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Fouda, A. S., M. A. Ismail, A. S. Abousalem y 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, n.º 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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Thriveni*, M. C., Raju Mondal, G. Thanavendan, G. Ravikumar y B. T. Sreenivasa. "Characterization of Mulberry Genetic Resources for Multiple Traits". Indian Journal of Botany 1, n.º 2 (10 de octubre de 2021): 8–15. http://dx.doi.org/10.35940/ijb.b2004.101221.
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Mulberry plants have wide range of variations in characters in view of its adaptability to cross pollination with no inter-specific reproduction barrier rendering it a heterozygous species. Every plant being different from the other in natural population, this great diversity makes it difficult to gather information and carry out studies on effect of different edaphic factors on the expression of genotypic characters for adjudging the variations. In lieu of this known diversity for posterity, the collection of mulberry genotypes from diverse genetic sources, their conservation, evaluation and consequent documentation is of prime importance. In the present study, 69 mulberry accessions were characterized for morphology, anatomy, and reproductive parameters. Evaluation for propagation, growth and yield characters were also carried out. Based on multiple trait analysis, 14 top performing accessions viz., MI-0879, MI-0882, MI-0908, MI-0931, MI-0907, MI-0940, MI-0881, MI-0941, MI0892, MI-0913, MI-0937, MI-0934, MI-0865, MI-0886 were identified. These accessions could serve as resources for further evaluation aimed at trait-specific crop improvement.
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Yang, Hongqin, Yanjun Ma, Hongjie Zhang y Junyi Ma. "PI3K/mTOR Dual Inhibitor Pictilisib Stably Binds to Site I of Human Serum Albumin as Observed by Computer Simulation, Multispectroscopic, and Microscopic Studies". Molecules 27, n.º 16 (9 de agosto de 2022): 5071. http://dx.doi.org/10.3390/molecules27165071.
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Pictilisib (GDC-0941) is a well-known dual inhibitor of class I PI3K and mTOR and is presently undergoing phase 2 clinical trials for cancer treatment. The present work investigated the dynamic behaviors and interaction mechanism between GDC-0941 and human serum albumin (HSA). Molecular docking and MD trajectory analyses revealed that GDC-0941 bound to HSA and that the binding site was positioned in subdomain IIA at Sudlow’s site I of HSA. The fluorescence intensity of HSA was strongly quenched by GDC-0941, and results showed that the HSA–GDC-0941 interaction was a static process caused by ground-state complex formation. The association constant of the HSA–GDC-0941 complex was approximately 105 M−1, reflecting moderate affinity. Thermodynamic analysis conclusions were identical with MD simulation results, which revealed that van der Waals interactions were the vital forces involved in the binding process. CD, synchronous, and 3D fluorescence spectroscopic results revealed that GDC-0941 induced the structural change in HSA. Moreover, the conformational change of HSA affected its molecular sizes, as evidenced by AFM. This work provides a useful research strategy for exploring the interaction of GDC-0941 with HSA, thus helping in the understanding of the transport and delivery of dual inhibitors in the blood circulation system.
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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, n.º 15_suppl (20 de mayo de 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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Ma, Xiaoju Max, Changchun Du, Laura Sun, Xiaoyan Shi, Lori Friedman, David Dornan y Allen J. Ebens. "PI3K Signaling Pathway Activation Predicts Class I PI3K Inhibitor GDC-0941 Sensitivity in AML." Blood 114, n.º 22 (20 de noviembre de 2009): 1057. http://dx.doi.org/10.1182/blood.v114.22.1057.1057.
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Abstract Abstract 1057 Poster Board I-79 The PI3K-Akt signal transduction pathway plays a key role in the pathogenesis of many human cancers. In AML malignancy, deregulation of upstream receptor tyrosine kinases such as FLT3, c-Kit, and c-FMS or mutations in K-Ras, N-Ras, B-Raf and CEBPA genes lead to activation of PI3K-Akt signaling to promote cell survival and cell growth. A highly selective Class I PI3K inhibitor, GDC-0941, provides exciting therapeutic opportunities for targeting this pathway in AML. Here we show that GDC-0941 significantly inhibits the viability of the majority of a large panel of AML cell lines tested in vitro (80% or 19/24) at a concentration of < 1 uM. Because not all AML cell lines responded to GDC-0941, we show that PI3K-Akt pathway activation, evidenced by basal pAkt level, can serve as a potential predictive biomarker for GDC-0941 in AML in that sensitive cell lines displayed higher level of pAkt relative to resistant cell lines. Consistently, GDC-0941 treatment leads to decreased pAkt, and therefore the down-regulation of this important pro-survival signaling. Our further analysis shows that GDC-0941 treatment can induce apoptosis and/or cell cycle arrest. We also obtained fresh AML tumor samples to test whether GDC-0941 can similarly induces apoptosis in blast cells and showed that GDC-0941 treatment results in a down-regulation of pAkt level and increased apoptosis. Other PD biomarkers such as phospho-BAD level and Bim expression are both consistent with the observed apoptotic responses. Furthermore, the mammalian target of rapamycin complex 1 (mTORC1) inhibitor, rapamycin, synergizes with GDC-0941 to produce an increased amount of apoptosis in several AML cell lines tested. This is likely due to the fact that long-term treatment with rapamycin induces the sensitivity of the PI3K –Akt signaling pathway by releasing the negative feedback loop of mTORC1-S6K-IRS1/2 module. Importantly, in some AML cell lines we observe synergies between GDC-0941 and AraC. Interestingly, while AraC alone does not induce apoptosis in AML cell lines with PTEN loss or mutation, the synergy between AraC and GDC-0941 comes from increased apoptotic response, suggesting that GDC-0941 can synergize with chemo agents that induces S/G2 cell cycle arrest. Together, our preclinical data suggest that GDC-0941 may be used as a targeted therapy in AML patients as a single agent or in combination with other chemotherapies in clinic. Disclosures: Ma: Genentech Inc.: Employment. Du:Genentech, Inc.: Employment, Equity Ownership. Sun:Genentech Inc.: Employment. Shi:Genentech, Inc.: Employment, Equity Ownership. Friedman:Genentech Inc.: Employment. Dornan:Genentech, Inc.: Employment, Equity Ownership. Ebens:Genentech, Inc.: Employment, Equity Ownership, Patents & Royalties.
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De, Pradip, Yuliang Sun, Lori Friedman, Nandini Dey y 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, n.º 15_suppl (20 de mayo de 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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Jin, Linhua, Yoko Tabe, Yixin Zhou, Takashi Miida, Michael Andreeff y Marina Konopleva. "Efficacy and Mechanisms of Apoptosis Induction by Simultaneous Inhibition of PI3K with GDC-0941 and Blockade of Bcl-2 (ABT-737) or FLT3 (Sorafenib) In AML Cells In the Hypoxic Bone Marrow Microenvironment". Blood 116, n.º 21 (19 de noviembre de 2010): 777. http://dx.doi.org/10.1182/blood.v116.21.777.777.
