell lymphoma (MCL) is an incurable, aggressive subtype of non-Hodgkin lymphoma in which there is a need for novel targeted therapies. Activation of the PI3K-Akt pathway and its role in the pathogenesis of MCL has been highlighted in a number of studies. Constitutive activation of the PI3K pathway inactivates GSK-3β, a downstream target of Akt, that can phosphorylate cyclin D1 resulting in its nuclear export. There is also evidence that cyclin D1 mRNA stability and translation is enhanced by this pathway. The class Ia PI3K p110 catalytic subunit isoforms α, β and δ are primarily implicated in oncogenesis. While the PI3K p110δ isoform is known to be enriched in lymphocytes, a gain of PIK3CA (the gene encoding PI3K p110α) copy number has been shown to be a frequent alteration in MCL. The expression and relative importance of the individual Class Ia PI3K isoforms has not been documented in this disease. With the development of isoform selective inhibitors, this is an important issue that needs to be addressed. Aims: We studied the expression of class Ia PI3K isoforms in primary MCL with relation to morphological variants and disease status. We also compared the efficacy of PI3K inhibition in MCL cell lines and primary samples using two novel inhibitors, GDC-0941(predominantly p110α/δ-selective) and CAL-101 (δ-selective), both of which are in early phase clinical trials. Methods: Tissue microarrays were constructed from triplicate 1mm cores from 144 MCL biopsies and 16 tonsil controls. The levels of p110α, p110β and p110δ isoforms were then determined by immunohistochemistry using isoform-specific antibodies. The in vitro effect of PI3K inhibitors on cell viability and apoptosis was studied in 4 MCL cell lines, (Jeko-1, Granta519, REC-1 and JVM-2), and 15 primary MCL samples. Expression of the class Ia PI3K isoforms and changes in downstream targets of PI3K were determined by western blotting. Results: P110δ was expressed at a consistently higher level in MCL samples and normal tonsil controls compared to the α and β isoforms, while p110β expression was weak and significantly lower than p110α expression. On comparing expression of isoforms at diagnosis and relapse, p110α expression was significantly increased beyond 1st relapse compared to diagnostic biopsies (p=0.04) and tonsil controls (p=0.02), an observation that was even more apparent in 6 paired samples [p=0.008, median IHC score 19.6 (5.0−53.2) at diagnosis vs. 91.5 (38.6 − 129) beyond 1st relapse]. No significant change was found in the expression of p110β or p110δ between diagnostic and relapse samples. There was no significant difference in expression levels of the 3 isoforms between blastoid and non-blastoid morphological variants. Expression of both the p110α and δ isoforms was detected by western blotting in 4 MCL cell lines, but only Jeko-1 cells were sensitive to inhibition with GDC-0941. CAL-101 produced little or no apoptosis in all 4 cell lines. In primary MCL samples, GDC-0941 was consistently more potent than CAL-101, with decrease in cell viability of 32 vs. 20% at 1μM (p=0.15), 51 vs. 25% at 5μM (p=0.02) and 67 vs. 35% at 10μM (p<0.0001) GDC-0941 and CAL-101 respectively. GDC-0941 was also able to partially overcome the stimulatory effect of sCD40L and IL4 on primary MCL samples. Western blotting showed a consistent reduction in the phosphorylation of Akt and GSK-3β in sensitive MCL cells. Conclusion: Our studies demonstrate that although p110δ is the most consistently expressed isoform, the expression of the p110α subunit increases significantly in multiply relapsed MCL. This observation, in combination with significantly greater in vitro sensitivity of MCL primary samples to GDC-0941, compared to the p110δ-selective inhibitor CAL-101, provides strong evidence for further evaluation of GDC-0941 in this disease. Disclosures: Gribben: Roche: Honoraria; Celgene: Honoraria; GSK: Honoraria; Mundipharma: Honoraria; Gilead: Honoraria; Pharmacyclics: Honoraria. Joel:Astra Zeneca: Research Funding; Intellikine: Research Funding.

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Ebens, Allen J., Leanne Berry, Yung-Hsiang Chen, Gauri Deshmukh, Jake Drummond, Changchun Du, Michael Eby, et al. "A Selective PIM Kinase Inhibitor Is Highly Active In Multiple Myeloma: The Biology of Single Agent and PI3K/AKT/mTOR Combination Activity." Blood 116, no. 21 (November 19, 2010): 3001. http://dx.doi.org/10.1182/blood.v116.21.3001.3001.

