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Shin, Kyun-Ho, Sang-Bum Kim, Ki-Mo Jang, Chul-Soo Lee, and Seung-Beom Han. "Posterior tibial slope is a modifiable predictor of relatively large extension gaps in total knee arthroplasty for degenerative osteoarthritis." Journal of Orthopaedic Surgery 29, no. 1 (January 1, 2021): 230949902110020. http://dx.doi.org/10.1177/23094990211002004.
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Background: During total knee arthroplasty (TKA) for osteoarthritis, the sagittal gap imbalance (SGI) with a relatively large extension gap is an important surgical challenge. We determined the predictors of SGI with a relatively large extension gap and evaluated the surgical outcomes of knees with SGI. Methods: 551 consecutive cases of primary TKA for osteoarthritis were retrospectively reviewed. The cohort was divided into two groups according to the SGI and statistically matched according to baseline characteristics via the inverse probability of treatment weighting method. Multiple linear and logistic regression analyses were performed to determine the predictors of sagittal gap difference (SGD) and SGI. Intergroup differences in clinical and radiological outcomes were analyzed. Results: Of all the knees included, 8.5% (n = 45) presented with SGI with a relatively large extension gap and required femoral sagittal balancing to manage SGI. The hyperextension angle (HA), preoperative joint line convergence angle (JLCA), and the change in posterior tibial slope (PTS) significantly correlated to SGD and predicted SGI with a relatively large extension gap. SGI group showed significant changes in femoral posterior condylar offset and joint line height compared to those without SGI (1.48 vs −0.45, 1.37 vs −0.51, respectively). Postoperative ROM and knee society knee scores were lower in SGI group. Conclusion: Knees requiring sagittal balancing to manage SGI with a relatively large extension gap is not uncommon in TKA for osteoarthritic knees. The change in PTS is an independent and modifiable predictor of SGI.
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Gresele, Amanda Dal Piva, Michele Vargas Garcia, Enma Mariángel Ortiz Torres, Sinéia Neujahr dos Santos Santos, and Maristela Julio Costa. "Bilingualism and auditory processing abilities: performance of adults in dichotic listening tests." CoDAS 25, no. 6 (December 2013): 506–12. http://dx.doi.org/10.1590/s2317-17822014000100003.
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Purpose: To evaluate and compare the dichotic listening abilities in non-hearing-impaired adults monolingual speakers of the Brazilian Portuguese language (CG) and simultaneous Brazilian Portuguese-German (GG) bilingual speakers or successive Brazilian Portuguese-Italian bilingual speakers (IG). Methods: This is about an observational, descriptive, transverse and quantitative research. The sample consisted of 87 subjects aged between 18 and 55 years, divided into: Control Group (CG), of 30 monolingual speakers of Brazilian Portuguese; Study Group A (SGA), of 31 simultaneous Brazilian Portuguese-German bilingual speakers; and Study Group I (SGI), of 26 successive Brazilian Portuguese-Italian speakers. The individuals were submitted to the Dichotic digits test (DDT) and to Staggered Spondaic Words (SSW). Results: The DTT results showed difference in right ear and total scores when comparing SGA to CG. Comparing the CG and the SGI, it was observed difference in right and left ears and total scores. Comparing the SGA and the SGI, no difference was observed between the groups. Results of SSW showed that both bilingual groups were significantly better in the right and left ears scores and even in total one when compared to CG. Comparing the SGA and the SGI, the SGI showed better significant scores in the right ear and total. Conclusion: Bilingual experiences seem to influence positively the ability of high predictability dichotic listening, evaluated by DDT, and the low predictability dichotic listening, evaluated by SSW test. The SSW results also showed statistically significantly better results for successive Brazilian Portuguese-Italian bilingual speakers when compared to simultaneous Brazilian Portuguese-German speakers.
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Faurissoux, Pierre, Moeata Lutui−Tefuka, Cyril Caubit, Bruno Lalanne, and Benjamin Nicot. "A fast method for trapped gas determination." E3S Web of Conferences 89 (2019): 02004. http://dx.doi.org/10.1051/e3sconf/20198902004.
