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Publicado: 25 de julho de 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, n.º 15_suppl (20 de maio 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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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 (29 de novembro de 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, n.º 3 (31 de março de 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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Henao Castañeda, Isabel C., Jaime A. Pereañez e Lina M. Preciado. "Synthetic Inhibitors of Snake Venom Enzymes: Thioesters Derived from 2-Sulfenyl Ethylacetate". Pharmaceuticals 12, n.º 2 (23 de maio de 2019): 80. http://dx.doi.org/10.3390/ph12020080.

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Snakebite envenomings are a global public health issue. The therapy based on the administration of animal-derived antivenoms has limited efficacy against the venom-induced local tissue damage, which often leads to permanent disability. Therefore, there is a need to find inhibitors against toxins responsible for local damage. This work aimed to synthesize thioesters derived from 2-sulfenyl ethylacetate and to evaluate the inhibitory effects on two snake venom toxins. Ethyl 2-((4-chlorobenzoyl)thio)acetate (I), Ethyl 2-((3-nitrobenzoyl)thio)acetate (II) and Ethyl 2-((4-nitrobenzoyl)thio)acetate (III) were synthesized and spectroscopically characterized. Computational calculations were performed to support the study. The inhibitory capacity of compounds (I–III) was evaluated on a phospholipase A2 (Cdcum6) isolated from the venom of the Colombian rattlesnake Crotalus durissus cumanensis and the P-I type metalloproteinase Batx-I isolated from Bothrops atrox. I–III inhibited PLA2 with IC50 values of 193.2, 305.4 and 132.7 µM, respectively. Otherwise, compounds II and III inhibited the proteolytic activity of Batx-I with IC50 of 2774 and 1879 µM. Molecular docking studies show that inhibition of PLA2 may be due to interactions of the studied compounds with amino acids in the catalytic site and the cofactor Ca2+. Probably, a blockage of the hydrophobic channel and some amino acids of the interfacial binding surface of PLA2 may occur.

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Liu, Xiao Zhen, Jun Hua Yang, Gang Wang, Ling Ling Song e Ge Shi Zhuang. "Effect of Preparation Conditions on the Performance of Anodic Aluminum Oxide Films". Applied Mechanics and Materials 164 (abril de 2012): 223–26. http://dx.doi.org/10.4028/www.scientific.net/amm.164.223.

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Neodymium salt was used as additives in preparing anodic aluminum oxide (AAO) films to improve its performance. AAO films were prepared by anodization method from a 15 vol. % sulphuric acid solution containing neodymium salt. The effects of anodization voltage, anodization temperature and anodization time on microhardness and thickness of AAO films were researched, respectively. The thickness of AAO film increases with the increase of anodization voltage, the microhardness of AAO film decreases with the increase of anodization voltage in 19 V～23 V. The thickness of AAO film increases with the increase of anodization temperature, the microhardness of AAO film decreases with the increase of anodization temperature in 11 °C～19°C. The thickness of AAO film increases with the increase of anodization time, the microhardness of AAO film decreases with the increase of anodization time in 30 min～3 h. When the anodizing parameters: anodization voltage: 22 V, temperature: 15°C, anodization time: 2 h, the thickness and microhardness of AAO film is as high as 135μm and 305.4 HV.

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Žiak, Peter, Juraj Halička, Karolína Kapitánová e Peter Mojžíš. "The Effect of Botulinum TOxin Application if Neuro-Ophthalmological Indications on the Results of Schirmer’s Test and Tear Osmolarity". Czech and Slovak Ophthalmology 75, n.º 2 (10 de março de 2019): 74–77. http://dx.doi.org/10.31348/2019/2/3.