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Abstract Abstract 3001 PIM kinases co-regulate several important elements of the PI3K/AKT/mTOR pathway in myeloma cells (Munugalavadla V. et al., ASH 2010 submitted abstr.). In this study we show that pan-PIM inhibition suppresses growth in myeloma cell lines, xenografts, and primary patient samples, both as a single-agent as well acting synergistically in combination with PI3K, AKT, and mTOR inhibition. The PIM kinases are a family of 3 ser/thr growth factor- & cytokine-induced proteins hypothesized to have redundant survival and growth functions. Although PIM-1,2 have been noted as highly expressed in myeloma (Claudio et al., 2002), there are few data to support potential therapeutic utility of PIM inhibition in this indication. We show myeloma cell lines express all 6 PIM protein isoforms to varying extents, and we describe the properties of a novel pan-PIM inhibitor GNE-652 with picomolar biochemical potency, an excellent selectivity profile, and favorable ADME properties. Myeloma cell lines exhibit a striking prevalence of response to GNE-652 (23 of 25 lines with IC50 < 1 micromolar, median < 0.1 micromolar) and synergy in combination with the PI3K inhibitor GDC-0941 (mean combination index values ~0.2 (n=25)). We used an unrelated compound GNE-568 which has a PIM-1,3 selective profile to test the hypothesis that PIM-2 may have a non-redundant role in myeloma cells. GNE-568 while having cellular potency against PIM-1 and PIM-3, did not have single agent activity in myeloma cell lines nor did it act synergistically with GDC-0941 (n=10 cell lines). Interestingly, PI3K and AKT inhibitors showed the greatest extent of synergy with GNE-652, whereas mTOR-selective inhibitors were synergistic to a lesser extent. Standard of care agents dexamethasone, revlimid, velcade, and melphalan also combined well with GNE-652, but to a lesser extent and not as broadly. The synergistic anti-tumor activity of GNE-652 and PI3K inhibitor GDC-0941 on cell lines or on primary myeloma bone marrow aspirates in vitro was associated with cell-cycle arrest and marked apoptosis. In addition, we found 4 of 4 myeloma xenograft mouse models tested with GNE-562 and GDC-0941 showed excellent combination efficacy that correlated with modulation of the expected pharmacodynamic markers. These results provide the rationale for further preclinical development of PIM inhibitors and provide the basis for a possible clinical development plan in multiple myeloma. Disclosures: Ebens: Genentech: Employment, Equity Ownership. Berry:Genentech: Employment, Equity Ownership. Chen:Genentech: Employment, Equity Ownership. Deshmukh:Genentech: Employment, Equity Ownership. Drummond:Genentech: Employment, Equity Ownership. Du:Genentech: Employment, Equity Ownership. Eby:Genentech: Employment, Equity Ownership. Fitzgerald:Genentech: Employment, Equity Ownership. S. Friedman:Genentech: Employment, Equity Ownership. E. Gould:Genentech: Employment, Equity Ownership. Kenny:Genentech: Employment, Equity Ownership. Maecker:Genentech: Employment, Equity Ownership. Moffat:Genentech: Employment, Equity Ownership. Moskalenko:Genentech: Employment, Equity Ownership. Pacheco:Genentech: Employment, Equity Ownership. Saadat:Genentech: Employment, Equity Ownership. Slaga:Genentech: Employment, Equity Ownership. Sun:Genentech: Employment, Equity Ownership. Wang:Genentech: Employment, Equity Ownership. Yang:Genentech: Employment, Equity Ownership. Munugalavadla:Genentech: Employment, Equity Ownership.

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Li, Haifu, Agnieszka Wozniak, Karel Van Den Bossche, Thomas Van Looy, Jasmien Wellens, Marguerite Stas, Giuseppe Floris, et al. "Efficacy of the phosphoinositol 3 kinase (PI3K) inhibitor GDC-0941 in patient- and cell-line-derived xenografts of dedifferentiated liposarcoma (DDLPS)." Journal of Clinical Oncology 31, no. 15_suppl (May 20, 2013): e13528-e13528. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.e13528.

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e13528 Background: Analysis of primary clinical specimens of DDLPS revealed evidence of AKT activation in 27% of cases (Gutierrez A, et al. Aberrant AKT activation drives well-differentiated liposarcoma. PNAS 2011; 108(39):16386-91). We evaluated the efficacy of the PI3K inhibitor GDC-0941 (GDC) alone and in combination with doxorubicin (DOX) in patient- and cell-line derived DDLPS xenografts with proven PI3K/AKT pathway activation. Methods: NMRI nu/nu mice were either injected bilaterally with 1x107SW872 cells or transplanted with human DDLPS (UZLX-STS3). Animals were randomized to 4 groups (6 mice/group) and treated for two weeks: vehicle, DOX (i.p., 1.2mg/kg/biw), GDC (p.o., 75mg/kg/qd), GDC+DOX (same dose/schedule as single agents). Efficacy was assessed by tumor volume assessment, Western blotting and histological evaluation (H&E). Mitotic and apoptotic effects were confirmed using immunostainings for phospho-histone H3 (p-H3) (for proliferation), and cleaved caspase 3 (CC3) (for apoptosis). Results: GDC and GDC+DOX significantly delayed the growth of both xenografts (74% decrease under GDC and 77% under GDC+DOX in SW872, 67% under GDC and 56% under GDC+DOX in UZLX-STS3, vs. control). GDC and GDC+DOX treatment resulted in reduced mitotic activity and increase in apoptosis, as compared to untreated tumors in both models (Table). The activation of PI3K signaling was nearly completely suppressed in the GDC and GDC+DOX treated groups in SW872, whilea weak activation of the pathway was still observed in UZLX-STS3. Conclusions: GDC-0941 has anti-tumor activity, decreases tumor proliferation and induces apoptosis in DDLPS with PI3K/AKT activation. The GDC+DOX combination did not show additive effect in vivo. [Table: see text]

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Pedraza Gracia, Manuel José, Maria Gioia Tavoni, Nicolás Bas Martín, and Antonio Carpallo Bautista. "Reseñas." Titivillus 2 (October 18, 2018): 213–28. http://dx.doi.org/10.26754/ojs_titivillus/titivillus.201603137.