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Abstract Abstract 777 Hypoxia and the interactions with bone marrow (BM) stromal cells have emerged as important mechanisms of leukemia cell survival and chemoresistance. The PI3K-Akt-mTOR-HIF1a signaling pathway has been shown to be activated in response to hypoxia in several cancer models including AML. Therefore, effective targeting of PI3K/Akt signaling pathway could suppress AML cell survival in the hypoxic BM microenvironment. Furthermore, concomitant intra-pathway blockade, or inhibition of the key pro-survival pathways may be more effective. In this study, we investigated the anti-leukemia effects and molecular mechanisms of apoptosis induction in the context of hypoxic bone marrow microenvironment by simultaneous use of a selective Class I PI3K inhibitor GDC-0941 (Genentech) with BH3 mimetic ABT-737 (Abbott) or FLT3 inhibitor sorafenib in AML cells. For hypoxia experiments, AML cells with FLT3-ITD mutation and wild-type FLT3 (FLT3-ITD: MOLM13, MV4;11, wt-FLT3: HL60) were cultured under 1.0% O2 for at least 14 days to assure their continuous proliferation and survival. Under hypoxia, more cells accumulated in G0/G1 phase, indicating that hypoxic conditions promote cell cycle quiescence in leukemic cells. GDC-0941 treatment in normoxia resulted in a reduction of cell proliferation with G0/G1 cell cycle arrest and minimal apoptosis induction, in a time and concentration-dependent manner (IC50 at 48 hrs; 0.7 μM for HL-60, 0.9 μM for MOLM13, 0.7 μM for MV4;11). In hypoxia, GDC-0941 further enhanced cell growth inhibition and G0/G1 cell cycle arrest. Importantly, co-culture with BM mesenchymal stroma cells (MSC), which protected AML cells from cytarabine induced apoptosis, did not affect cell growth inhibition by GDC-0941 both in normoxia and hypoxia. Combined treatment of GDC-0941 synergistically enhanced the ABT-737- or sorafenib induced apoptosis under both normoxic- and hypoxic conditions (p<0.05). Combination Index of GDC-0941/ABT-737 was 0.25 for HL-60 and 0.86 for MOLM13 cells; GDC-0941/sorafenib 0.58 for MV4;11 and 0.65 for MOLM13. In FLT3/ITD harboring MOLM13 and MV4;11 cells, ABT-737 and GDC-0941/ABT-737, or sorafenib and GDC-0941/sorafenib-induced apoptosis was partially reversed by MSC co-culture in normoxia, but not in hypoxia. We next examined the molecular mechanisms of apoptosis induction by simultaneous blockade of PI3K and mutant FLT3 in MOLM13 cells. GDC-0941 inhibited phospho-AktSer473, irrespective of oxygen tension. Hypoxia increased/induced phosphorylation of AktSer473, and of the pro-survival serine/threonine-protein kinase Pim-1, known to promote hypoxia-induced chemoresistance. Pim-1 is a downstream target of Akt and FLT-3 signaling that promotes cell survival and inhibits apoptosis through Bcl-2-dependent mechanisms. While GDC-0941 or ABT-737 alone did not affect hypoxia-induced Pim-1 levels, the GDC-0941/ABT-737 combination down-regulated Pim-1 by 86% (24 hrs). Treatment with sorafenib induced Pim-1 down-regulation by itself by 70%. Under hypoxia, expression levels of Bcl-2 family proteins Bcl-2 and BIM were not significantly changed by any treatment and cell culture conditions. In turn, Mcl-1 expression was upregulated by MSC co-cultures. Further, sorafenib alone but not GDC-0941 or ABT-737 decreased Mcl-1 protein levels, which was reversed by MSC co-culture in hypoxia; in turn, the GDC-0941/sorafenib or GDC-0941/ABT-737 combination potently suppressed Mcl-1 expression under MSC/hypoxia conditions. These changes were associated with the observed apoptotic responses. In summary, our findings indicate that hypoxic conditions of BM microenvironment result in stimulation of the pro-survival Akt and PIM kinase pathways and increase anti-apoptotic Mcl-1 protein in AML cells with mutated FLT3. In turn, simultaneous blockade of PI3K and FLT3 pathways, or of PI3K and Bcl-2 results in inhibition of these signaling modules and synergistic induction of apoptosis in AML. This data suggest that combined inhibition of Bcl-2 with PI3K or FLT3-ITD may constitute a targeted approach to eradicate chemoresistant AML cells sequestered in the hypoxic BM niches. Disclosures: No relevant conflicts of interest to declare.
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Sarker, D., R. Kristeleit, K. E. Mazina, J. A. Ware, Y. Yan, M. Dresser, M. K. Derynck y 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, n.º 15_suppl (20 de mayo de 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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Kikuchi, Hugh, Eunice Amofa, Maeve Mcenery, Steve Arthur Schey, Karthik Ramasamy, Farzin Farzaneh y Yolanda Calle. "Inhibition of PI3K Class IA Kinases Using GDC-0941 Overcomes Cytoprotection of Multiple Myeloma Cells in the Osteoclastic Bone Marrow Microenvironment Enhancing the Efficacy of Current Clinical Therapeutics". Cancers 15, n.º 2 (11 de enero de 2023): 462. http://dx.doi.org/10.3390/cancers15020462.
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Osteoclasts contribute to bone marrow (BM)-mediated drug resistance in multiple myeloma (MM) by providing cytoprotective cues. Additionally, 80% of patients develop osteolytic lesions, which is a major cause of morbidity in MM. Although targeting osteoclast function is critical to improve MM therapies, pre-clinical studies rarely consider overcoming osteoclast-mediated cytoprotection within the selection criteria of drug candidates. We have performed a drug screening and identified PI3K as a key regulator of a signalling node associated with resistance to dexamethasone lenalidomide, pomalidomide, and bortezomib mediated by osteoclasts and BM fibroblastic stromal cells, which was blocked by the pan-PI3K Class IA inhibitor GDC-0941. Additionally, GDC-0941 repressed the maturation of osteoclasts derived from MM patients and disrupted the organisation of the F-actin cytoskeleton in sealing zones required for bone degradation, correlating with decreased bone resorption by osteoclasts. In vivo, GDC-0941 improved the efficacy of dexamethasone against MM in the syngeneic GFP-5T33/C57-Rawji mouse model. Taken together, our results indicate that GDC-0941 in combination with currently used therapeutic agents could effectively kill MM cells in the presence of the cytoprotective BM microenvironment while inhibiting bone resorption by osteoclasts. These data support investigating GDC-0941 in combination with currently used therapeutic drugs for MM patients with active bone disease.
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Dail, Monique, Jason Wong, Jessica Lawrence, Daniel O'Connor, Joy Nakitandwe, Shann-Ching Chen, Keiko Akagi et al. "Preclinical Testing Of a PI3K Inhibitor In T Lineage Leukemia: Target Validation and Notch1/Myc Down-Regulation In Drug Resistant Clones". Blood 122, n.º 21 (15 de noviembre de 2013): 2677. http://dx.doi.org/10.1182/blood.v122.21.2677.2677.
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Abstract Mutations that deregulate Notch1 and Ras/PI3K/Akt signaling are common in T-ALL and often coexist. Thus, inhibiting these pathways alone and in combination has been advocated as a rational therapeutic strategy. GDC-0941 is a pan-PI3K inhibitor that is advancing in clinical development that we evaluated for efficacy and mechanisms of drug resistance in T-ALL cell lines and primary murine T-ALLs. Cell lines are uniformly sensitive to GDC-0941; however gradual dose escalation results in resistant lines. By contrast, primary leukemia cells display variable in vivo sensitivity to treatment with GDC-0941 +/- a MEK inhibitor. Importantly, mice invariably relapse with drug resistant clones. A majority of GDC-0941-resistant T-ALL cell lines and primary leukemias unexpectedly showed reduced levels of activated Notch1 protein, down-regulate many Notch1 target genes including Myc, and display cross-resistance to gamma secretase inhibitors (GSIs). In multiple cases, Notch1 mutations that were present in drug-sensitive parental leukemias were absent at relapse. Importantly, resistant clones that emerge both in vitro and in vivo up-regulate PI3K signaling indicating an “on pathway” mechanism of resistance. Consistent with these data, inhibition of Notch1 signaling promotes GDC-0941 resistance and enhances PI3K signaling, whereas expression of activated Notch1 increases the GDC-0941 sensitivity of mouse and human T-ALL cell lines. Thus, oncogenic Notch1 mutations that promote clonal outgrowth during malignant transformation unexpectedly undergo negative selection during treatment with GDC-0941. Together, these in vivo studies: (1) validate PI3K as an important therapeutic target in T-ALL; (2) demonstrate that active Notch1 and elevated Myc expression are dispensable for T-ALL growth in vivo; and, (3) indicate that therapeutic PI3K inhibition selects for the outgrowth of leukemia cells with reduced Notch1 signaling. Importantly, our data also raise the possibility that simultaneously administering Notch1 and PI3K inhibitors will accelerate drug resistance in T-ALL, and support alternative approaches for deploying combination regimens against these dominant oncogenic “driver” pathways. Disclosures: Lee: Genentech: Employment. Aster:Cell Signaling Technology: Consultancy; Merck, Inc.: Research Funding; Pfizer, Inc.: Research Funding; Genentech, Inc.: Honoraria. Sampath:Genentech: Employment, Equity Ownership.
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Tsumura, Yoshinori, Yu Tsushima, Azusa Tamura, Hirotsugu Kato y Tsunefumi Kobayashi. "Disruptions in hepatic glucose metabolism are involved in the diminished efficacy after chronic treatment with glucokinase activator". PLOS ONE 17, n.º 3 (21 de marzo de 2022): e0265761. http://dx.doi.org/10.1371/journal.pone.0265761.