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Botulinum toxin type A (BT-A) is used in the treatment of neuroophthalmologic disorders such as essential blepharospasm and facial hemispasm for more than 20 years. Although the long-term effect of repeated application of the BT-A was confirmed, the BT-A effect on tears production and retention is not clear. In our work we investigated whether applied BT-A in patients with blepharospasm and hemifacial spasm affect tears production. Tears quality was measured with Schirmer’s and tear osmolarity test during neuro-ophthalmologic diseases treatment, which was evaluated before and 14 days after application of BT-A (Botox inj, Allergan, Irvine, USA) into the orbicularis oculi muscle. BT-A doses of 16-18 U with unilateral and 32 to 36 U bilateral applications were used. The mean tear production in Schirmer’s test before BT-A application was 8.38 ± 0.63 mm, and 2 weeks after BT-A application was 7.12 ± 0,6 mm (n = 50). Tear osmolarity was 305.4 ± 9.2 mOsm before BT-A application, and 2 weeks after BT-A application it was 305.2 ± 8,6 mOsm (n = 13). We found significant difference between two groups in tear quantity (p < 0.012), but not quality (p > 0.05). Application of the BT-A reduced the amount of tears measured by Schirmer’s test. These results confirm rational basis of the empirical clinical experience where an artificial tears substitution is recommended for patients with neuro-ophthalmologic disorders treated by BT-A.

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Sumaryadi, Mas Yedi, Dadang Mulyadi Saleh, Aras Prasetiyo Nugroho, Nu'man Hidayat e Chomsiatun Nurul Hidayah. "Oxytocin Hormone Induction on Milk Production in Relation to Dairy Kid Performance". ANIMAL PRODUCTION 21, n.º 3 (25 de março de 2020): 117. http://dx.doi.org/10.20884/1.jap.2019.21.3.747.

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The application of oxytocin induction to milk production in relation to the performance of kids in dairy goats had been carried out in the "PEGUMAS" dairy goat farmer group Gumelar District, Banyumas. This activity aimed to increase milk production and kid performance through the induction of the hormone oxytocin in dairy goats. The approach method was designed in two stages: the first stage carried out the socialization activities and demonstration of techniques for applying IPTEKS, and the second stage applied hormonal technology in the form of oxytocin hormone induction in dairy goats. The material used was dairy goat parity I aged 1.5 - 2 years allocated into 2 groups of 10 individuals each. Group I was dairy goat experiment not induced with the oxytocin hormone as the control. Group II was dairy goat experiment induced with the oxytocin hormone at a dose of 1 ml (10 IU) intramuscularly before milking. Milk production was measured morning and evening as daily milk production in milliliters (ml). Milk was given to the kid of each parent. The kid's performance was measured based on the daily weight gain of the kid during the study. Overall, the application of science and technology could be adopted by farmers, and oxytocin-induced dairy goat milk production (503.2 ml) was significantly higher (P<0.05) than control (305.4 ml) with an increase of 64.77%, with a positive level of correlation (r = 0.45) and contributed 19.83% to the kids daily body weight gain.

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Lieven, Elena V. M., Julian M. Pine e Helen Dresner Barnes. "Individual differences in early vocabulary development: redefining the referential-expressive distinction". Journal of Child Language 19, n.º 2 (junho de 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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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, n.º 1 (30 de novembro de 2017): 336. http://dx.doi.org/10.15581/006.36.13845.

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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, n.º 23 (3 de dezembro de 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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Abbasi, S., e A. Honaramooz. "305 OPTIMIZING DONOR AND RECIPIENT FACTORS IN XENOGRAFTING OF TESTIS TISSUE". Reproduction, Fertility and Development 22, n.º 1 (2010): 308. http://dx.doi.org/10.1071/rdv22n1ab305.