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Manuel José Pedraza Gracia = Incunabula universitatis: los incunables de las bibliotecas universitarias españolas. Edición a cargo de Ramón Rodríguez Álvarez. Oviedo, Universidad de Oviedo, 2015. 313 p. ISBN: 978-84-16046-82-9. Maria Gioia Tavoni = Atti del convegno Incunabula. Printing, Trading, Collecting, Cataloguing, 10-12 settembre 2013, La Bibliofilia, 116, n. 1/3 (2014). ISSN 0006-0941. Nicolás Bas Martín = Rosa M. GREGORI ROIG, La impressora Jerònima Galés i els Mey (València, segle XVI), Valencia, Biblioteca Valenciana, 2012. 611 p. ISBN 978-84-482-5722-4. Nicolás Bas Martín = Juan GOMIS COLOMA, Menudencias de imprenta. Producción y circulación de la literatura popular (Valencia, siglo XVIII), Valencia, Institució Alfons el Magnànim, 2015. 557 p. ISBN 978-84-7822-2015. Antonio Carpallo Bautista = José Luis GONZALO SÁNCHEZ-MOLERO, Leyendo a Edo. Madrid, Consejo Superior de Investigaciones Científicas, 2013, 163 p. ISBN: 978-84-00-09660-1.

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Dey, Nandini, Yuliang Sun, Jennifer Carlson, Lori Friedman, Pradip De, and Brian Leyland-Jones. "A combination of dual PI3K-mTOR inhibitor, GDC-0980, with PARP inhibitor plus carboplatin blocked tumor growth of BRCA-competent triple-negative breast cancer cells." Journal of Clinical Oncology 31, no. 15_suppl (May 20, 2013): 2613. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.2613.

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2613 Background: PARP is a promising target in the TNBC. The PI3K pathway, in addition to its pro-proliferative effects on tumor cells, also controls the repair of DSB (Kumar, 2010; Friedman, 2009; Juvekar, 2012; Ibrahim, 2012). We hypothesize that the growth of TNBC tumor will be blocked due to the inhibition of (1) HR / NHEJ, and (2) PI3K-mTOR pathway mediated survival signals following GDC-0980 (G), when combined with PARP inhibitor (impaired DNA-SSB-repair), and carboplatin (C) (increased DNA-DSB). Methods: We tested the in vivo efficacy of a combination of G with ABT888 (A) plus C in BRCA-competent TNBC cells, and compared the triple combination arm (A+C+G) with a combination arm of A+C+ pan PI3K inhibitor GDC-0941 in mice xenograft (MDA-MB231) model. Mechanistically, we tested, (1) cell survival/ proliferation (5-7 BRCA-wt and mutant cell lines) using MTT assay, CelltiterGLO, and cell cycle analyses, (2) anchorage independent and dependent clonogenic growth (3D ON-TOP and soft-agar assay), (3) apoptosis, and (4) cell signaling marker(s). Results: (1) G alone decreased the tumor growth by 40-50%. (2) The G + A + C combination blocked the growth of established tumors by 90% as compared to control(s). (3) Interestingly, G + A + C combination had markedly higher percentage of inhibition of tumor growth than the inhibition observed in the A+C+GDC-0941 arm (36%). (4) G treatment time-dependently increased cl-caspase 3, 9, and cl-PARP and increased AnnexinV positivity both time (24 and 48 hrs) and dose dependently (50 and 200 nM) in cells. (5) G when combined with A+C was most effective in inducing apoptosis in PIK3CA-mutated BT20 cells. (6) The triple combination (50 nM G+10 μM A + 10 μM C) inhibited clonogenic growth of MDA-MB231, MDA-MB468 and BT20 cells. (7)Treatment of G decreased downstream effectors of PI3K-mTOR pathway, pAKTS473, pP70S6K and pS6RP. Conclusions: Tumor growth of BRCA-competent TNBC cells is blocked by a combination treatment of G with A+C. The profound anti-tumor effect of this triple combination can be explained by the anti-proliferative and pro-apoptotic actions of the drugs. The combination of G with A+C merits further investigation in TNBC.

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Murahashi, Satoshi, Takashi Akiyoshi, Takeshi Sano, Yosuke Fukunaga, Tetsuo Noda, Masashi Ueno, and Hitoshi Zembutsu. "Serial circulating tumour DNA analysis for locally advanced rectal cancer treated with preoperative therapy: prediction of pathological response and postoperative recurrence." British Journal of Cancer 123, no. 5 (June 22, 2020): 803–10. http://dx.doi.org/10.1038/s41416-020-0941-4.

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Bakas, Ioannis, Michael Z. Hauschild, Thomas F. Astrup, and Ralph K. Rosenbaum. "Preparing the ground for an operational handling of long-term emissions in LCA." International Journal of Life Cycle Assessment 20, no. 10 (July 28, 2015): 1444–55. http://dx.doi.org/10.1007/s11367-015-0941-4.

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Mehta, H., T. Giglia, V. A. Parnell, and D. Kholwadwala. "Complete Agenesis of the Right and Left Pulmonary Arteries, with Main Pulmonary Artery Originating from the Right Ventricle, Presenting as Primary Pulmonary Hypertension of the Newborn: Case Report." Pediatric Cardiology 26, no. 6 (October 18, 2005): 856–58. http://dx.doi.org/10.1007/s00246-005-0941-4.