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Glucokinase activators are regarded as potent candidates for diabetes treatment, however, in clinical studies on patients with type 2 diabetes, a diminishing efficacy was observed after chronic treatment with them. The mechanism of this reduction has not been elucidated, and whether it is a class effect of glucokinase activators remains inconclusive. Here, we firstly identified a diabetic animal model that shows the diminished efficacy after long-term treatment with MK-0941, a glucokinase activator that exhibited diminished efficacy in a clinical study, and we analyzed the mechanism underlying its diminished efficacy. In addition, we evaluated the long-term efficacy of another glucokinase activator, TMG-123. Goto-Kakizaki rats were treated with MK-0941 and TMG-123 for 24 weeks. The results showed that glycated hemoglobin A1C levels and plasma glucose levels decreased transiently but increased over time with the continuation of treatment in the MK-0941-treated group, while decreased continuously in the TMG-123-treated group. Only in the TMG-123-treated group, higher plasma insulin levels were shown at the later stage of the treatment period. For the mechanism analysis, we conducted a hepatic enzyme assay and liver perfusion study in Goto-Kakizaki rats after chronic treatment with MK-0941 and TMG-123, and revealed that, only in the MK-0941-treated group, the activity of glucose-6-phosphatase was increased, and hepatic glucose utilization was decreased compared to the non-treated group. These data indicate that disruptions in hepatic glucose metabolism are involved in the diminished efficacy of glucokinase activators.
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Li, Xiaodong, Yuanyue Zhang, Williams Walana, Feng Zhao, Fang Li y Fuwen Luo. "GDC-0941 and CXCL8 (3-72) K11R/G31P combination therapy confers enhanced efficacy against breast cancer". Future Oncology 16, n.º 14 (mayo de 2020): 911–21. http://dx.doi.org/10.2217/fon-2020-0035.
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Aim: Herein is presented the combined effect of PI3K inhibitor (GDC-0941) and CXCR1/2 analogue (G31P) in breast cancer. Materials & methods: Breast cancer cell lines and xenograft model were employed to test the efficacy of the combination therapy. Results: GDC-0941+G31P treatment substantially inhibited multiplication of all the breast cancer cell lines used in this study (BT474, HCC1954 and 4T1). Even though single therapies caused a meaningful S-phase cell cycle arrest, the inhibition effect was more potent with the combined treatment. Similarly, enhanced apoptosis accompanied GDC-0941+G31P treatment. Furthermore, the migration ability of the breast cancer cell lines were significantly curtailed by the combination therapy compared with the single treatments. Conclusion: The findings suggest that combination treatment involving PI3K inhibitor and CXCR1/2 analogue (G31P) could be a potent therapeutic option for breast cancer treatment.
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Tabe, Yoko, Linhua Jin, Takashi Miida, Michael Andreeff y Marina Konopleva. "Growth-Inhibitory Effects of a Class I PI3K Inhibitor GDC-0941 Are Modulated by Hypoxia-Induced mTOR Pathway Activation in Mantle Cell Lymphoma". Blood 118, n.º 21 (18 de noviembre de 2011): 1424. http://dx.doi.org/10.1182/blood.v118.21.1424.1424.
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Abstract Abstract 1424 Hypoxia confers pro-survival signals to tumor cells via multiple mechanisms including activation of phosphatidylinositol 3-kinase (PI3K)/Akt/mTOR pathway. Constitutive activation of PI3K/Akt signaling pathway is documented in aggressive blastoid variants of mantle cell lymphoma (MCL) and is implicated in the pathogenesis of MCL. mTOR signaling, one of the important downstream targets of Akt, positively regulates protein translation by phosphorylating p70 ribosomal S6 kinase (S6K) or eukaryotic initiation factor 4E-binding protein-1 (4E-BP1). We have reported that the Class IA PI3K isoforms, mainly p110α and partially p110δ, are responsible for PI3K/Akt/mTOR signaling activation in blastoid MCL cells (Zhou et al., ASH abstract 2010). In this study, the activity and molecular mechanisms of action of a selective pan-isoform class I PI3K inhibitor GDC-0941 (Genentech) were investigated in the context of hypoxic microenvironment in MCL cells. For hypoxia experiments, MCL cells were cultured under 1% O2 for at least 14 days to assure their sustained proliferation and survival. Under hypoxia, more cells accumulated in G0/G1 phase, indicating that hypoxic conditions promote cell cycle quiescence in MCL cells. GDC-0941 treatment in normoxia resulted in a reduction of cell proliferation in a dose-dependent manner (IC50 at 48 hrs; 0.7 μM for Granta519, 0.5 μM for JVM2, 1.0 μM for MINO, 0.7 μM for Jeko-1, MTT test). In hypoxia, higher doses of GDC-0941 were required to cause cell growth inhibition compared to normoxic conditions in Granta519 (IC50; 1.7 μM), JVM2 (3.5 μM) and MINO (1.2 μM). Further, GDC-0941 failed to inhibit growth of Jeko-1 cells under hypoxia. GDC-0941 (0.5 μM) induced G0/1 cell cycle arrest under both normoxic and hypoxic conditions in Granta519, JVM2 and MINO cells. No significant induction of apoptosis by GDC-0941 (0.5 μM) was observed in any of the tested MCL cells. GDC-0941 completely inhibited phosphorylated (p-Ser473) Akt in all cell lines analyzed under both normoxic and hypoxic conditions, which resulted in decreased expression of p-GSK-3β and its downstream target cyclin D1. GDC-0941 further downregulated the mTOR downstream targets p-S6K and p-4EBP1 in Granta519, JVM2 and MINO cells under both, normoxia and hypoxia. On the contrary, GDC-0941 failed to affect hypoxia-induced p-S6K and p-4EBP1 expression levels in Jeko-1 cells, whereas potently suppressed these proteins at ambient oxygen level. These results suggest that in Jeko-1 cells hypoxia activates mTOR through PI3K-independent pathways. To test this, we examined consequences of mTOR blockade in Jeko-1 cells. mTOR inhibitor rapamycin (100 nM) moderately diminished cell growth under normoxic conditions causing accumulation of cells in G0/1 cell cycle phase but no apoptosis. In turn, under hypoxia rapamycin profoundly inhibited cell growth, inducing >80% of MCL cells to undergo cell death. These findings indicate that in certain MCL cells hypoxia activates mTOR through alternative, PI3K-independent pathways, which facilitate cell survival under hypoxia. Hence, blockade of class I PI3K may eliminate circulating MCL cells but not tissue-resident cells in hypoxic areas of the bone marrow or lymph nodes. In turn, simultaneous therapeutic ablation of PI3K/Akt and mTOR pathway may represent a promising strategy to target the aggressive blastoid variants of MCL cells in the hypoxic microenvironments. Disclosures: No relevant conflicts of interest to declare.
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Thriveni, Mallegowdanakoppalu C., Sampathkumar Deepa, Ganesan Thanavendan, G. Ravikumar y B. T. Sreenivasa. "Characterization and Evaluation of Mulberry Genetic Resources for the Identification of Promising Accessions". Indian Journal of Plant Genetic Resources 36, n.º 01 (9 de diciembre de 2023): 85–95. http://dx.doi.org/10.61949/0976-1926.2023.v36i01.12.
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Mulberry is a dioecious species but, is usually cultivated as low bush or dwarf tree form by repeated pruning. Apart from its importance in silkworm rearing, it is also valued for its delicious fruits, medicinal properties in infusions, and ornamental shade tree. The conservation of mulberry genetic resources for future use and their subsequent usage in plant breeding are two critical areas of action in any genetic resource management programme. The current study used morphological, reproductive, anatomical, biochemical, propagation, growth, and yield variables to know the potential value of 22 mulberry accessions. Based on multiple trait analysis, the accessions MI-0946, MI-0945, MI-0953, MI-0948, MI-0935, MI-0948, MI-0936 and MI-0952 were identified as top performers for anatomy, propagation, biochemical, growth and yield parameters. These accessions may serve as potential parents for the future breeding program.
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Munugalavadla, Veerendra, Leanne Berry, Changchun Du, Sanjeev Mariathasan, Dion Slaga, Laura Sun, Marta Chesi, Peter Leif Bergsagel y Allen J. Ebens. "The PI3K Inhibitor GDC-0941 Synergizes with Standard of Care Therapies to Induce Growth Inhibition and Apoptosis of Multiple Myeloma Cells." Blood 114, n.º 22 (20 de noviembre de 2009): 3788. http://dx.doi.org/10.1182/blood.v114.22.3788.3788.
