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Journal articles on the topic '333.793/2/0973'

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Published: 29 July 2024

Last updated: 31 July 2024

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1

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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Padua, Rose Ann, Laure Sarda-Mantel, Mathieu Chiquet, Claire Kappel, Patricia Krief, Niclas Setterblad, Fortune Hontonnou, et al. "BCL-2 Inhibitor Venetoclax (ABT-199) and MEK Inhibitor GDC-0973 Synergise to Target AML Progenitors and Overcome Drug Resistance with the Use of PET Scanning in a Mouse Model of HR-MDS to Monitor Response to Treatment." Blood 132, Supplement 1 (November 29, 2018): 5497. http://dx.doi.org/10.1182/blood-2018-99-114212.

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Abstract Introduction: Targeted drugs are needed for HR-MDS/AML, particularly in elderly patients and Venetoclax, approved for some CLL, gives promising results in elderly AML. Assays to predict response to treatment may enable us to deliver personalized treatment. We sought to determine the most informative assay to predict response; viability assays can directly measure the effects of reagents on growth. Progenitor assays can potentially determine if the reagents can target diseased primitive cells. PET scanning can be used to follow response to treatment. Methods: Peripheral blood (PB) or bone marrow (BM) from 7 MDS/AML patients were incubated in a) no treatment, b) ABT-199 (1 µM) (Abbvie), c) GDC-0973 (1 µM) (Genentech) or d) ABT-199+GDC-0973 (1 µM of each) and assessed for viability using the MTT assay (n=2); cell death followed using the Incucyte® Zoom System (Essen Bioscience) (n=2) or methocult progenitor assays (Stem Cell Technologies) (n=4). Having shown that RAS:BCL-2 co-localization correlated with prognosis in MDS/AML patients (Leuk Res 37:312-9, 2013), immunofluorescence was undertaken. A micro PET device dedicated to mice was used to measure BM blast proliferation. After injection of 18F-FLT(a thymidine analogue) in mice untreated (n=7) or ABT-199 (75mg/kg)+GDC-0973(10mg/kg) treated (n=5) normal FVB/N, HR-MDS mice treated with vehicle (n=4), 2-month old HR-MDS before (n=5) and 3-month old before (n=4) and after ABT-199 (75mg/kg)+GDC-0973(10mg/kg) treatment (n=8), PET imaging was performed (Inveon Siemens Medical Systems), analyzed for signal and quantified. Results: Patient details and results are summarized on Table 1. Using the MTT assay 2 PB patient samples were found to be sensitive to ABT-199 treatment (Figure 1A, AS, p=0.00042 and YA, 0.00002) and more sensitive to the combination compared to untreated (AS, p=0.00007 and YA, 0.000003). With the incucyte the BM of one patient (AE) was found to be resistant to both ABT-199 and GDC-0973, but sensitive to the combination (Figure 1B). PB and BM from patient JA were assayed for apoptosis with the incucyte and were found to be sensitive to ABT-199 with increased apoptosis, resistant to GDC-0973 with decreased apoptosis and sensitive to the combination. Four bone marrow samples were tested in the 4 conditions using the progenitor assay (Figure 1C). Three patients were sensitive to GDC-0973, inhibiting any colony formation and the fourth had reduced colony numbers. In this assay patient JA appeared to be sensitive to GDC-0973 treatment whereas the incucyte assay scored this sample to be resistant to apoptosis; thus the cytotoxic effects of GDC-0973 may not be via apoptopsis. As the progenitor assay is likely to score the primitive disease population, this assay may prove more informative than the others without prior selection. One patient (DH) was clearly resistant to ABT-199, whereas the other three (JA, CB and FL) had reduced colony growth. All patients were sensitive to the combination treatment and inhibited colony growth. The RAS:BCL-2 co-localization in the PB revealed no complex in either the Mito or PM upon treatment with ABT-199 alone and some localization in the Mito with GDC-0973. With both ABT-199 and GDC-0973, there were hardly any cells confirming the cytotoxic effects of the combination. As we have previously shown that PM co-localization of the complex is associated with drug resistance (Blood 130:2613, 2017Suppl), we used the combination on our HR-MDS mouse model, where the complex co-localizes in the PM and followed the mice by PET scanning (Figure 1D). Weak signal was visualized in the femurs of untreated and ABT-199+GDC-0973 treated FVB/N mice (FBR 1.17+/-0.34 and 1.02+/-0.08 respectively). Mild PET signal was seen in the femurs of 2 month-old HR-MDS mice, (FBR 1.79+/-0.98). Intense PET signal was seen in the femurs and proximal humerus of HR-MDS mice treated with vehicle (3 month-old, FBR=2.35+/-1.32). Low PET signals were seen in the femurs of 5/8 HR-MDS mice treated with ABT-199+GDC-0973 (FBR=1.93+/-0.84). FBRs of the 3 groups of HR-MDS mice were significantly higher than those of FBV/N groups. Conclusion: Combined Venetoclax (ABT-199) and GDC-0973 targets MDS/AML progenitors and can potentially overcome drug resistance with the disruption of the RAS:BCL-2 complex. Bone marrow disease progression in HR-MDS mice can be monitored with 18F-FLT-PET imaging; PET data shows that the combination slows down disease progression. Disclosures Padua: Abbvie: Research Funding; Genentech: Research Funding. Giraudier:Novartis: Research Funding. Konopleva:Stemline Therapeutics: Research Funding. Andreeff:Oncoceutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; United Therapeutics: Patents & Royalties: GD2 inhibition in breast cancer ; Reata: Equity Ownership; Celgene: Consultancy; Jazz Pharma: Consultancy; Oncolyze: Equity Ownership; Amgen: Consultancy, Research Funding; Eutropics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Aptose: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Consultancy, Patents & Royalties: MDM2 inhibitor activity patent, Research Funding; SentiBio: Equity Ownership; Astra Zeneca: Research Funding.