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Thunberg, Johan, Milos Ljubisavljevic, Mats Djupsjöbacka, and Håkan Johansson. "Effects on the fusimotor-muscle spindle system induced by intramuscular injections of hypertonic saline." Experimental Brain Research 142, no. 3 (February 1, 2002): 319–26. http://dx.doi.org/10.1007/s00221-001-0941-4.

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Neumaier, Judith. "Mammakarzinom: Ki-67 nach brusterhaltender Therapie ohne prognostische Bedeutung." Im Focus Onkologie 17, no. 3 (March 2014): 38. http://dx.doi.org/10.1007/s15015-014-0941-4.

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Ota, Shigeyasu, Shohachi Suzuki, Hiroshi Mitsuoka, Naoki Unno, Shoichi Inagawa, Yasuo Takehara, Takanori Sakaguchi, Hiroyuki Konno, and Satoshi Nakamura. "Effect of a portal venous stent for gastrointestinal hemorrhage from jejunal varices caused by portal hypertension after pancreatoduodenectomy." Journal of Hepato-Biliary-Pancreatic Surgery 12, no. 1 (February 23, 2005): 88–92. http://dx.doi.org/10.1007/s00534-004-0941-4.

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Tilscher, H. "Grußworte der ÖÄGMM." Manuelle Medizin 50, no. 4 (August 2012): 267–68. http://dx.doi.org/10.1007/s00337-012-0941-4.

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Guillem, José G., and Steven A. Lee-Kong. "Autonomic Nerve Preservation During Rectal Cancer Resection." Journal of Gastrointestinal Surgery 14, no. 2 (June 23, 2009): 416–22. http://dx.doi.org/10.1007/s11605-009-0941-4.

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Kim, Kyoung Yee, Hyung Won Lee, and Yun Soo Myung. "On the Ricci dark energy model." General Relativity and Gravitation 43, no. 4 (February 22, 2010): 1095–101. http://dx.doi.org/10.1007/s10714-010-0941-4.

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Martinez, M., T. Arnold, and D. Perner. "The role of bromine and chlorine chemistry for arctic ozone depletion events in Ny-Ålesund and comparison with model calculations." Annales Geophysicae 17, no. 7 (July 31, 1999): 941–56. http://dx.doi.org/10.1007/s00585-999-0941-4.

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Abstract. During the Arctic Tropospheric Ozone Chemistry (ARCTOC) campaigns at Ny-Ålesund, Spitsbergen, the role of halogens in the depletion of boundary layer ozone was investigated. In spring 1995 and 1996 up to 30 ppt bromine monoxide were found whenever ozone decreased from normal levels of about 40 ppb. Those main trace gases and others were specifically followed in the UV-VIS spectral region by differential optical absorption spectroscopy (DOAS) along light paths running between 20 and 475 m a.s.l.. The daily variation of peroxy radicals closely followed the ozone photolysis rate J(O3(O1D)) in the absence of ozone depletion most of the time. However, during low ozone events this close correlation was no longer found because the measurement of radicals by chemical amplification (CA) turned out to be sensitive to peroxy radicals and ClOx. Large CA signals at night can sometimes definitely be assigned to ClOx and reached up to 2 ppt. Total bromine and iodine were both stripped quantitatively from air by active charcoal traps and measured after neutron activation of the samples. Total bromine increased from background levels of about 15 ppt to a maximum of 90 ppt during an event of complete ozone depletion. For the spring season a strong source of bromine is identified in the pack ice region according to back trajectories. Though biogenic emission sources cannot be completely ruled out, a primary activation of halogenides by various oxidants seems to initiate an efficient autocatalytic process, mainly driven by ozone and light, on ice and perhaps on aerosols. Halogenides residing on pack ice surfaces are continuously oxidised by hypohalogenous acids releasing bromine and chlorine into the air. During transport and especially above open water this air mixes with upper layer pristine air. As large quantities of bromine, often in the form of BrO, have been observed at polar sunrise also around Antarctica, its release seems to be a natural phenomenon. The source strength of bromine from halogen activation on the pack ice, as based on the measured inorganic bromine levels, averages about 1012 Br-atoms m-2 s-1 during sunlit periods in Arctic spring. The total source strength of inorganic bromine from sunlit polar regions may therefore amount to 30 kt y-1.Key words. Atmospheric composition and structure (troposphere · composition and chemistry; instruments and techniques)

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Lemke, Angelika K., John D. Sandy, Henning Voigt, Rita Dreier, Jennifer H. Lee, Alan J. Grodzinsky, Rolf Mentlein, Jakob Fay, Michael Schünke, and Bodo Kurz. "Interleukin-1α treatment of meniscal explants stimulates the production and release of aggrecanase-generated, GAG-substituted aggrecan products and also the release of pre-formed, aggrecanase-generated G1 and m-calpain-generated G1-G2." Cell and Tissue Research 340, no. 1 (March 9, 2010): 179–88. http://dx.doi.org/10.1007/s00441-010-0941-4.

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Strube, Wolfgang, Peter Falkai, and Alkomiet Hasan. "Neue Ansätze in der Schizophrenietherapie." DNP - Der Neurologe und Psychiater 16, no. 1 (January 2015): 46–56. http://dx.doi.org/10.1007/s15202-015-0941-4.

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Braun, Jörg. "Weiterentwicklung notfallmedizinischer Strukturen – State of the Art." Notfall + Rettungsmedizin 10, no. 6 (September 2, 2007): 441–42. http://dx.doi.org/10.1007/s10049-007-0941-4.