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Grafting of donor mammalian testis tissue into recipient mice allows completion of spermatogenesis in the grafted tissue and therefore can serve as a new option for preservation of male germ line. For testis tissue xenografting, castrated male nude mice typically serve as recipients, each receiving 8 testis tissue fragments; however, no study has comprehensively investigated donor and recipient factors. The objective of this study was to determine the effects of strain of immunodeficient recipient mouse (nude v. SCID), gonadal status (intact v. gonadectomized), and gender (male v. female) on the outcome of testis tissue xenografting. A secondary objective was to determine the optimal number of testis tissue fragments per mouse most suitable for xenografting. Testis parenchyma from newborn piglets were cut into small fragments (5 mg each) and grafted under the back skin of different groups of immunodeficient mice. In Experiment 1, 8 groups of mice (n = 7/group) served as recipients: castrated male nude, intact male nude, ovariectomized female nude, intact female nude, castrated male SCID, intact male SCID, ovariectomized female SCID, and intact female SCID. In Experiment 2, 4 groups of mice (n = 10/group) served as recipients of 2, 4, 8, or 16 testis tissue fragments per mouse. Recipient mice were sacrificed 8 months after grafting and the weight of the grafts and vesicular glands (male mice) were compared among groups by analysis of variance. In Experiment 1, mouse gonadal status (intact v. gonadectomized) did not affect the total graft weight (P > 0.05), but both the recipient mouse strain (nude v. SCID) and gender (male v. female) affected the total graft weight (2460 ± 320.9, 1420 ± 290.0, 758 ± 156.7, and 2780 ± 297.4, mean ± SEM, P < 0.0001 for SCID, nude, female, and male mice, respectively). In Experiment 2, the total graft weight was highest in the group of mice receiving 8 testis tissue fragments (192 ± 76.1, 695 ± 96.5, 2443 ± 338.8, and 1458 ± 305.4, mean ± SEM, P < 0.0001 for 2, 4, 8, or 16 fragment groups, respectively). These results collectively indicate that male SCID mice receiving 8 testis tissue fragments provide optimized conditions for the recovery of largest grafts. Research was supported by grants from the Natural Sciences and Engineering Research Council of Canada (NSERC) and the Saskatchewan Health Research Foundation (SHRF) to A. Honaramooz and scholarships from the Western College of Veterinary Medicine and the International Peace Scholarship to S. Abbasi.

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Behyari, Mahla, Rana Imani e Hamid Keshvari. "Evaluation of Silk Fibroin Nanofibrous Dressing Incorporating Niosomal Propolis, for Potential Use in Wound Healing". Fibers and Polymers 22, n.º 8 (26 de abril de 2021): 2090–101. http://dx.doi.org/10.1007/s12221-021-0973-2.

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Lehrnbecher, Thomas, Stefan Schöning, Luciana Porto e Jan Sörensen. "Die Langerhanszell-Histiozytose: eine interdisziplinäre Herausforderung". Pädiatrie 29, n.º 1 (fevereiro de 2017): 40–42. http://dx.doi.org/10.1007/s15014-017-0973-2.

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Ozeki, Kenta, e Tomoki Yamashita. "Spanning Trees: A Survey". Graphs and Combinatorics 27, n.º 1 (1 de setembro de 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 e 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, n.º 12 (6 de outubro de 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 e Hillary A. Keenan. "Bone health in subjects with type 1 diabetes for more than 50 years". Acta Diabetologica 54, n.º 5 (25 de fevereiro de 2017): 479–88. http://dx.doi.org/10.1007/s00592-017-0973-2.

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Schneider, S. S., e G. DeGrandi-Hoffman. "Queen replacement in African and European honey bee colonies with and without afterswarms". Insectes Sociaux 55, n.º 1 (4 de dezembro de 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 e Oliver J. Wiseman. "Do renal stones that fail lithotripsy require treatment?" Urolithiasis 45, n.º 6 (15 de março de 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 e Rafael Diaz. "Saharan dust, climate variability, and asthma in Grenada, the Caribbean". International Journal of Biometeorology 59, n.º 11 (24 de fevereiro de 2015): 1667–71. http://dx.doi.org/10.1007/s00484-015-0973-2.

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Kushnir, R. M., M. M. Nykolyshyn, U. V. Zhydyk e V. M. Flyachok. "On the theory of inhomogeneous anisotropic shells with initial stresses". Journal of Mathematical Sciences 186, n.º 1 (26 de agosto de 2012): 61–72. http://dx.doi.org/10.1007/s10958-012-0973-2.

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Akiyoshi, Takashi, Toshiaki Watanabe e Masashi Ueno. "Risk Factors for and Long-term Outcomes of Anastomotic Leakage after Colorectal Cancer Surgery". World Journal of Surgery 35, n.º 7 (3 de fevereiro de 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 e 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, n.º 4 (19 de agosto de 2014): 431–41. http://dx.doi.org/10.1007/s00420-014-0973-2.