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Ali Khan, Mohd Wajid. "Optimization of methods for peripheral blood mononuclear cells isolation and expansion of human gamma delta T cells." Bioinformation 17, no. 3 (March 31, 2021): 460–70. http://dx.doi.org/10.6026//97320630017460.

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Human Vγ9/Vδ2 T cells (γδ T cells) are immune surveillance cells both in innate and adaptive immunity and are a possible target for anticancer therapies, which can induce immune responses in a variety of cancers. Small non-peptide antigens such as zoledronate can do activation and expansion of T cells in vitro. It is evident that for adoptive cancer therapies, large numbers of functional cells are needed into cancer patients. Hence, optimization of methods needs to be carried out for the efficient expansion of these T cells. Standardization of peripheral blood mononuclear cells (PBMCs) isolation was devised. Cytokines (interleukin 2 (IL-2) and interleukin 15 (IL-15)) and zoledronate were also standardized for different concentrations. It was found that an increased number of PBMCs were recovered when washing was done at 1100 revolution per minute (rpm). Significantly high expansion fold was (2524 ± 787 expansion fold) achieved when stimulation of PBMCs was done with 1 μM of zoledronate and both cytokines IL-2 and IL-15 supported the expansion and survival of cells ISSN 0973-2063 (online) 0973-8894 (print) Bioinformation 17(3): 460-469 (2021) ©Biomedical Informatics (2021) 461 at the concentrations of 100 IU/ml and 10 ng/ml respectively. 14-day cultures showed highly pure (91.6 ± 5.1%) and live (96.5 ± 2.5%) expanded γδ T cells. This study aimed to standardize an easy to manipulate technique for the expansion of γδ T cells, giving a higher yield.

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Lieven, Elena V. M., Julian M. Pine, and Helen Dresner Barnes. "Individual differences in early vocabulary development: redefining the referential-expressive distinction." Journal of Child Language 19, no. 2 (June 1992): 287–310. http://dx.doi.org/10.1017/s0305000900011429.

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ABSTRACTThe existence of stylistic variation between children in the early stages of language acquisition has been most frequently studied using Nelson's 0973) referential—expressive distinction. While the use of this distinction has generated a great deal of interesting research, there are a number of major problems associated with it. The present study presents a simple scheme, based on formal categories, for coding stylistic variation in the early lexicon. When applied to the first 50 and 100 words of 12 children collected between 0; 11 and 2; 3, the major dimensions of difference are found to be the relative proportion of common nouns and the relative proportion of frozen phrases. Moreover, the proportion of frozen phrases is also found to be significantly positively related to children's early productivity, suggesting that, rather than being a ‘deadend’ in early language development, the acquisition of frozen phrases may provide an alternative route into multiword speech.