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Zhang, Xi, and Ran-chao Wu. "Modified Projective Synchronization of Fractional-order Chaotic Systems with Different Dimensions." Acta Mathematicae Applicatae Sinica, English Series 36, no. 2 (March 2020): 527–38. http://dx.doi.org/10.1007/s10255-020-0941-4.

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K�bler, W. "Der Impact-Faktor oder das M�rchen von der Gerechtigkeit." Zeitschrift f�r Kardiologie 92, no. 7 (July 1, 2003): 529–31. http://dx.doi.org/10.1007/s00392-003-0941-4.

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Goreczny, S., T. Moszura, P. Dryzek, M. Lukaszewski, A. Krawczuk, J. Moll, and G. J. Morgan. "Three-dimensional image fusion guidance of percutaneous pulmonary valve implantation to reduce radiation exposure and contrast dose: A comparison with traditional two-dimensional and three-dimensional rotational angiographic guidance." Netherlands Heart Journal 25, no. 2 (December 13, 2016): 91–99. http://dx.doi.org/10.1007/s12471-016-0941-4.

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Li, Hongkun, Yinhu Wang, Pengshi Zhao, Xiaowen Zhang, and Peilin Zhou. "Cutting tool operational reliability prediction based on acoustic emission and logistic regression model." Journal of Intelligent Manufacturing 26, no. 5 (July 1, 2014): 923–31. http://dx.doi.org/10.1007/s10845-014-0941-4.

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Arakawa, Kensuke, Jennifer M. S. Koh, Ben Crossett, Allan M. Torres, and Philip W. Kuchel. "Detection of platypus-type l/d-peptide isomerase activity in aqueous extracts of papaya fruit." Biotechnology Letters 34, no. 9 (May 22, 2012): 1659–65. http://dx.doi.org/10.1007/s10529-012-0941-4.

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Cheng, Yang, Liang An, Zongshan Zhao, and Guanghui Wang. "Preparation of polyaniline/TiO2 composite nanotubes for photodegradation of AZO dyes." Journal of Wuhan University of Technology-Mater. Sci. Ed. 29, no. 3 (June 2014): 468–72. http://dx.doi.org/10.1007/s11595-014-0941-4.

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Fuentes, Javier, and Ramon L. Cerro. "Flow patterns and interfacial velocities near a moving contact line." Experiments in Fluids 38, no. 4 (March 2, 2005): 503–10. http://dx.doi.org/10.1007/s00348-005-0941-4.

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Spencer, M. M., D. Landau-Ellis, E. J. Meyer, and V. R. Pantalone. "Molecular markers associated with linolenic acid content in soybean." Journal of the American Oil Chemists' Society 81, no. 6 (June 2004): 559–62. http://dx.doi.org/10.1007/s11746-006-0941-4.

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31

Szlachetko, Dariusz L., and Marta Kolanowska. "A new species of Scaphyglottis (Orchidaceae, Epidendroideae) from Colombia." Plant Systematics and Evolution 300, no. 5 (November 9, 2013): 1031–34. http://dx.doi.org/10.1007/s00606-013-0941-4.

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Weber, M. A., A. Kroll, M. G�nther, S. Delorme, J. Debus, F. L. Giesel, M. Essig, H. U. Kauczor, and L. R. Schad. "Nichtinvasive Messung des relativen zerebralen Blutflusses mit der MR-Blutbolusmarkierungstechnik (arterial-spin-labeling): Physikalische Grundlagen und klinische Anwendungen." Der Radiologe 44, no. 2 (February 1, 2004): 164–74. http://dx.doi.org/10.1007/s00117-003-0941-4.

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Shimohata, T., T. Ozawa, H. Nakayama, M. Tomita, H. Shinoda, and M. Nishizawa. "Frequency of nocturnal sudden death in patients with multiple system atrophy." Journal of Neurology 255, no. 10 (July 28, 2008): 1483–85. http://dx.doi.org/10.1007/s00415-008-0941-4.

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Caldarelli, Massimo. "Reply to the comments by Dr. Udayakumaran on our article “A late complication of CSF shunting: acquired Chiari I malformation”." Child's Nervous System 25, no. 11 (July 8, 2009): 1393. http://dx.doi.org/10.1007/s00381-009-0941-4.

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35

Eder, Maximilian, Stefan Raith, Jalil Jalali, Daniel Müller, Yves Harder, Martin Dobritz, Nikolaos A. Papadopulos, Hans-Günther Machens, and Laszlo Kovacs. "Three-dimensional prediction of free-flap volume in autologous breast reconstruction by CT angiography imaging." International Journal of Computer Assisted Radiology and Surgery 9, no. 4 (October 5, 2013): 541–49. http://dx.doi.org/10.1007/s11548-013-0941-4.

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36

Önder, Burcu, Aydan Kurtaran, Songül Kimyon, Barın Selçuk, and Müfit Akyüz. "Association of anti-CCP positivity with serum ferritin and DAS-28." Rheumatology International 30, no. 2 (May 15, 2009): 223–27. http://dx.doi.org/10.1007/s00296-009-0941-4.

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Pralle, Kristina. "Nicht den Fuß verlieren." Der Hausarzt 49, no. 17 (October 2012): 36–39. http://dx.doi.org/10.1007/s15200-012-0941-4.