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Abstract Abstract 3788 Poster Board III-724 Multiple myeloma (MM) is a malignancy characterized by clonal expansion and accumulation of long-lived plasma cells within the bone marrow. Phosphatidylinositol 3' kinase (PI3K) -mediated signaling is frequently dysregulated in cancer and controls fundamental cellular functions such as cell migration, growth, survival and development of drug resistance in many cancers, including MM, and therefore represents an attractive therapeutic target. Here, we demonstrate in vitro, that a potent and selective pan-isoform PI3Kinhibitor, GDC-0941, modulates the expected pharmacodynamic markers, inhibits cell-cycle progression and induces apoptosis; overcomes resistance to apoptosis in MM cells conferred by IGF-1 and IL-6; and is additive or synergistic with current standard of care drugs including dexamethasone, melphalan, lenolidamide and bortezomib. In cell lines we find sensitivity to GDC-0941 is positively correlated with pathway activation as determined by phospho-AKT-specific flow-cytometry and Western-blot analysis. Preliminary results indicate apoptosis of MM cells is correlated with increased expression of the proapoptotic BH3-only protein BIM; mechanisms of increased apoptosis in MM will be further explored and an update presented. We further extend these in vitro findings to show that GDC-0941 has activity as a single agent in vivo and combines well with standard of care agents in several murine xenograft models to delay tumor progression and prolong survival. Our results suggest that GDC-0941 may combine well with existing therapies, providing a framework for the clinical use of this agent, and a rational approach to improving the efficacy of myeloma treatment. Disclosures: Munugalavadla: Genentech: Employment, Patents & Royalties. Berry:Genentech: Employment, Patents & Royalties. Du:Genentech, Inc.: Employment, Equity Ownership. Mariathasan:Genentech: Employment, Patents & Royalties. Slaga:Genentech: Employment, Patents & Royalties. Sun:Genentech Inc.: Employment. Chesi:Genentech, Inc.: Consultancy; Amgen: Consultancy; Celgene: Consultancy; Merck: Research Funding. Bergsagel:Genentech: Consultancy; Amgen: Consultancy; Celgene: Consultancy; Merck: Research Funding. Ebens:Genentech, Inc.: Employment, Equity Ownership, Patents & Royalties.
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Wagner, A. J., D. H. Von Hoff, P. M. LoRusso, R. Tibes, K. E. Mazina, J. A. Ware, Y. Yan, M. K. Derynck y G. D. Demetri. "A first-in-human phase I study to evaluate the pan-PI3K inhibitor GDC-0941 administered QD or BID in patients with advanced solid tumors". Journal of Clinical Oncology 27, n.º 15_suppl (20 de mayo de 2009): 3501. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.3501.
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3501 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 the class I PI3K with 3 nM IC50 for the p110-alpha subunit in vitro and 28 nM IC50 in a cell-based pAKT assay and demonstrates broad activity in breast, ovarian, lung, and prostate cancer models. Methods: A Phase I dose escalation study using a 3+3 design was initiated in patients (pts) with solid tumors. GDC-0941 was given on d1, followed by 1 wk washout to study single-dose PK and PD markers. GDC-0941 was then administered qd on a 3 wk on, 1 wk off, schedule. Steady-state PK and PD were evaluated after 1 wk of continuous dosing. A separate concurrent dose-escalation arm with bid dosing was initiated after the third qd cohort. Results: Nineteen pts have been enrolled in 5 successive dose-escalation cohorts in the qd arm with dose levels up to 80 mg daily. Seven pts were enrolled in 2 cohorts in the bid arm at total daily doses of 60 and 80 mg. The most frequently reported drug-related AEs were Grade 1/2 nausea, fatigue, diarrhea, peripheral edema, and dysgeusia; no drug related grade >3 events have been reported. PK data suggest dose-proportional increases in Cmax and AUC. Potential signs of anti-tumor activity have been observed with a soft tissue sarcoma pt on-study for >176 days with stable disease (30 mg qd), an ovarian cancer pt with an on-study 2.8-fold decrease in CA-125 response to normal levels (30 mg bid) and a pt with endometrial cancer with a decrease in tumor FDG-PET uptake (80 mg qd). Conclusions: GDC-0941 is generally well-tolerated with potential signs of anti-tumor activity. Preliminary PK data suggest dose-proportional increases in exposure over the dose levels evaluated. Dose-escalation on both the qd and bid schedules continues with updated data to be presented. [Table: see text]
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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, n.º 21 (18 de noviembre de 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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Choi, Jae Hyeog, Ki Hyang Kim, Kug Hwan Roh, Hana Jung, Su Kil Seo, Il Whan Choi, Sung Su Yea y SaeGwang Park. "Combination therapy of a PI3K p110α-isoform-selective inhibitor and anti-HER2/neu antibody enhances the anti-tumor immunity in breast cancer mouse model". Journal of Immunology 198, n.º 1_Supplement (1 de mayo de 2017): 204.9. http://dx.doi.org/10.4049/jimmunol.198.supp.204.9.
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Abstract Trastuzumab (Herceptin) is a humanized recombinant monoclonal antibody against HER2 that has shown the clinical benefit in HER2+ breast cancer patients. Because non-responders to trastuzumab have been observed, one strategy to overcome the resistance is combination therapy. Combination therapies with phosphoinositide 3-kinase (PI3K) inhibitors and trastuzumab (anti-HER2/neu antibody) are effective against HER2+ breast cancer mouse model. The therapeutic effect and anti-tumor immunity of combination therapy with an anti-HER2/neu antibody and a pan-PI3K inhibitor (GDC-0941) or a p110a isoform-selective inhibitor (A66) was evaluated in vivo breast cancer models. Combined the anti-neu and PI3Ki treatment synergistically occurred in anti-tumor immunity and HER2/neu-mediated memory T cell responses. In the presence of the anti-neu antibody, A66 was more effective in increasing the T cells and IFN-γ+ CD8+ T cells in TILs. IFN-γ ELISPOT data showed that tumor-specific T cells against neu and non-neu tumor antigens increased synergistically after combination PI3Ki and anti-neu treatment, and A66 was more potent. In a TUBO (neu+) and TUBO-P2J (neu-) mixed model representing IHC2+ tumors, A66 showed greater tumor mass control and survival prolongation than GDC-0941, when combined with the anti-neu antibody. Combined with the anti-neu antibody, A66 was more effective than GDC-0941, and A66 synergized with the anti-neu antibody in terms of anti-tumor immunity. We propose A66 plus anti-HER2/neu antibody as an effective strategy in trastuzumab-resistant breast cancers.
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Maski, K. P., F. Pizza, A. Colclasure, E. Steinhart, E. Little, C. Diniz Behn, S. Vandi, E. Antelmi, G. Plazzi y T. Scammell. "0941 Defining Disrupted Nighttime Sleep in Pediatric Narcolepsy". Sleep 43, Supplement_1 (abril de 2020): A357—A358. http://dx.doi.org/10.1093/sleep/zsaa056.937.
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Abstract Introduction Disrupted nighttime sleep (DNS) is a core narcolepsy symptom subjectively described as spontaneous awakenings during the night, but researchers use varied polysomnogram (PSG) definitions based on sleep state transitions, NREM 1% and poor sleep efficiency. These sleep measures have yet to be validated to determine the best objective measure of DNS. Furthermore, it unknown to what extent DNS occurs in pediatric narcolepsy as children have greater sleep drive than adults. Here, we assess the construct validity of various DNS objective measures and evaluate its diagnostic utility for pediatric Narcolepsy Type 1 (NT1) when combined with a nocturnal Sleep Onset REM period (nSOREMP) in a large cohort of pediatric patients with CNS hypersomnias. Methods Retrospective, cross-sectional study of consecutive PSGs and multiple sleep latency tests (MSLTs) obtained at Boston Children’s Hospital and University of Bologna. Participants were drug-free or drug naïve, ages 6-18 years and slept at least 6 hours during the PSG. We analyzed associations between objective DNS measures and outcomes of self-reported sleep disturbance, Epworth Sleepiness Score, mean sleep latency, NT1 diagnosis, and CSF hypocretin values when available. We then combined the best performing DNS measure with the presence of a nSOREMP to determine the diagnostic value for NT1 using bootstrap analysis. We included n=151 NT1, n=21 narcolepsy type 2 (NT2), n=27 idiopathic hypersomnia (IH) and n= 117 subjectively sleepy controls in this analysis. Results Across groups, the Wake and NREM 1 bouts index had the most robust associations with objective sleepiness, subjective sleep disturbance and CSF hypocretin levels (p’s <0.0001). From 1000 bootstrap samples, the Wake/N1 index and presence of a nSOREMP have greater diagnostic accuracy for NT1 than the nSOREMP alone (p<0.0001). Conclusion Among a variety of sleep quality measures, we find that a Wake and NREM 1 bout index is the best objective measure of DNS. In combination with a nSOREMP, this DNS measure can aid in pediatric NT1 diagnosis using PSG alone and potentially reduce diagnostic delays. Support This study was supported by K23 National Institutes of Health (NINDS, K23 NS104267-01A1) grant and Investigator Initiated Research grant from Jazz Pharmaceuticals, Inc. to Dr. Maski
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Auge, Oliver y Adelina Wallnöfer. "Rezension von: Adelina Wallnöfer: Die politische Repräsentation des gemeinen Mannes in Tirol. Die Gerichte und ihre Vertreter auf den Landtagen vor 1500". Zeitschrift für Württembergische Landesgeschichte 78 (17 de enero de 2022): 441–42. http://dx.doi.org/10.53458/zwlg.v78i.1481.