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5

Izquierdo, César. "René VIRGOULAY (ed.), Le Christ de Maurice Blondel, Desclée, Paris 2003, 229 pp., 15 x 22, ISBN 2-7189-0973-0." Scripta Theologica 36, no. 1 (November 30, 2017): 336. http://dx.doi.org/10.15581/006.36.13845.

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6

Han, Lina, Qi Zhang, Ce Shi, Joel Leverson, Monique Dail, Darren C. Phillips, Jun Chen, et al. "Concomitantly Targeting BCL-2 with Venetoclax (ABT-199/GDC-0199) and MAPK Signaling with Cobimetinib (GDC-0973) in Acute Myeloid Leukemia Models." Blood 126, no. 23 (December 3, 2015): 2544. http://dx.doi.org/10.1182/blood.v126.23.2544.2544.

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Abstract Pro-survival molecules including BCL-2 play critical roles in leukemia transformation and chemoresistance. ABT-199/GDC-0199 (venetoclax) is an orally available BH3-mimetic that binds with high affinity to BCL-2, but lacks affinity for BCL-XL and MCL-1. We have recently demonstrated anti-leukemia potency of venetoclax in acute myeloid leukemia (AML) models (Pan et al. Cancer Discovery 2014). However, venetoclax poorly inhibits MCL-1, causing resistance in leukemia cells that rely on MCL-1 for survival. The RAF/MEK/ERK (MAPK) cascade is a major effector pathway in AML that is activated by upstream mutant proteins such as FLT3, KIT and RAS. Additionally, the MAPK pathway regulates BCL-2 family proteins by stabilizing anti-apoptotic MCL-1 and inactivating pro-apoptotic BIM. In this study, we evaluated the anti-tumor effects of concomitant BCL-2 and MAPK blockade by venetoclax in combination with MEK1/2 inhibitor GDC-0973 (cobimetinib).. We initially examined activity of these agents in a panel of myeloid leukemia cell lines with diverse genetic alterations (Fig. 1A). The IC50 values of cobimetinib ranged from < 0.01 µM to > 1 µM after 72 hours of drug treatment but did not correlate with the basal level of p-ERK1/2. In 7 out of 11 cell lines, combination of the agents elicited synergistic growth inhibition. Notably synergism of venetoclax with cobimetinib was observed in venetoclax-resistant cell lines (MOLM14, OCI-AML3, NB4 and THP1). Ongoing analysis of pharmacodynamic markers include transcriptome assessment by RNA sequencing, functional proteomics by reverse phase protein array (RPPA) and quantification of BCL-2:BIM and MCL-1:BIM complexes using the electrochemiluminescent ELISA assay (Meso Scale Discovery, MSD-ELISA). The preliminary MSD data revealed that BCL-2:BIM complex was disrupted in most cell lines and accumulated following cobimetinib treatment, which may be due to the disruption of MCL-1:BIM complex by inhibition of MEK (Fig. 1B). In a long-term culture of primary AML blasts in serum-free stem cell growth medium supplemented with cytokines and StemRegenin 1 (SR1) to main the immature state of leukemia cells, the combination of venetoclax and cobimetinib induced distinct apoptotic cell death, with AML #1 sensitive to venetoclax but resistant to cobimetinib. Alternatively, AML #2 and #3 samples were resistant to venetoclax but sensitive to cobimetinib and the combination of both drugs (Fig. 1C). We next investigated signaling patterns and BCL-2 family protein expression in AML stem/progenitor cells using a 34-antibody panel and time-of-flight mass cytometry (CyTOF). In AML#1, BCL-2 was expressed in leukemia blasts, with enrichment in a progenitor AML population phenotypically defined as CD45dim CD34+ CD38+ CD123+ CD33+ (Fig. 1D). The high expression level of BCL-2 and low expression of MCL-1 and BCL-XL may account for sensitivity to venetoclax in AML#1. Both basal and G-CSF- or SCF-stimulated p-ERK was efficiently down-regulated by cobimetinib; however, G-CSF-evoked p-STAT3/5 and SCF-induced p-AKT were only slightly reduced (Fig. 1E). Notably we observed increased phosphorylation of STAT5 pathway upon treatment with cobimetinib, suggesting that active MAPK signals inhibit phosphorylation of the JAK-STAT pathway, as previously reported (Krasilnikov et al. Oncogene, 2003 and Lee at al. Cancer Cell, 2014). To test the efficacy of both compounds in vivo, we injected NSG mice with genetically engineered OCI-AML3/Luc/GFP cells. Bioluminescent imaging (BLI) demonstrated significantly reduced leukemia burden in treated groups compared to controls, more prominently in the cobimetinib single agent and venetoclax plus cobimetinib co-treated mice (Fig. 1F). The efficacy study is ongoing and median survival for cobimetinib and venetoclax co-treated mice has yet to be determined (Fig. 1G). In summary, our data demonstrates that combinatorial blockade of MAPK and BCL-2 pathways is synergistic in the majority of AML cell lines tested and can overcome intrinsic resistance to venetoclax. Ongoing studies will evaluate efficacy of this combination therapy in primary human AML xenografts and elucidate mechanisms of synergy. Disclosures Leverson: AbbVie: Employment, Equity Ownership. Dail:Genentech: Employment, Equity Ownership. Phillips:AbbVie: Employment, Other: Shareholder, Patents & Royalties. Chen:Abbvie: Employment, Equity Ownership. Jin:Abbvie: Employment, Equity Ownership. Jabbour:Pfizer: Consultancy, Research Funding. Sampath:Genentech: Employment, Equity Ownership. Konopleva:Novartis: Research Funding; AbbVie: Research Funding; Stemline: Research Funding; Calithera: Research Funding; Threshold: Research Funding.