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Cai, Ning, Junwei Cao, Minghua Liu e Haiying Ma. "On Controllability Problems of High-Order Dynamical Multi-Agent Systems". Arabian Journal for Science and Engineering 39, n.º 5 (1 de março de 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 e Rafaela Piccoli. "Prolonged infusion of dexmedetomidine in critically-ill children". Indian Pediatrics 53, n.º 11 (novembro de 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, n.º 4 (julho de 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, n.º 1 (21 de setembro de 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 e 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, n.º 3 (22 de maio de 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 e Anil Kumar Saxena. "Bioprospecting and indexing the microalgal diversity of different ecological habitats of India". World Journal of Microbiology and Biotechnology 28, n.º 4 (17 de dezembro de 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 e Giuseppe Rengo. "Predisposing factors to heart failure in diabetic nephropathy: a look at the sympathetic nervous system hyperactivity". Aging Clinical and Experimental Research 31, n.º 3 (1 de junho de 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 e 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, n.º 4 (16 de setembro de 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 e 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, n.º 7 (21 de agosto de 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 e 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, n.º 1 (6 de setembro de 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 e 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, n.º 1 (3 de outubro de 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 e Hae-Dong Kim. "Interdecadal changes in TC activities that affect Korea". Theoretical and Applied Climatology 116, n.º 3-4 (25 de julho de 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 e S. J. Pearton. "Shallow and Deep Centers in As-Grown and Annealed MgZnO/ZnO Structures with Quantum Wells". Journal of Electronic Materials 39, n.º 5 (18 de novembro de 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 e Trine Madsen. "Community integration after deployment to Afghanistan: a longitudinal investigation of Danish soldiers". Social Psychiatry and Psychiatric Epidemiology 50, n.º 4 (12 de outubro de 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 e Yoshihide Fujigaki. "Disturbed circadian rhythm of the intrarenal renin-angiotensin system: relevant to nocturnal hypertension and renal damage". Clinical and Experimental Nephrology 19, n.º 2 (12 de abril de 2014): 231–39. http://dx.doi.org/10.1007/s10157-014-0973-2.

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Ahmadiniaz, N., A. Bashir e C. Schubert. "Multiphoton Amplitudes and Generalized LKF Transformation in Scalar QED Using the Worldline Formalism". Russian Physics Journal 59, n.º 11 (março de 2017): 1752–60. http://dx.doi.org/10.1007/s11182-017-0973-2.

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Risinger, Fred, e Janel Boyce. "Conditioning tastant and the acquisition of conditioned taste avoidance to drugs of abuse in DBA/2J mice". Psychopharmacology 160, n.º 3 (1 de março de 2002): 225–32. http://dx.doi.org/10.1007/s00213-001-0973-2.

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Miyaishi, S., M. Miura, K. Taniguchi e K. Püschel. "„Verschwinden“ des Epiduralhämatoms im Verlauf". Rechtsmedizin 24, n.º 5 (1 de agosto de 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 e W. F. Gale. "Capillary Hysteresis in Neutrally Wettable Fibrous Media: A Pore Network Study of a Fuel Cell Electrode". Transport in Porous Media 121, n.º 3 (1 de dezembro de 2017): 597–620. http://dx.doi.org/10.1007/s11242-017-0973-2.

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Mohieldin, Ahmed, Abdulmoneim Eldali e Ali Aljubran. "Knowledge, Perception, and Attitudes of Cancer Patients Towards Cancer and Cancer Care: Local Perspective from Saudi Arabia". Journal of Cancer Education 32, n.º 2 (23 de janeiro de 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 e G. Daskalakis. "Serum levels of adipokines in gestational diabetes: a systematic review". Journal of Endocrinological Investigation 42, n.º 6 (3 de novembro de 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 e 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, n.º 8 (23 de maio de 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 e 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, n.º 10 (23 de abril de 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, n.º 12 (12 de março de 2018): 2921–35. http://dx.doi.org/10.1007/s00216-018-0973-2.

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Hassan, Jihaan, Jan Jaap van der Net e Annet van Royen-Kerkhof. "Treatment of refractory juvenile dermatomyositis with tacrolimus". Clinical Rheumatology 27, n.º 11 (21 de agosto de 2008): 1469–71. http://dx.doi.org/10.1007/s10067-008-0973-2.

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Van Gorder, Robert A., K. V. Prasad e 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, n.º 7 (18 de janeiro de 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 e 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, n.º 1 (janeiro de 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 e 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, n.º 2 (19 de setembro de 2017): 233–42. http://dx.doi.org/10.1007/s12031-017-0973-2.

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