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Adelina Wallnöfer, Die politische Repräsentation des gemeinen Mannes in Tirol. Die Gerichte und ihre Vertreter auf den Landtagen vor 1500 (Veröffentlichungen des Südtiroler Landesarchivs/Pubblicazioni dell’Archivio provinciale di Bolzano, Bd. 41), Innsbruck: Universitätsverlag Wagner 2017. 550 S., 69 größtenteils farb. Abb., ISBN 978-3-7030-0941-9. Geb. € 49,–
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IWASE, Toshinori, Takako MORIKAWA, Hideo FUKUDA, Kiyosuke SASAKI y Masafumi YOSHITAKE. "Production of Acetic Esters by Williopsis beijerinckii IFO 0941". JOURNAL OF THE BREWING SOCIETY OF JAPAN 90, n.º 4 (1995): 307–12. http://dx.doi.org/10.6013/jbrewsocjapan1988.90.307.
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Makieieva, N., A. Penkov, R. Marabyan, M. Kholodova y I. Vasheva. "PO-0941 The Causes Of Psychosomatic Disorders In Children". Archives of Disease in Childhood 99, Suppl 2 (octubre de 2014): A558.2—A558. http://dx.doi.org/10.1136/archdischild-2014-307384.1562.
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Robar, J., J. Allan, R. L. Macdonald, R. Rutledge, T. Joseph, J. Clancey y K. Moran. "PO-0941: 3D printed bolus for chestwall radiation therapy". Radiotherapy and Oncology 119 (abril de 2016): S456—S457. http://dx.doi.org/10.1016/s0167-8140(16)32191-0.
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Akutagawa, Jon, Monique Dail, Lori S. Friedman, Kevin M. Shannon, Deepak Sampath y Benjamin S. Braun. "The PI3K Inhibitor GDC-0941 Attenuates Disease in a KrasG12D Mouse Model of CMML and JMML." Blood 120, n.º 21 (16 de noviembre de 2012): 2862. http://dx.doi.org/10.1182/blood.v120.21.2862.2862.
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Abstract Abstract 2862 Chronic and juvenile myelomonocytic leukemias (CMML and JMML) are overlap myelodysplastic/myeloproliferative neoplasia (MDS/MPN) syndromes that respond poorly to conventional treatment regimens. Both diseases are characterized by aberrant N-Ras, K-Ras, Cbl, and SHP-2 proteins, which are not attractive drug target candidates. Focus has shifted to downstream effector pathways, which include Raf/MEK/ERK, phosphoinositide-3-OH kinase (PI3K)/Akt, and Ral-GDS/Ral-A cascades. However, it is unclear which pathways, if any, should be targeted. In part to address this question, we previously developed a mouse model of CMML and JMML by expressing a conditional “knock-in” KrasG12D oncogene in bone marrow. Our earlier studies showed that inhibition of MEK yields a significant reduction in disease burden in this model, including reduced leukocytosis, improved anemia and enhanced survival. Here, we interrogate the role of the PI3K/Akt pathway in KrasG12D driven MPN and further explore which specific pathways are responsible for leukemogenesis due to hyperactive Ras. We administered GDC-0941, a selective PI3K inhibitor, to Mx1-Cre, KrasG12D mutant mice Mice with well established MPN and wild-type (WT) littermates were randomly chosen to receive daily oral administration of GDC-0941 or a control vehicle. Treated mice exhibited dramatic corrections of leukocytosis and anemia as well as decrease in splenomegaly. Flow cytometry of bone marrow and peripheral populations also imply that GDC-0941 treatment corrects the aberrant proliferation, amends differentiation of bone marrow progenitors, and revives ineffective erythropoiesis found in KrasG12D mice. Treatment also resulted in markedly improved survival of KrasG12D mice; virtually all KrasG12Dmice in the treatment arm outlived their control counterparts. Our data suggest PI3K inhibition may play a role in suppressing hematologic dysfunction in JMML and CMML patients. Potential crosstalk between PI3K and MEK signaling further suggest that combinatorial activities of PI3K and MEK inhibition should be investigated. Disclosures: Friedman: Genentech, Inc.: Employment. Sampath:Genentech, Inc.: Employment.
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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, n.º 21 (19 de noviembre de 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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Friedman, L., M. Belvin, L. Berry, P. Haverty, K. Hoeflich, M. Lackner, D. Sampath, J. Wallin y B. Yauch. "142 GDC-0941 PI3K inhibitor activity in preclinical lung cancer models". European Journal of Cancer Supplements 8, n.º 7 (noviembre de 2010): 51. http://dx.doi.org/10.1016/s1359-6349(10)71847-4.
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Lam, Nhi, Monica Singh y Alejandra Lastra. "0941 Sleep Apnea Testing in Hospitalized Patients: Are Patients Following Up?" SLEEP 46, Supplement_1 (1 de mayo de 2023): A415. http://dx.doi.org/10.1093/sleep/zsad077.0941.
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Abstract Introduction Obstructive sleep apnea (OSA) can often be recognized in an inpatient setting where patients are continuously monitored. Although an unattended portable sleep study can successfully diagnose OSA in many inpatients, allowing for earlier intervention, a loss to follow up can compromise effective treatment. This study aims to determine the rate of hospital follow-up in patients who are diagnosed with OSA on a portable inpatient sleep study. Methods We included adult inpatients who underwent portable sleep studies from 2013 to 2022. This is a retrospective study design. Individual charts were reviewed to determine demographics including age, gender, and race. Co-morbidities and length of stay were recorded. Sleep study data analyzed included total recording time, total estimated sleep time, overall apnea-hypopnea index (AHI) and nadir oxygen saturation. Primary outcome was percentage of patients with AHI 5/h with scheduled follow up visit. Secondary outcome was percentage of patients with AHI 5/h completed outpatient follow-up visit. Results 104 patients were included for analysis. Majority were middle aged (55.2 SD15.9 years-old), black (n=71, 68.2%) and male gender (n=64, 62%). A minority identified as Hispanic (n=7, 6.7%). The total number of sleep studies with AHI 5/h was 95 (91.3%) and the mean AHI was in the severe range (42.8 SD31.4/h) with significant associated oxygen desaturations (mean nadir oxygen saturation 77.1 SD10.6%). Primary outcome: the number of patients with a positive sleep study for OSA (AHI 5/h) who had scheduled for follow-up at discharge was 57 (60%). Secondary outcome: 54.4% of patients with positive sleep study and scheduled follow-up completed the outpatient visit. Conclusion The percentage of patients lost to follow-up is high despite diagnosing OSA successfully with an inpatient portable sleep study. Close to half of the patients had no scheduled follow-up, and the “no show” rate remained high (close to 50%) in those who had a sleep medicine appointment. Future studies should explore effective interventions to improve the follow-up rate and overall adherence to treatment. Support (if any)
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Chen, Haifeng, Mingming Cheng, Pengcheng Gao, Xiangzhong Zhang, Ganggang Li, Liting Wang, Long Qin y Hongrui Li. "GDC-0941 activates integrin linked kinase (ILK) expression to cause resistance to GDC-0941 in breast cancer by the tumor necrosis factor (TNF)-α signaling pathway". Bioengineered 13, n.º 4 (1 de abril de 2022): 10944–55. http://dx.doi.org/10.1080/21655979.2022.2066758.