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Behyari, Mahla, Rana Imani, and Hamid Keshvari. "Evaluation of Silk Fibroin Nanofibrous Dressing Incorporating Niosomal Propolis, for Potential Use in Wound Healing." Fibers and Polymers 22, no. 8 (April 26, 2021): 2090–101. http://dx.doi.org/10.1007/s12221-021-0973-2.

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Lehrnbecher, Thomas, Stefan Schöning, Luciana Porto, and Jan Sörensen. "Die Langerhanszell-Histiozytose: eine interdisziplinäre Herausforderung." Pädiatrie 29, no. 1 (February 2017): 40–42. http://dx.doi.org/10.1007/s15014-017-0973-2.

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Ozeki, Kenta, and Tomoki Yamashita. "Spanning Trees: A Survey." Graphs and Combinatorics 27, no. 1 (September 1, 2010): 1–26. http://dx.doi.org/10.1007/s00373-010-0973-2.

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Gu, Yuqi, Tobias Witter, Patty Livingston, Purnima Rao, Terry Varshney, Tom Kuca, and M. Dylan Bould. "The effect of simulator fidelity on acquiring non-technical skills: a randomized non-inferiority trial." Canadian Journal of Anesthesia/Journal canadien d'anesthésie 64, no. 12 (October 6, 2017): 1182–93. http://dx.doi.org/10.1007/s12630-017-0973-2.

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Maddaloni, Ernesto, Stephanie D’Eon, Stephanie Hastings, Liane J. Tinsley, Nicola Napoli, Mogher Khamaisi, Mary L. Bouxsein, Savitri M. R. Fouda, and Hillary A. Keenan. "Bone health in subjects with type 1 diabetes for more than 50 years." Acta Diabetologica 54, no. 5 (February 25, 2017): 479–88. http://dx.doi.org/10.1007/s00592-017-0973-2.

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Schneider, S. S., and G. DeGrandi-Hoffman. "Queen replacement in African and European honey bee colonies with and without afterswarms." Insectes Sociaux 55, no. 1 (December 4, 2007): 79–85. http://dx.doi.org/10.1007/s00040-007-0973-2.

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Pullar, Ben, Catherine Lunter, Jane Collie, Syed Shah, Nimish Shah, Sami Hayek, and Oliver J. Wiseman. "Do renal stones that fail lithotripsy require treatment?" Urolithiasis 45, no. 6 (March 15, 2017): 597–601. http://dx.doi.org/10.1007/s00240-017-0973-2.

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Akpinar-Elci, Muge, Francis E. Martin, Joshua G. Behr, and Rafael Diaz. "Saharan dust, climate variability, and asthma in Grenada, the Caribbean." International Journal of Biometeorology 59, no. 11 (February 24, 2015): 1667–71. http://dx.doi.org/10.1007/s00484-015-0973-2.

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15

Kushnir, R. M., M. M. Nykolyshyn, U. V. Zhydyk, and V. M. Flyachok. "On the theory of inhomogeneous anisotropic shells with initial stresses." Journal of Mathematical Sciences 186, no. 1 (August 26, 2012): 61–72. http://dx.doi.org/10.1007/s10958-012-0973-2.