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Gas reservoirs are mainly produced by depletion with an aquifer rise; reservoir simulation requires two main SCAL inputs: the amount of trapped gas by the aquifer (residual gas saturation: Sgr) and the relative permeability to water due to aquifer flooding. As it is quasi impossible to predict aquifer strength, the primary SCAL input for reservoir simulation is the Sgr. The recovery factor is directly defined by initial and residual gas saturations. In fact, the residual gas saturation Sgr highly depends on the initial gas saturation Sgi and there is no universal petrophysical parameter governing the shape of this curve. This relationship can be described by several different models (Land, Aissaoui…). While Land’s model is widely used, the Aissaoui model better fits the experimental results (Suzanne et al. 2003), at least for homogeneous sandstones. For a given threshold of initial gas saturation Sg0, this relationship typically exhibits a plateau at high Sgi>Sg0 and an increasing linear trend at low Sgi<Sg0. The challenge here is to properly estimate the value of the Sg0 threshold. Classical laboratory method would require one experiment per point in the Sgr/Sgi plot, and therefore can be achieved in a matter of months. Here we propose a laboratory method allowing the acquisition of the Sgr/Sgi curve in a few days. The proposed method combines centrifugation and capillary rise under imaging. First, the centrifuge allows creating a saturation profile along a sample; measured by NMR. Then, capillary rise is used to capture Sgr under NMR monitoring. By adding NMR imaging, this technique allows combining the benefits of centrifugation to explore a wide range of Sgi; and the ease and cost effectiveness of capillary rise to measure the resulting Sgr. Therefore, at a timescale close to a traditional capillary rise, the proposed technique avoids Land extrapolation and provides a direct measurement of Sgr in a wide range of Sgi. As an additional benefit, the combination of NMR and centrifuge can provide at the same time a direct measurement of capillary pressure, providing information on the gas in place and potential imbibition process in the reservoir.
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Laudon, James, and Daniel Lenoski. "The SGI Origin." ACM SIGARCH Computer Architecture News 25, no. 2 (May 1997): 241–51. http://dx.doi.org/10.1145/384286.264206.
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Pelaz, C., L. García, and C. Martín-Bourgon. "Legionellae isolated from clinical and environmental samples in Spain (1983–90): monoclonal typing ofLegionella pneumophilaserogroup 1 isolates." Epidemiology and Infection 108, no. 3 (June 1992): 397–402. http://dx.doi.org/10.1017/s0950268800049906.
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SUMMARYLegionella isolates recovered in 21 different Spanish provinces over 8 years from both clinical (67 isolates) and environmental (181) samples, mostly from case-associated buildings, are described: 92·5% of clinical isolates wereL. pneumophilaserogroup 1 (SGI), only five isolates belonging to other species or serogroups: twoL. pneumophilaSG6, two SG8 and oneL. bozemaniiSG1 not clearly related with clinical infection.L. pneumophilaSG1 accounted for 53·6% of isolates from the environment, followed by SG8 (27·6%). SG3 (9·4%) and SG6 (7·2%). Three isolates were labelled as SG8/10.Subtyping ofL. pneumophilaSG1 by the standardized panel of monoclonal antibodies revealed 90·3% of clinical and 78·3% of environmental isolates as belonging to Pontiac subgroup. Pontiac isolates were further divided into 55·3% Philadelphia 1 or Allentown 1, 21·9% Benidorm 030E and 20·4% Knoxville 1.Characterization of samples from four outbreaks in which both clinical and environmental isolates had been recovered permitted the recognition of three Philadelphia 1 or Allentown 1 and one Knoxville 1 strains as the aetiological agents.
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Stroopinsky, Dina, Athalia Rachel Pyzer, Kristen A. Palmer, Maxwell D. Coll, Michal Bar-Natan, Hasan Rajabi, Poorvi Somaiya, et al. "Immunomodulatory Effect of SGI-110, a Novel Hypomethylating Agent in Acute Myeloid Leukemia (AML)." Blood 124, no. 21 (December 6, 2014): 2303. http://dx.doi.org/10.1182/blood.v124.21.2303.2303.
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Abstract Introduction: We have developed a promising leukemia vaccine in which patient derived AML cells are fused with autologous dendritic cells (DCs) effectively presenting a broad array of antigens that capture the heterogeneity of the leukemia cell population. A major challenge of developing effective immunotherapy is overcoming the immunosuppressive milieu that characterizes patients with AML. AML cells evade immune targeting, in part, through the limited presentation of antigen by primitive leukemia progenitors. In contrast, induction of differentiation through upregulation of reactive oxygen species may enhance antigen presentation and the capacity to target AML cell by a tumor vaccine. Hypomethylating agents have been shown to be effective therapeutic agents for patients with AML and MDS, in part due to immunomodulatory effects. In the current study, we have examined the immunomodulatory properties of the novel DNA hypomethylating agent SGI-110, a dinucleotide of decitabine (DAC) and deoxyguanosine, which is resistant to in-vivo inactivation by cytidine deaminase. We have explored the in-vitro