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Wani, Khalida, Terri S. Armstrong, Elizabeth Vera-Bolanos, Aditya Raghunathan, David Ellison, Richard Gilbertson, Brian Vaillant, et al. "A prognostic gene expression signature in infratentorial ependymoma." Acta Neuropathologica 123, no. 5 (February 10, 2012): 727–38. http://dx.doi.org/10.1007/s00401-012-0941-4.

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39

Catani, Fabio, Bernardo Innocenti, Claudio Belvedere, Luc Labey, Andrea Ensini, and Alberto Leardini. "The Mark Coventry Award Articular: Contact Estimation in TKA Using In Vivo Kinematics and Finite Element Analysis." Clinical Orthopaedics and Related Research® 468, no. 1 (June 23, 2009): 19–28. http://dx.doi.org/10.1007/s11999-009-0941-4.

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Kumar, Niranjan, S. Ghosh, and S. C. Gupta. "Early detection of Fasciola gigantica infection in buffaloes by enzyme-linked immunosorbent assay and dot enzyme-linked immunosorbent assay." Parasitology Research 103, no. 1 (March 16, 2008): 141–50. http://dx.doi.org/10.1007/s00436-008-0941-4.

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41

Wei, Jiaqun. "Tilting complexes and Auslander–Reiten conjecture." Mathematische Zeitschrift 272, no. 1-2 (October 4, 2011): 431–41. http://dx.doi.org/10.1007/s00209-011-0941-4.

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42

Lee, Seung Mi, and Hyun Ho Park. "In vitro analysis of the complete CIDE domain interactions of the Drep system in fly." Apoptosis 19, no. 3 (November 15, 2013): 428–35. http://dx.doi.org/10.1007/s10495-013-0941-4.

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43

Wellman, Tristan P., Clifford I. Voss, and Michelle A. Walvoord. "Impacts of climate, lake size, and supra- and sub-permafrost groundwater flow on lake-talik evolution, Yukon Flats, Alaska (USA)." Hydrogeology Journal 21, no. 1 (January 23, 2013): 281–98. http://dx.doi.org/10.1007/s10040-012-0941-4.

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44

Islinger, Markus, Sandra Grille, H. Dariush Fahimi, and Michael Schrader. "The peroxisome: an update on mysteries." Histochemistry and Cell Biology 137, no. 5 (March 14, 2012): 547–74. http://dx.doi.org/10.1007/s00418-012-0941-4.

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45

Wang, Sheng, Biyao Mao, Mingxi Wu, Jingjing Liang, and Le Deng. "Influence of aptamer-targeted antibiofilm agents for treatment of Pseudomonas aeruginosa biofilms." Antonie van Leeuwenhoek 111, no. 2 (November 2, 2017): 199–208. http://dx.doi.org/10.1007/s10482-017-0941-4.

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46

Folkes, Adrian J., Khatereh Ahmadi, Wendy K. Alderton, Sonia Alix, Stewart J. Baker, Gary Box, Irina S. Chuckowree, et al. "The Identification of 2-(1H-Indazol-4-yl)-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (GDC-0941) as a Potent, Selective, Orally Bioavailable Inhibitor of Class I PI3 Kinase for the Treatment of Cancer†." Journal of Medicinal Chemistry 51, no. 18 (September 25, 2008): 5522–32. http://dx.doi.org/10.1021/jm800295d.

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47

Reidy, Mairead, Marianne VanDijk, Michael O'Neill, and Michael O'Dwyer. "The Dual PIM/PI3-K Inhibitor Ibl-202 Overcomes Microenvironmental Mediated Resistance in Multiple Myeloma and Prevents PIM1 Induced CXCR4 Upregulation." Blood 126, no. 23 (December 3, 2015): 5350. http://dx.doi.org/10.1182/blood.v126.23.5350.5350.

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Abstract:

Abstract Background: The interaction of multiple myeloma (MM) cells with bone marrow (BM) cells along with factors in the BM milieu such as chemokines and cytokines play a crucial role in both progression of MM and drug resistance. Activation of the PI3-K/Akt survival pathway is a characteristic of both human MM cell lines and patient samples. This activation can be linked to BM microenvironmental signalling and use of proteasome inhibitors in treatment, suggesting this as a crucial point of therapeutic intervention to abrogate growth and survival signals in MM. However, the efficacy of such therapeutics has been modest and is likely to be compromised by the stimulation of compensatory signalling pathways, such as the PIM kinases, which like the PI3-K/Akt pathway are also induced by BM microenvironmental influences and share similar downstream targets. These proto-oncogenic kinases are constitutively active and play an important role in proliferation and survival in MM. The influence of these kinases on homing and migration has been observed in other malignancies, this has yet to be reported in MM. Here we report the effects of a dual inhibitor of PIM/PI3-K, IBL-202, and provide novel insights into effects on cell survival, signaling and migration. Methods: We investigated the effect of IBL-202 against a panel of MM cell lines (MM.IS, NCI-H929s, KMS11 and RPMI-8226) and primary MM patient samples. The in vitro efficacy of IBL-202 was compared to that of single pan-PIM inhibitors pPIMi and AZD1208 and also the pan-PI3-K inhibitor GDC-0941. Apoptosis was measured with AnnexinV staining and cell cycle analysed with Edu/DAPI staining. To mimic BM microenvironmental conditions MM cells were cultured under hypoxic conditions (1% O2) and in co-culture with the human stromal cell line HS5. Surface expression of CXCR4 was assessed in MM cell lines by flow cytometry. PIM kinases, pCXCR4 and downstream targets of PIM/PI3-K were examined by western blot. Transwell migration assays were carried out in the presence of 50ng SDF-1α for 4h @ 37o C. Results: Simultaneous inhibition of PIM and PI3-K using IBL-202 in vitro was significantly more potent at inducing apoptosis than GDC-0941, pPIMi or AZD1208 in all MM cell lines tested. IC50 values were under 1μM for IBL-202 at 48h whilst in comparison the pan PIM inhibitors pPIMi and AZD1208 scored IC50 values between 5 and 10μM. The IC50 for GDC-0941 was on average 5μM (Figure 1). At the molecular level there was a notable decrease in phosphorylation of known PIM/PI3-K targets Akt (Ser473), Bad (Ser112) and the translational targets S6 (Ser235/236) and 4EBP1 (Thr37/46). The levels of total proteins were unchanged. Treatment with increasing doses of IBL-202 led to a marked reduction in cells in S phase of the cell cycle. These changes were paralled by down regulation of the cell cycle promoting proteins cyclin D1 and c-myc. IBL-202 was also effective in inducing apoptosis in primary MM patient samples (n=4) after just 24h as assessed by Annexin-V staining (Figure 2). To explore the role of the BM microenvironment we co-cultured MM cell lines with HS5s. This led to strong induction of PIM2 in MM cells. While MM cells in this setting were protected from Bortezomib-induced cell death, the apoptotic effect of IBL-202 was enhanced. In a further effort to mimic the tumour microenvironment we cultured MM cell lines in hypoxia. This may be of particular relevance as Pim-1 has been reported to be a pivotal regulator involved in hypoxia-induced chemoresistance. MM cells were further sensitised to IBL-202 in hypoxia. In addition, hypoxia increased the surface expression of CXCR4, a chemokine receptor critical for homing of MM cells to the bone marrow, with a concomitant increase in PIM1. Treatment of MM cell lines with IBL-202 reduced the level of PIM1 and CXCR4 Ser339 phosphorylation, along with down regulation of CXCR4 surface expression resulting in reduced migration of MM cells along an SDF-1 gradient. Conclusion: Together these data provide direct evidence of the potency of IBL-202 in MM in conditions that mimic the BM microenvironment. Moreover, they indicate a potential role for PIM kinases in facilitating dissemination and invasiveness of MM by CXCR4 and provide an added rationale for targeting PIM kinases in MM. Figure 1. Figure 1. Figure 2. Figure 2. Disclosures O'Neill: Inflection Biosciences: Employment.

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48

CARAMICO-FAVERO, Deise Cristina Oliva, Zelita Caldeira Ferreira GUEDES, and Mauro Batista de MORAIS. "FOOD INTAKE, NUTRITIONAL STATUS AND GASTROINTESTINAL SYMPTOMS IN CHILDREN WITH CEREBRAL PALSY." Arquivos de Gastroenterologia 55, no. 4 (December 2018): 352–57. http://dx.doi.org/10.1590/s0004-2803.201800000-78.

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ABSTRACT BACKGROUND: Cerebral palsy may be associated with comorbidities such as undernutrition, impaired growth and gastrointestinal symptoms. Children with cerebral palsy exhibit eating problems due to the effect on the anatomical and functional structures involved in the eating function resulting in malnutrition. OBJECTIVE: The aim of this study was to investigate the association between food intake, nutritional status and gastrointestinal symptoms in children with cerebral palsy. METHODS: Cross-sectional study that included 40 children with cerebral palsy (35 with spastic tetraparetic form and 5 with non-spastic choreoathetoid form of cerebral palsy, all requiring wheelchairs or bedridden) aged from 4 to 10 years. The dietary assessment with the parents was performed using the usual household food intake inquiry. Anthropometric data were collected. Gastrointestinal symptoms associated with deglutition disorders, gastroesophageal reflux and chronic constipation were also recorded. RESULTS: The median of height-for-age Z-score (-4.05) was lower (P<0.05) than the median of weight-for-age (-3.29) and weight-for-height (-0.94). There was no statistical difference between weight-for-age and weight-for-height Z-scores. Three patients with cerebral palsy (7.5%) exhibited mild anemia, with normal ferritin levels in two. Symptoms of dysphagia, gastroesophageal reflux, and constipation were found in 82.5% (n=33), 40.0% (n=16), and 60.0% (n=24) of the sample, respectively. The patients with symptoms of dysphagia exhibited lower daily energy (1280.2±454.8 Kcal vs 1890.3±847.1 Kcal, P=0.009), carbohydrate (median: 170.9 g vs 234.5 g, P=0.023) and fluid intake (483.1±294.9 mL vs 992.9±292.2 mL, P=0.001). The patients with symptoms of gastrointestinal reflux exhibited greater daily fluid intake (720.0±362.9 mL) than the patients without symptoms of gastroesophageal reflux (483.7±320.0 mL, P=0.042) and a greater height-for-age deficit (Z-score: -4.9±1.7 vs 3.7±1.5, P=0.033). The patients with symptoms of constipation exhibited lower daily dietary fiber (9.2±4.3 g vs 12.3±4.3 g, P=0.031) and fluid (456.5±283.1 mL vs 741.1±379.2 mL, P=0.013) intake. CONCLUSION: Children with cerebral palsy exhibited wide variability in food intake which may partially account for their severe impaired growth and malnutrition. Symptoms of dysphagia, gastroesophageal reflux, and constipation are associated with different food intake patterns. Therefore, nutritional intervention should be tailored considering the gastrointestinal symptoms and nutritional status.