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Akiyoshi, Takashi, Toshiaki Watanabe, and Masashi Ueno. "Risk Factors for and Long-term Outcomes of Anastomotic Leakage after Colorectal Cancer Surgery." World Journal of Surgery 35, no. 7 (February 3, 2011): 1689–90. http://dx.doi.org/10.1007/s00268-011-0973-2.

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Kreuzer, M., F. Dufey, D. Laurier, D. Nowak, J. W. Marsh, M. Schnelzer, M. Sogl, and L. Walsh. "Mortality from internal and external radiation exposure in a cohort of male German uranium millers, 1946–2008." International Archives of Occupational and Environmental Health 88, no. 4 (August 19, 2014): 431–41. http://dx.doi.org/10.1007/s00420-014-0973-2.

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Cai, Ning, Junwei Cao, Minghua Liu, and Haiying Ma. "On Controllability Problems of High-Order Dynamical Multi-Agent Systems." Arabian Journal for Science and Engineering 39, no. 5 (March 1, 2014): 4261–67. http://dx.doi.org/10.1007/s13369-014-0973-2.

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Andreolio, Cinara, Jefferson Pedro Piva, Elisa Baldasso, Roberta Ferlini, and Rafaela Piccoli. "Prolonged infusion of dexmedetomidine in critically-ill children." Indian Pediatrics 53, no. 11 (November 2016): 987–89. http://dx.doi.org/10.1007/s13312-016-0973-2.

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Hallman, Birgit. "Gekonnt reagieren, wenn der Patient wütend ist." gynäkologie + geburtshilfe 21, no. 4 (July 2016): 44. http://dx.doi.org/10.1007/s15013-016-0973-2.

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Pasten, Hector. "Definability of Frobenius orbits and a result on rational distance sets." Monatshefte für Mathematik 182, no. 1 (September 21, 2016): 99–126. http://dx.doi.org/10.1007/s00605-016-0973-2.

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Li, Zhengkui, Yueming Wang, Ningmei Wu, Qichun Chen, and Kai Wu. "Removal of heavy metal ions from wastewater by a novel HEA/AMPS copolymer hydrogel: preparation, characterization, and mechanism." Environmental Science and Pollution Research 20, no. 3 (May 22, 2012): 1511–25. http://dx.doi.org/10.1007/s11356-012-0973-2.

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Ratha, Sachitra Kumar, Radha Prasanna, Vishal Gupta, Dolly Wattal Dhar, and Anil Kumar Saxena. "Bioprospecting and indexing the microalgal diversity of different ecological habitats of India." World Journal of Microbiology and Biotechnology 28, no. 4 (December 17, 2011): 1657–67. http://dx.doi.org/10.1007/s11274-011-0973-2.

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Komici, Klara, Grazia Daniela Femminella, Claudio de Lucia, Alessandro Cannavo, Leonardo Bencivenga, Graziamaria Corbi, Dario Leosco, Nicola Ferrara, and Giuseppe Rengo. "Predisposing factors to heart failure in diabetic nephropathy: a look at the sympathetic nervous system hyperactivity." Aging Clinical and Experimental Research 31, no. 3 (June 1, 2018): 321–30. http://dx.doi.org/10.1007/s40520-018-0973-2.

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Wolf, E., C. J. Kähler, D. R. Troolin, C. Kykal, and W. Lai. "Time-resolved volumetric particle tracking velocimetry of large-scale vortex structures from the reattachment region of a laminar separation bubble to the wake." Experiments in Fluids 50, no. 4 (September 16, 2010): 977–88. http://dx.doi.org/10.1007/s00348-010-0973-2.

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Chen, You-Shyang, Huan-Ming Chuang, Arun Kumar Sangaiah, Chien-Ku Lin, and Wen-Bin Huang. "A study for project risk management using an advanced MCDM-based DEMATEL-ANP approach." Journal of Ambient Intelligence and Humanized Computing 10, no. 7 (August 21, 2018): 2669–81. http://dx.doi.org/10.1007/s12652-018-0973-2.

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Teunissen, Cas, Jesse Habets, Birgitta K. Velthuis, Maarten J. Cramer, and Peter Loh. "Double-contrast, single-phase computed tomography angiography for ruling out left atrial appendage thrombus prior to atrial fibrillation ablation." International Journal of Cardiovascular Imaging 33, no. 1 (September 6, 2016): 121–28. http://dx.doi.org/10.1007/s10554-016-0973-2.