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Kikuchi, Hugh, Amofa Eunice, Maeve McEnery, Farzin Farzaneh, Stephen A. Schey y Yolanda Calle. "Inhibition Of PI3K Classia Kinases Using GDC0941 Overcomes Protection Of Multiple Myeloma Cells In The Bone Marrow Microenvironment". Blood 122, n.º 21 (15 de noviembre de 2013): 3169. http://dx.doi.org/10.1182/blood.v122.21.3169.3169.
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Abstract Despite of newly developed and more efficacious therapies, multiple myeloma (MM) remains incurable as most patient will eventually relapse and become refractory. The bone marrow (BM) microenvironment provides niches that are advantageous for drug resistance. Effective therapies against MM should ideally target the various protective BM niches that promote MM cell survival and relapse. In addition to stromal mesenchymal/myofibroblastic cells, osteoclasts play a key supportive role in MM cell viability. Additionally, 80% of patients develop osteolytic lesions, which is a major cause of morbidity. Increased osteoclast activity is characteristic in these patients and targeting osteoclast function is desirable to improve therapies against MM. Osteoclasts need to form an F-actin containing ring along the cell margin that defines a resorbing compartment where protons and degradative enzymes are secreted for dissolution of bone mineral. Remodelling of F-actin and vesicle secretion are regulated by the class IA PI3K pathway during osteoclastic bone resorption. Additionally, it has recently been shown that inhibition of the class IA PI3K pathway in MM cells with GDC0941 induces apoptosis-mediated killing. We hypothesised that GDC0941 could be used as a therapeutic agent to overcome MM-induced osteoclast activation. GDC0941 inhibited maturation of osteoclasts derived from BM aspirates from MM patients in a dose dependent manner. This correlated with decreased bone resorption of osteoclasts cultured on dentine discs. Exposure of mature osteoclasts to GC0941 resulted in abnormal organisation of larger F-actin rings, suggesting a negative effect on the dynamics of the actin cytoskeleton required for bone resorption. We also found that GDC-0941 can prevent protection of the MM cell lines MM1.S and MM1.R by osteoclasts against killing. GDC-0941 alone blocked MM cell proliferation independently of the presence of BM stromal cells and synergised with other therapeutic agents including Lenalidomide, Pomalidomide, Bortezomid and Dexamethasone. We also found that in the presence of MM cells, Dexamethasone (a drug commonly used alone or in combination with new drugs against MM) induced the proliferation of BM stromal cells and adhesion of MM cells on this protective stroma in a dose dependent manner. Dexamethasone is highly effective at MM cell killing when cells are cultured alone. However, we found that at low doses (below 1 uM) and in the presence of BM stromal cells, Dexamethasone could induce MM cell proliferation. GDC0941 enhanced Dexamethasone killing even in the presence of BM stromal cells by blocking Dexamethasone-induced stromal cell proliferation and adhesion of MM cells on the stroma. Targeting individual the PI3K Class IA isoforms alpha, beta, delta or gamma proved to be a less efficient strategy to enhance Dexamethasone killing. Previous work has shown that efficacy of targeting individual PI3K Class I A isoforms would be low for activation of caspases in MM cells as it would be dependent on relative amounts of isoforms expressed by the MM patient. GDC-0941 also inhibited the proliferation of MM1.R and RPMI8266 MM cell lines, which are less sensitive to treatment to Dexamethasone. Co-culture of MM cells with BM stromal cells induced the secretion of IL-10, IL-6, IL-8, MCP-1 and MIP1-alpha. The dose-dependant increased proliferation of Dexamethasone-treated MM cells in the presence of the BM stroma correlated with the pattern of secretion of IL-10 (a cytokine that can induce B-cell proliferation) and this was blocked by the combination of Dexamethasone with GDC0941. GDC-0941 alone or in combination with Dexamethasone was more efficacious at inducing MM cell apoptosis in the presence of the BM stroma cells vs treatment of MM cells alone. These are very encouraging results as they suggest that GDC-0941 in combination with Dexamethasone would be potentially highly efficacious for targeting MM cells in the BM microenvironment. We are currently performing in vivo data using C57BL/KaLwRij mice injected with 5T33-eGFP MM cells that will be discussed at the meeting. We propose that MM patients with active bony disease may benefit from treatment with GDC0941 alone or in combination with currently used therapeutic drugs against MM. Disclosures: No relevant conflicts of interest to declare.
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Fan, Xiu Cai, Hai Sheng Sun, Ying Zhang, Jian Fu Jiang, Min Li y Chong Huai Liu. "Genetic Diversity of Vitis davidii Accessions Revealed Using Microsatellite and Sequence-related Amplified Polymorphism Markers". HortScience 53, n.º 3 (marzo de 2018): 283–87. http://dx.doi.org/10.21273/hortsci12506-17.
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In this study, simple sequence repeat (SSR) and sequence-related amplified polymorphism (SRAP) markers were used to analyze the genetic diversity of 48 wild Vitis davidii accessions. A total of 78 distinct alleles were amplified by 11 SSR primers, and the average allele number was 8.8. The average observed heterozygosity (Ho) and expected heterozygosity (He) values were 0.785 and 0.814, respectively. The effective allele numbers ranged from 3.92 to 9.61. The average polymorphism information content (PIC) was 0.798. Twelve of 169 SRAP primer combinations were selected for SRAP analysis. A total of 188 bands were produced, and the average was 15.7 bands per primer combination; the average percentage of polymorphic bands was 84.0%. The average PIC was 0.76. The results of the clustering analysis based on SSR markers showed that the 48 wild V. davidii accessions could be classified into five main clusters and had a genetic similarity coefficient level of 0.68. The dendrogram obtained from the SRAP data showed that 48 wild V. davidii accessions could be classified into five main clusters and had a genetic similarity coefficient of 0.72. SSR and SRAP markers differentiated all accessions studied including those with a similar pedigree. We speculated on the origin of Ciputao 0941♀, Ciputao 0940♂, and Fu’an-ci-01 using SSR markers and used both SSR and SRAP markers to resolve homonymy. The result will be valuable for further management and protection of V. davidii germplasm resources.
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leung, W. K., E. P. P. Pang, S. K. T. Cheung, W. H. Mui, B. B. W. Wo, H. Liu, J. C. W. Siang et al. "PD-0941 Feasibility of prostatic calcifications tracking using 4D transperineal ultrasound (TPUS)." Radiotherapy and Oncology 161 (agosto de 2021): S783—S784. http://dx.doi.org/10.1016/s0167-8140(21)07220-0.
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MANABE, Masashi y Shunji HIROKAWA. "0941 Assessment of kinematics of knee prosthesis after TKA about flexion motion". Proceedings of the Bioengineering Conference Annual Meeting of BED/JSME 2009.22 (2010): 353. http://dx.doi.org/10.1299/jsmebio.2009.22.353.
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KAMEO, Yoshitaka, Taiji ADACHI y Masaki HOJO. "0941 Theoretical Analysis of Interstitial Fluid Flow in Trabecula as Poroelastic Materials". Proceedings of the JSME annual meeting 2007.5 (2007): 183–84. http://dx.doi.org/10.1299/jsmemecjo.2007.5.0_183.
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Trojani, V., A. Botti, M. Grehn, B. Balgobind, A. Savini, E. Pruvot, J. Verhoeff, M. Iori y O. Blanck. "OC-0941 STereotactic Arrhythmia Radioablation in Europe: STOPSTORM Consortium Treatment Planning Benchmark". Radiotherapy and Oncology 182 (mayo de 2023): S788—S790. http://dx.doi.org/10.1016/s0167-8140(23)08767-4.
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Al-Negheimish, Abdulaziz, Abdulrahman Alhozaimy, Raja Rizwan Hussain, Rajeh Al-Zaid, J. K. Singh y D. D. N. Singh. "Role of Manganese Sulfide Inclusions in Steel Rebar in the Formation and Breakdown of Passive Films in Concrete Pore Solutions". CORROSION 70, n.º 1 (enero de 2014): 74–86. http://dx.doi.org/10.5006/0941.
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Edge, Sarah D., Isaline Renard, Emily Pyne, Chun Li, Hannah Moody, Rajarshi Roy, Andrew W. Beavis et al. "PI3K inhibition as a novel therapeutic strategy for neoadjuvant chemoradiotherapy resistant oesophageal adenocarcinoma". British Journal of Radiology 94, n.º 1119 (1 de marzo de 2021): 20201191. http://dx.doi.org/10.1259/bjr.20201191.