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49

Morales, José. "Santiago SANZ SÁNCHEZ, El futuro creador del Dios Trinitario. Un estudio en la Teología Sistemática de Wolfhart Pannenberg, Edicep, Valencia 2007, 221 pp., 16 x 23, ISBN 978-8-4705-0941-4." Scripta Theologica 41, no. 3 (November 13, 2017): 1005. http://dx.doi.org/10.15581/006.41.13304.

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50

Diaz-Flores, Ernesto, Evan Q. Comeaux, Kailyn Kim, Kyle Beckman, Kara L. Davis, Kevin Wu, Jon Akutagawa, et al. "BCL-2, a Therapeutic Target for High Risk Hypodiploid B-Cell Acute Lymphoblastic Leukemia." Blood 128, no. 22 (December 2, 2016): 280. http://dx.doi.org/10.1182/blood.v128.22.280.280.

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Abstract Acute lymphoblastic leukemia (ALL) is the most common cancer of childhood. Specific genetic subsets, including hypodiploid ALL, are associated with particularly high rates of relapse. Despite the poor outcomes of hypodiploid B-ALL with traditional therapeutic approaches, there have been no known effective alternative therapies or novel candidates tested to improve outcome. We hypothesized that new therapeutic targets could by identified by integrated biochemical and genomic profiling, combined with functional drug assays in order to determine which pathways play an essential role in transformation. For biochemical profiling, we analyzed multiple pathways commonly deregulated in leukemias using phosphoflowcytometry (including receptor tyrosine kinases, JAK/STAT, MAPK, PI3K, PTEN, Bcl-2 survival and pro-apoptotic family members and p53). We subjected hypodiploid cell lines (NALM-16, MHH-CALL2) and patient derived xenograft samples in vitro to inhibitors against each of these pathways (PP2:Src family;Ruxolitinib: JAK/STAT; PD235901/CI1040: MAPK; GDC-0941, PI-90, PI-103, p110 (a, b, g, d): PI3K isoform specific; PP-242:mTOR; ABT-263/ABT-737: Bcl-2/Bcl-xl, and ABT-199: Bcl-2 specific). We found that the Bcl-2 inhibitors (ABT-263, ABT-737 and ABT-199) and to a lesser extent PI3K pathway inhibitors GDC-0941 and PP-242, but not the MAPK or RTK inhibitors, efficiently reduced proliferation of hypodiploid cells. However, only ABT-263/ABT-199 induced high levels of apoptosis at nanomolar concentrations. Based on the consistent efficacy observed with ABT-199 against hypodiploid patient-derived cells and cell lines in culture, we selected eight cryopreserved, previously xenografted (F3 generation) hypodiploid patient samples (4 low hypodiploid, chromosomal number between 32 and 39; and 4 Near Haploid, chromosomal number between 24 and 31) and three non-hypodiploid patient samples (Ph-positive,Ph-Like and Erg+) for a preclinical trial in immunodeficient mice. Each patient sample was engrafted into six mice, which were randomized to receive vehicle or ABT-199 daily over 60 days (Figure 1). Treatment started when the peripheral blood (PB) human CD45 count reached 15%. A rapid decrease in PB blasts was noted at 7 days (Figure 1). Eighty-five percent of the hypodiploid xenografts survived 60 days with either undetectable or low levels of leukemia in the PB. In contrastPh+ andPh-Like xenografts died within 10-20 days regardless of treatment. Importantly, hypodiploid leukemic blasts gradually emerged after discontinuing ABT-199 after 60 days. Additionally, despite low or undetectable levels of leukemic blasts in PB and reduced levels in bone marrow and spleen, all mice had high percentages of leukemic cells in the liver (Figure 2). In conclusion we have identified the survival protein Bcl-2 as a promising molecular target in hypodiploid B-ALL. ABT-199 for dramatically reduced leukemia cells in vitro and in vivo in patient-derived xenograft models of hypodiploid B-ALL. However, the liver represented a protective niche for these leukemias. In addition, our biochemical characterization of the organ infiltrating blasts collected from mice on trial indicate that the sensitivity of hypodiploid ALL to ABT-199 relies not only on high levels of Bcl-2 and deficiency for other survival proteins such as Bcl-xl but also on high levels of proapoptotic proteins, providing two different signatures that correlate with response to ABT-199. Using genome editing (CRISPR/Cas9) we interrogated the necessity for individual proapoptotic genes, including PUMA, NOXA, and BAD, for ABT-199-induced cell death. This study provides encouraging preclinical data that Bcl-2 may be a promising target for the treatment of hypodiploid B-ALL. Our studies identify signature biomarkers that correlate with drug response and identify essential proteins mediating ABT-199-induced cell death. Importantly, this report also identifies the limitations of using ABT-199 as single drug, and provides the rationale for using combinatorial therapies in order to improve the efficacy of the drug. Disclosures Mullighan: Loxo Oncology: Research Funding; Amgen: Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees. Loh:Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Abbvie: Research Funding.

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