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Zauer, Mario, Anne Kowalewski, Robert Sproßmann, Holger Stonjek, and André Wagenführ. "Thermal modification of European beech at relatively mild temperatures for the use in electric bass guitars." European Journal of Wood and Wood Products 74, no. 1 (October 3, 2015): 43–48. http://dx.doi.org/10.1007/s00107-015-0973-2.

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Choi, Ki-Seon, Yu-Mi Cha, Sung-Dae Kang, and Hae-Dong Kim. "Interdecadal changes in TC activities that affect Korea." Theoretical and Applied Climatology 116, no. 3-4 (July 25, 2013): 491–500. http://dx.doi.org/10.1007/s00704-013-0973-2.

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Polyakov, A. Y., N. B. Smirnov, A. V. Govorkov, E. A. Kozhukhova, A. I. Belogorokhov, D. P. Norton, H. S. Kim, and S. J. Pearton. "Shallow and Deep Centers in As-Grown and Annealed MgZnO/ZnO Structures with Quantum Wells." Journal of Electronic Materials 39, no. 5 (November 18, 2009): 601–7. http://dx.doi.org/10.1007/s11664-009-0973-2.

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Karstoft, Karen-Inge, Cherie Armour, Søren B. Andersen, Mette Bertelsen, and Trine Madsen. "Community integration after deployment to Afghanistan: a longitudinal investigation of Danish soldiers." Social Psychiatry and Psychiatric Epidemiology 50, no. 4 (October 12, 2014): 653–60. http://dx.doi.org/10.1007/s00127-014-0973-2.

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Isobe, Shinsuke, Naro Ohashi, Tomoyuki Fujikura, Takayuki Tsuji, Yukitoshi Sakao, Hideo Yasuda, Akihiko Kato, Hiroaki Miyajima, and Yoshihide Fujigaki. "Disturbed circadian rhythm of the intrarenal renin-angiotensin system: relevant to nocturnal hypertension and renal damage." Clinical and Experimental Nephrology 19, no. 2 (April 12, 2014): 231–39. http://dx.doi.org/10.1007/s10157-014-0973-2.

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Ahmadiniaz, N., A. Bashir, and C. Schubert. "Multiphoton Amplitudes and Generalized LKF Transformation in Scalar QED Using the Worldline Formalism." Russian Physics Journal 59, no. 11 (March 2017): 1752–60. http://dx.doi.org/10.1007/s11182-017-0973-2.

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Risinger, Fred, and Janel Boyce. "Conditioning tastant and the acquisition of conditioned taste avoidance to drugs of abuse in DBA/2J mice." Psychopharmacology 160, no. 3 (March 1, 2002): 225–32. http://dx.doi.org/10.1007/s00213-001-0973-2.

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Miyaishi, S., M. Miura, K. Taniguchi, and K. Püschel. "„Verschwinden“ des Epiduralhämatoms im Verlauf." Rechtsmedizin 24, no. 5 (August 1, 2014): 418–20. http://dx.doi.org/10.1007/s00194-014-0973-2.

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Tranter, T. G., J. T. Gostick, A. D. Burns, and W. F. Gale. "Capillary Hysteresis in Neutrally Wettable Fibrous Media: A Pore Network Study of a Fuel Cell Electrode." Transport in Porous Media 121, no. 3 (December 1, 2017): 597–620. http://dx.doi.org/10.1007/s11242-017-0973-2.

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Mohieldin, Ahmed, Abdulmoneim Eldali, and Ali Aljubran. "Knowledge, Perception, and Attitudes of Cancer Patients Towards Cancer and Cancer Care: Local Perspective from Saudi Arabia." Journal of Cancer Education 32, no. 2 (January 23, 2016): 314–19. http://dx.doi.org/10.1007/s13187-015-0973-2.

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Bellos, I., G. Fitrou, V. Pergialiotis, D. N. Perrea, and G. Daskalakis. "Serum levels of adipokines in gestational diabetes: a systematic review." Journal of Endocrinological Investigation 42, no. 6 (November 3, 2018): 621–31. http://dx.doi.org/10.1007/s40618-018-0973-2.

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de Carvalho Pinto, P. C., M. M. de Oliveira Carvalho, F. M. Linhares, T. R. da Silva, and G. M. de Lima. "A cleaner production of sodium hydrogen carbonate: partial replacement of lime by steel slag milk in the ammonia recovery step of the Solvay process." Clean Technologies and Environmental Policy 17, no. 8 (May 23, 2015): 2311–21. http://dx.doi.org/10.1007/s10098-015-0973-2.