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Objective: Neoadjuvant chemoradiotherapy (neo-CRT) prior to surgery is the standard of care for oesophageal adenocarcinoma (OAC) patients. Unfortunately, most patients fail to respond to treatment. MiR-187 was previously shown to be downregulated in neo-CRT non-responders, whist in vitro miR-187 overexpression enhanced radiosensitivity and upregulated PTEN. This study evaluates the role of miR-187 and downstream PI3K signalling in radiation response in OAC. Methods: The effect of miR-187 overexpression on downstream PI3K signalling was evaluated in OAC cell lines by qPCR and Western blotting. PTEN expression was analysed in OAC pre-treatment biopsies of neo-CRT responders and non-responders. Pharmacological inhibition of PI3K using GDC-0941 was evaluated in combination with radiotherapy in two-dimensional and three-dimensional OAC models in vitro and as a single agent in vivo. Radiation response in vitro was assessed via clonogenic assay. Results: PTEN expression was significantly decreased in neo-CRT non-responders. MiR-187 overexpression significantly upregulated PTEN expression and inhibited downstream PI3K signalling in vitro. GDC-0941 significantly reduced viability and enhanced radiation response in vitro and led to tumour growth inhibition as a single agent in vivo. Conclusion: Targeting of PI3K signalling is a promising therapeutic strategy for OAC patients who have repressed miR-187 expression and do not respond to conventional neo-CRT. Advances in knowledge: This is the first study evaluating the effect of PI3K inhibition on radiosensitivity in OAC, with a particular focus on patients that do not respond to neo-CRT. We have shown for the first time that targeting of PI3K signalling is a promising alternative therapeutic strategy for OAC patients who do not respond to conventional neo-CRT.
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Gupta, Madhulika. "0941 Limb Movements in Sleep [LMS] and PTSD-related Physical Symptoms: Preliminary Observations". SLEEP 47, Supplement_1 (20 de abril de 2024): A404. http://dx.doi.org/10.1093/sleep/zsae067.0941.
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Abstract Introduction Periodic Limb Movements in Sleep [PLMS] can be present in over 60% of Posttraumatic Stress Disorder [PTSD] patients versus about 10% in the general population. PTSD is often associated with physical complaints. In the general population PLMS can be associated with physical symptoms . To my knowledge the association of PLMS and physical complaints in PTSD has not been reported. Methods 106 PTSD patients [all from MAG’s practice] completed a battery of instruments. 44/106 patients (mean age+/-SD = 47.04+/-13.27 years; 89.6% female) met the inclusion criteria (no current use of benzodiazepines or narcotics; ability to have LMS ratings completed by bed partner). All participants met the DSM-5 criteria for moderate-to-severe PTSD during their initial consultation, with a Clinician Administered PTSD Scale for DSM-5 (CAPS-5) score of at least 55. The PTSD Checklist for DSM-5 (PCL-5) was used to obtain an index of the current PTSD severity (mean = 37.41, SD = 19.84; PCL-5 > 30 cut-off for PTSD). Limb Movements in Sleep [LMS] were considered a proxy for PLMS [ICSD3, 2014] and were measured using Item 10c of the Pittsburgh Sleep Quality Index [PSQI] [Buysse DJ,1989] where the patients’ bed partner rated the patients’ severity of “Legs twitching or jerking while they slept”; Low-LMS frequency included "< one time per week" or "not during the past month" and High-LMS frequency included " once or twice a week " and " three or more times a week".Physical symptoms were rated using the Pennebaker Inventory of Limbic Languidness [PILL][Pennebaker JW,1982] which rates 54 physical symptoms using the following scale: 1=Have never or almost never experienced the symptom; 2=Less than 3 or 4 times per year; 3=Every month or so; 4=Every week or so; and 5=More than once every week. Results The mean scores of 20/54 PILL items were significantly [ p< 0.05] lower between the Low- versus High-LMS groups. The total 54 item mean PILL score was significantly [p=0.002] greater in the PTSD group with High-LMS [PILL score of 105 ] versus the Low-LMS scores [PILL score of 73]. Conclusion PTSD patients with more frequent limb movements during sleep had greater daytime physical complaints. Support (if any) None
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Nováková, Jana, Pavel Talacko, Petr Novák y Karel Vališ. "The MEK-ERK-MST1 Axis Potentiates the Activation of the Extrinsic Apoptotic Pathway during GDC-0941 Treatment in Jurkat T Cells". Cells 8, n.º 2 (21 de febrero de 2019): 191. http://dx.doi.org/10.3390/cells8020191.
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The discrete activation of individual caspases is essential during T-cell development, activation, and apoptosis. Humans carrying nonfunctional caspase-8 and caspase-8 conditional knockout mice exhibit several defects in the progression of naive CD4+ T cells to the effector stage. MST1, a key kinase of the Hippo signaling pathway, is often presented as a substrate of caspases, and its cleavage by caspases potentiates its activity. Several studies have focused on the involvement of MST1 in caspase activation and also reported several defects in the immune system function caused by MST1 deficiency. Here, we show the rapid activation of the MEK-ERK-MST1 axis together with the cleavage and activation of caspase-3, -6, -7, -8, and -9 after PI3K signaling blockade by the selective inhibitor GDC-0941 in Jurkat T cells. We determined the phosphorylation pattern of MST1 using a phosphoproteomic approach and identified two amino acid residues phosphorylated in an ERK-dependent manner after GDC-0941 treatment together with a novel phosphorylation site at S21 residue, which was extensively phosphorylated in an ERK-independent manner during PI3K signaling blockade. Using caspase inhibitors and the inhibition of MST1 expression using siRNA, we identified an exclusive role of the MEK-ERK-MST1 axis in the activation of initiator caspase-8, which in turn activates executive caspase-3/-7 that finally potentiate MST1 proteolytic cleavage. This mechanism forms a positive feed-back loop that amplifies the activation of MST1 together with apoptotic response in Jurkat T cells during PI3K inhibition. Altogether, we propose a novel MEK-ERK-MST1-CASP8-CASP3/7 apoptotic pathway in Jurkat T cells and believe that the regulation of this pathway can open novel possibilities in systemic and cancer therapies.
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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, n.º 15_suppl (20 de mayo de 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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Huang, Tannie, Jon Akutagawa, Inbal Epstein, Charisa Cottonham, Maricel Quirindongo-Crespo y Benjamin S. Braun. "Inhibition of Akt Signaling Alleviates MDS/MPN Driven By KrasD12 or Nf1 Loss". Blood 126, n.º 23 (3 de diciembre de 2015): 360. http://dx.doi.org/10.1182/blood.v126.23.360.360.
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Abstract Juvenile and chronic myelomonocytic leukemias (JMML and CMML) are aggressive myeloid malignancies categorized as myelodysplastic syndromes/myeloproliferative neoplasms (MDS/MPN). Chemotherapy has little benefit for MDS/MPN patients, and new therapies are needed. We have used mouse models investigate the potential of signal transduction inhibitors in MDS/MPN, as JMML and CMML are associated with mutations in NRAS, KRAS, PTPN11, CBL, or NF1 that activate Ras signaling. Conditional Mx1-Cre, KrasLSL-D12 (designated KrasD12) mice develop an aggressive and fully penetrant MDS/MPN characterized by leukocytosis, splenomegaly, anemia, and death by 10-16 weeks of age. Mx1-Cre, Nf1flox/- mice (hereafter Nf1Δ/-) undergo conditional loss of Nf1. These mice also develop MDS/MPN, but the disease is more indolent. We and others have investigated inhibition of effector networks downstream of Ras, such as the Raf/MEK/ERK (MAPK) and phosphotidylinositol-3 kinase (PI3K)/Akt pathways. We previously showed that the MEK inhibitor PD0325901 induced sustained hematologic improvement in both KrasD12 and Nf1Δ/- mice. We also have reported that the class I PI3K inhibitor GDC-0941 improves hematologic function and prolongs survival in KrasD12 mice. However, GDC-0941 and other PI3K inhibitors attenuate both PI3K/Akt and Raf/MEK/ERK pathways due to effects of PI3K upstream of Ras. Therefore, the benefit from GDC-0941 could have been due to its modulation of Raf/MEK/ERK signaling. Here, we specifically test the importance of Akt signaling in MDS/MPN in KrasD12 and Nf1 mouse models using the allosteric inhibitor MK-2206. This compound binds to the interface of the PH and kinase domains of Akt1, Akt2, and Akt3, and does not inhibit any of 250 other kinases at 1 µM. MK-2206 induced substantial improvement in both KrasD12 and Nf1Δ/- mice. Mice treated with MK-2206 had pronounced reduction in leukocytosis, reticulocytosis and splenomegaly, increased hemoglobin concentration, and prolonged survival. MK-2206 had no hematologic effects in control WT mice, indicating some selectivity against aberrant hematopoiesis. Importantly, MK-2206 inhibited Akt but not Raf/MEK/ERK or Jak/STAT signaling. This demonstrates that canonical PI3K/Akt signaling plays an important role in Ras-driven MDS/MPN. Furthermore, combined inhibition of MEK and Akt with PD0325901+MK-2206 yielded a greater improvement in splenomegaly than either agent alone in both KrasD12 and Nf1Δ/- models. Akt has multiple effectors relevant to hematopoiesis and leukemia. Of these, mTOR is of particular interest for targeted cancer therapy. Therefore, we tested the response of KrasD12 mice to rapamycin, a partial inhibitor of mTOR with preferential activity against the mTORC1 complex. KrasD12 mice demonstrated variable responses to rapamycin, with approximately half undergoing a complete and durable hematologic response and the remainder having no response. Together, these studies further implicate PI3K/Akt signaling as a pathogenic effector downstream of Ras in MDS/MPN and support the idea that inhibitors targeting this pathway may have a role in treatment of JMML or CMML. Disclosures No relevant conflicts of interest to declare.