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Bisdas, Sotirios, Zoran Rumboldt, Katarina Surlan, Tong San Koh, John Deveikis, and Maria Vittoria Spampinato. "Perfusion CT measurements in healthy cervical spinal cord: feasibility and repeatability of the study as well as interchangeability of the perfusion estimates using two commercially available software packages." European Radiology 18, no. 10 (April 23, 2008): 2321–28. http://dx.doi.org/10.1007/s00330-008-0973-2.

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Wu, Jia, Zilin Xu, Yixuan Pan, Yi Shi, Xiujie Bao, Jun Li, Yu Tong, et al. "Combination of in situ metathesis reaction with a novel “magnetic effervescent tablet-assisted ionic liquid dispersive microextraction” for the determination of endogenous steroids in human fluids." Analytical and Bioanalytical Chemistry 410, no. 12 (March 12, 2018): 2921–35. http://dx.doi.org/10.1007/s00216-018-0973-2.

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Hassan, Jihaan, Jan Jaap van der Net, and Annet van Royen-Kerkhof. "Treatment of refractory juvenile dermatomyositis with tacrolimus." Clinical Rheumatology 27, no. 11 (August 21, 2008): 1469–71. http://dx.doi.org/10.1007/s10067-008-0973-2.

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Van Gorder, Robert A., K. V. Prasad, and K. Vajravelu. "Convective heat transfer in the vertical channel flow of a clear fluid adjacent to a nanofluid layer: a two-fluid model." Heat and Mass Transfer 48, no. 7 (January 18, 2012): 1247–55. http://dx.doi.org/10.1007/s00231-012-0973-2.

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Shui, Linqi, Jianmin Gao, Xiaojun Shi, Jiazeng Liu, and Liang Xu. "The effect of cooling conditions on convective heat transfer and flow in a steam-cooled ribbed duct." Journal of Mechanical Science and Technology 28, no. 1 (January 2014): 331–41. http://dx.doi.org/10.1007/s12206-013-0973-2.

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Wang, Baoying, Chenghu Hu, Xiaobei Yang, Fangying Du, Yan Feng, Hongbo Li, Chunhui Zhu, and Xiaorui Yu. "Inhibition of GSK-3β Activation Protects SD Rat Retina Against N-Methyl-N-Nitrosourea-Induced Degeneration by Modulating the Wnt/β-Catenin Signaling Pathway." Journal of Molecular Neuroscience 63, no. 2 (September 19, 2017): 233–42. http://dx.doi.org/10.1007/s12031-017-0973-2.

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Grumett, David. "Le Christ de Maurice Blondel. Edited by René Virgoulay. Pp. 229. (Jésus et Jésus-Christ, 86). Paris: Desclée, 2003. isbn 2 7189 0973 0. Paper €18." Journal of Theological Studies 57, no. 1 (April 1, 2006): 390–92. http://dx.doi.org/10.1093/jts/flj035.

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Comeaux, Evan, Wenwei Lin, Taosheng Chen, Burgess Freeman, and Charles G. Mullighan. "PI3K and MEK Inhibition in Hypodiploid Acute Lymphoblastic Leukemia." Blood 128, no. 22 (December 2, 2016): 1635. http://dx.doi.org/10.1182/blood.v128.22.1635.1635.

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Abstract:

Abstract Introduction: Hypodiploid acute lymphoblastic leukemia (ALL) is a rare, high-risk subtype of B-ALL associated with poor outcome. Genomic analysis of over 130 Hypodiploid ALL patients defined the distinct genomic landscape of this disease, defining two principal subtypes including Ras-activating alterations and IKZF3 loss in near haploid tumors (24-31 chromosomes) and mutation of TP53 coupled with homozygous IKZF2 loss in low hypodiploid tumors (32-39 chromosomes). New therapies are needed to improve outcome of this disease, necessitating preclinical studies in hypodiploid tumors in vitro, ex vivo and in vivo. Hypothesis: The observation of frequent Ras pathway activating mutations in hypodiploid ALL tumors, as well as increased phosphorylation of downstream Ras signaling targets, suggests that these tumors may be susceptible to PI3K/MEK inhibition. Ras signaling target activation was observed in hypodiploid tumors irrespective of mutational status. Here we used cell lines and representative xenograft models to explore the therapeutic efficacy of inhibiting PI3K/MAPK signaling in hypodiploid ALL. Methods: The near haploid cell lines NALM-16 and MHH-CALL-2 and eight patient-derived xenograft (PDX) models (four near haploid and four low hypodiploid) were selected for preclinical studies. Xenografts were representative of the most common genomic lesions observed in hypodiploid ALL patients, including deletion of NF1, PAG1 and IKZF3 in near haploid and mutation of TP53 and IKZF2 deletion in low hypodiploid (Holmfeldt et al. Nat Genet 2013; Mullighan et al. Blood 2015). Next-gen sequencing of xenograft and diagnosis tumor DNA confirmed the presence of key genetic alterations in the xenografts. A lentiviral vector was used for stable expression of luciferase in xenograft tumors for in vivo disease burden monitoring. Cell lines were treated in vitro with PI3K, mTOR, MEK, CDK4/6 and BET inhibitors either as single agents, inhibitor combinations or combined with chemotherapeutic agents. Xenografts were treated ex vivo with single agents and in vivo with PI3K and MEK inhibitors with or without chemotherapy. Results: NALM-16 and MHH-CALL-2 cell lines were most sensitive to PI3K, mTOR and BET inhibitors with IC50 values in the sub-micromolar range (Fig. 1).Treatment of xenografts ex vivo showed near haploid and low hypodiploid tumors to be four-fold more sensitive to pan-PI3K inhibitors and PI3K/mTOR dual inhibitors compared to PI3K α and d isoform-specific inhibitors. Near haploid and low hypodiploid xenografts were sensitive to MEK and BET inhibition ex vivo, but MEK inhibitors showed weak activity in the near haploid cell lines. Treatment with CDK4/6 inhibitors either as single agents or in combination with MEK inhibitors revealed minimal efficacy. Changes in cell signaling upon treatment was assayed by phosphoflow (Fig. 2). Akt and Erk1/2 phosphorylation was variable between tumors, whereas 4E-BP1 and S6 phosphorylation was consistently elevated, suggesting strong signaling through mTOR pathways. Pan-PI3K and PI3K/mTOR dual inhibitors showed potent activity against hypodiploid ALL tumors in vitro and ex vivo, however PI3K inhibition alone was insufficient to eliminate tumors in vivo. Substantial weight loss in mice treated with PI3K/mTOR dual inhibitors limited prolonged study in vivo. MAPK inhibition showed activity in both near haploid and low hypodiploid tumors ex vivo and displayed a modest reduction in tumor growth as a single agent in vivo. Combining the MEK inhibitor GDC-0973 with dexamethasone treatment increased efficacy, but induced significantly more weight loss than either monotherapy. Conclusion: Treatment of hypodiploid cell lines and xenografts in vitro and ex vivo, respectively, with PI3K and MEK inhibitors showed promising results, however the anti-tumor effect in vivo appeared mostly cytostatic and inhibitors were not sufficient as single agents to kill the tumor cells. MEK inhibitors showed stronger activity than PI3K inhibitors on xenografts in vivo and ex vivo, but this was not significantly increased when combined with dexamethasone treatment. The notable resistance of hypodiploid cells to dexamethasone may underlie this limited efficacy in addition to the increase in GDC-0973 clearance observed upon combination. Our findings also highlight the need to consider the PK properties of agents in the preclinical setting, particularly in combinations. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures No relevant conflicts of interest to declare.

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Pérez domínguez, G., M. Torrens, and R. Martín-santos. "Adhesión al tratamiento antirretroviral en pacientes toxicómanos con infección por el VIH." Trastornos Adictivos 3, no. 1 (January 2001): 43–50. http://dx.doi.org/10.1016/s1575-0973(01)70006-2.

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Escarabajal Arrieta, M. D. "¿Alcoholismo o acetaldehismo? el papel de la catalasa y la aldehído deshidrogenasa cerebrales." Trastornos Adictivos 3, no. 4 (January 2001): 290–91. http://dx.doi.org/10.1016/s1575-0973(01)78583-2.

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Rodríguez-martos dauer, A., and L. Torralba novella. "La reducción de daños relacionados con el alcohol desde una perspectiva municipal: la estrategia de Barcelona*." Trastornos Adictivos 4, no. 1 (January 2002): 28–38. http://dx.doi.org/10.1016/s1575-0973(02)70048-2.

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