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Shi, L., X. Gao, X. Li, N. Jiang, F. Luo, C. Gu, M. Chen, H. Cheng y P. Liu. "Ellagic Acid Enhances the Efficacy of PI3K Inhibitor GDC-0941 in Breast Cancer Cells". Current Molecular Medicine 15, n.º 5 (10 de julio de 2015): 478–86. http://dx.doi.org/10.2174/1566524015666150505161046.
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Persoon, L. C. G. G., A. Sanizadeh, B. De Ruiter, S. Nijsten, F. Verhaegen y E. G. C. Troost. "PO-0941: Adaptive radiotherapy based on integrated transit planar dosimetry for lung cancer patients". Radiotherapy and Oncology 115 (abril de 2015): S492—S493. http://dx.doi.org/10.1016/s0167-8140(15)40933-8.
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Floyd, R., N. McDermott, A. Meunier y L. Marignol. "PO-1061: Radiosensitisation properties of PI3K/AKT inhibitor GDC-0941 in prostate cancer cells". Radiotherapy and Oncology 115 (abril de 2015): S572. http://dx.doi.org/10.1016/s0167-8140(15)41053-9.
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Van den Bosch, M., B. Vanneste, R. Voncken y L. Lutgens. "PO-0941: Verifying the treatment planning system in individualized HDR brachytherapy of cervical cancer". Radiotherapy and Oncology 123 (mayo de 2017): S521. http://dx.doi.org/10.1016/s0167-8140(17)31378-6.
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Kirkegård, Jakob, Jennifer L. Lund, Frank Viborg Mortensen y Deirdre Cronin‐Fenton. "Author's Reply to: “Design flaws in statins and pancreatic cancer research” (IJC‐19‐0941)". International Journal of Cancer 145, n.º 5 (12 de mayo de 2019): 1450–51. http://dx.doi.org/10.1002/ijc.32349.
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Al Mamun, Md Zia Uddin, Md Mamunur Rashid, Mohajira Begum, Maesha Musarrat, Md Ariful Haq y Rahima Akter Sathee. "Appraisal of Vitamin D3 Concentration in Dietary Supplement Marketed in Bangladesh using HPLC". Oriental Journal Of Chemistry 38, n.º 6 (30 de diciembre de 2022): 1440–44. http://dx.doi.org/10.13005/ojc/380615.
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This research work provides information about the concentration level of fat soluble vitamin D3 in different types of dietary supplements marketed in Bangladesh. Selected twenty-five samples were taken for analysis because physicians are prescribing randomly and available in local market. Vitamin D3 concentration levels were quantified using HPLC with C18 column and diode array detector(DAD). The mobile phase was isocratic mode with ACN and methanol (60:40) and detection wavelength was (ƛ)265nm. Quantification level of D3 was ranging from 1. 80(µg.mlˉ1) to 24.91 (µg.mlˉ1) in analyzed samples. Quantification of vitamin D3 was conducted basis on the standard solution retention time (Rt) and peak area. The analyzed method provides excellent results with linearity, correlation co-efficient (r² ≥ 0.9995), LOD (0.0282, µg. mlˉ1), LOQ (0. 0941, µg. mlˉ1) and reproducibility with analyte recovery.
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Ehrhardt, Michael, Rogerio B. Craveiro, Martin I. Holst, Torsten Pietsch y Dagmar Dilloo. "The PI3K inhibitor GDC-0941 displays promisingin vitro and in vivoefficacy for targeted medulloblastoma therapy". Oncotarget 6, n.º 2 (6 de diciembre de 2014): 802–13. http://dx.doi.org/10.18632/oncotarget.2742.
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Marampon, F., G. L. Gravina, M. E. La Verghetta, M. Cerasani, S. Parente, M. Mancini, D. Di Genova, L. Ferella, M. Reale y E. Di Cesare. "PO-0941: MEK/ERK inhibition radiosensitizes rhabdomyosarcoma cells by downregulating growth and DNA repair signals". Radiotherapy and Oncology 111 (2014): S123—S124. http://dx.doi.org/10.1016/s0167-8140(15)31059-8.
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Sun, Laura, Leanne Berry, Changchun Du, Xiaoju Max Ma, Lily Shi, Bruno C. Medeiros y Allen J. Ebens. "The PI3K Inhibitor GDC-0941 Induces Growth Arrest and Apoptosis of Acute Myeloid Leukemia Cells." Blood 114, n.º 22 (20 de noviembre de 2009): 3787. http://dx.doi.org/10.1182/blood.v114.22.3787.3787.
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Abstract Abstract 3787 Poster Board III-723 Acute myeloid leukemia (AML) is a biologically and molecularly heterogeneous malignancy characterized by an accumulation of myeloid-lineage cells in the blood and bone marrow. Phosphatidylinositol 3' kinase (PI3K) -mediated signaling is frequently dysregulated in cancer and controls fundamental cellular functions such as cell migration, growth, survival and development of drug resistance in many cancers, including AML, and therefore represents an attractive therapeutic target, even against the backdrop of AML disease heterogeneity. In AML, for example, activating mutations in Ras and Flt3 are common and a number of autocrine and paracrine signaling mechanisms have been proposed as important disease mediators; all converge on PI3K as an important signal transduction node to provide growth- and survival-promoting effects. Here, we demonstrate that PI3K p110-a,b,d catalytic subunits are all prevalent across a panel of ∼30 cell lines and that the majority of cell lines as well as primary patient samples show evidence of PI3K pathway activation. We demonstrate in vitro with both cell lines and patient cell isolates, that a potent and selective pan-isoform PI3K inhibitor, GDC-0941, modulates pharmacodynamic markers such as p-Akt, p-4E-BP1, and p-FOXO-3a, and that treated cells show a G0/G1 cell-cycle arrest. A strong induction of apoptosis is observed by annexin/PI staining with upregulation of cleaved caspases and PARP. Preliminary observations suggest significant induction of p27 and Bim as direct transcriptional targets of FOXO-3a, as well as downregulation of c-Myc levels; these targets may represent key mediators of observed cellular effects and are the subject of ongoing work. Additional studies are currently underway to identify clinical standard-of-care agents and new molecular entities (pipeline NMEs) that combine favorably with PI3k-inhibition in vitro, and the results of several in-vivo xenograft studies will also be presented. Disclosures: Sun: Genentech Inc.: Employment. Berry:Genentech: Employment, Patents & Royalties. Du:Genentech, Inc.: Employment, Equity Ownership. Ma:Genentech: Employment, Patents & Royalties. Shi:Genentech: Employment, Patents & Royalties. Medeiros:Genentech: Research Funding. Ebens:Genentech, Inc.: Employment, Equity Ownership, Patents & Royalties.
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Dolde, K., S. Schneider, A. Pfaffenberger y A. Hoffmann. "PO-0941: 3D motion validation with clinically used cine-MRI and an MR-LINAC phantom". Radiotherapy and Oncology 127 (abril de 2018): S511—S512. http://dx.doi.org/10.1016/s0167-8140(18)31251-9.
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