effect of treatment with SGI-110 on ROS, AML immunogenicity and efficacy of the AML/DC fusion vaccine. Methods and results: AML blasts were isolated by ficoll density centrifugation of bone marrow mononuclear cells (BMMCs) from patients with AML at presentation. AML blasts were cultured for 4 days in the presence or absence of 1 uM SGI-110, added twice daily on days 1 and 2 of culture. ROS as detected by levels of H2O2 expression demonstrated a 40% increase after treatment with SG1-110 (n=2). We subsequently evaluated whether the increase in ROS levels correlated with enhanced targeting by immune effector cells. SGI-110 or control treated AML cells were assessed for their susceptibility to T cell mediated targeting, using a standardized flourochrome CTL assay. Remarkably, a 72% increase in autologous cytotoxic T lymphocyte-mediated lysis as measured by Granzyme B activity, was demonstrated following SGI-110 treatment of AML blasts (n=3). The expression of co-stimulatory molecules CD80 and CD86, were unchanged following treatment with SGI-110 (n=3). In contrast, exposure to SGI-110 resulted in increased expression of the antigen processing TAP proteins by immunocytochemical analysis. We have previously demonstrated that DC/AML fusion cells potently stimulate the expansion of leukemia specific T cells. The effect of SGI-110 on T cell response to DC/AML fusion vaccine stimulation in vitro was assessed. Autologous Dendritic cells (DCs) were generated by culture of adherent peripheral mononuclear cells obtained from AML patients following remission in the presence of GM-CSF, IL-4 and TNF-α. DCs were fused with AML blasts by co-culture at a 1:1 ratio in the presence of polyethylene glycol (PEG). DC/AML fusions were cultured at a 1:10 ratio with autologous T cells for 5-6 days in the presence and absence of 1uM of SGI-110. Exposure of fusion stimulated autologous T cells to SGI-110 resulted in an increase in T cell expression of IFN-γ, with mean fold increase of 2.2 and 2.3 for CD4 and CD8 T cells respectively (n=4). The percentage of CD4+CD25+FOXP3+ regulatory T cells (TRegs) and T cell expression of PD1 was not significantly changed in the presence of SGI-110. The effect of SGI-110 on CTL mediated killing by vaccine stimulated T cells was assessed. Following stimulation with the DC/AML fusion vaccine, T cells mediated killing of autologous AML blasts increased to 11% from 4% following co-culture with unstimulated T cells. Interestingly, exposure of the AML cells to SGI-110 led to a further increase in T cells mediated killing with mean levels of 20% tumor lysis (n=2). Conclusions: The results demonstrate that treatment with SGI-110 results in increased ROS levels and an associated enhanced susceptibility of AML blasts to immune mediated targeting. The addition of SGI-110 to T cell stimulation by an autologous DC/AML fusion vaccine results in an increase in interferon gamma and increased susceptibility of AML cells to T cell mediated killing. The immunomodulatory properties of SGI-110, combined with its favorable pharmacologic and pharmacokinetic features, identify SGI-110 as a useful agent to implement novel combined epigenetic–immunotherapeutic strategies in AML. A clinical trial evaluating SGI-110 in combination with DC/AML fusion cell vaccination is planned. Disclosures Taverna: Astex Pharmaceuticals, Inc.: Employment. Avigan:Astex Pharmaceuticals: Research Funding.
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Fiskus, Warren, Pace Johnston, Rajeshree Joshi, Rekha Rao, Celalettin Ustun, Anand Jillella, Peter Atadja, Stuart Hwang, Sanjeev Redkar, and Kapil N. Bhalla. "Anti-AML Activity of Combined Epigenetic Therapy with Novel DNMT1 Inhibitors SGI-110 or SGI-1036 and Histone Deacetylase Inhibitor Panobinostat." Blood 112, no. 11 (November 16, 2008): 3355. http://dx.doi.org/10.1182/blood.v112.11.3355.3355.
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Abstract Lysine specific histone methylation and deacetylation and DNA hypermethylation are involved in the epigenetic silencing of tumor suppressor genes (TSG), e.g., p15 and p16. DNA methyltransferase (DNMT) inhibitors 5-azacytidine and 5-aza-2’-deoxycytidine demethylate the CpG dinucleotide islands in or near gene promoters, leading to derepression of TSGs in AML. SGI-110 (S110) (Cancer Res.2007; 67:6400) and SGI-1036 (SuperGen, Inc.) are novel, DNMT inhibitors, which also deplete DNMT1 levels. SGI-110 is a dinucleotide containing 5-aza-2’-deoxycytidine and SGI-1036 is a non-nucleoside heterocycle. The multi-protein complex PRC (polycomb repressive complex) 2 that contains the three core proteins EZH2, SUZ12 and EED, has intrinsic histone methyltransferase (HMTase) activity. This is mediated by the SET domain of EZH2, which induces trimethylation of histone H3 on lysine (K)-27. We recently reported that treatment with the pan-HDAC inhibitor panobinostat (LBH589, Novartis Pharmaceutical Corp) acetylates and inhibits the ATP binding and chaperone function of hsp90, as well as depletes the levels of EZH2, Suz12 and EED in cultured and primary AML cells (Mol Cancer Ther.2006; 5:3096). Within the PRC2 complex, EZH2 was shown to interact with and modulate the DNA methyltransferases DNMT1, DNMT3a and DNMT3b, which affects their binding to the EZH2-targeted gene promoters. In the present studies we determined the effects of SGI-110 or SGI-1036 and LBH589 on the PRC2 proteins EZH2 and SUZ12, and DNMT1, in the cultured (HL-60, OCI-AML3 and K562) and primary AML cells. Treatment with SGI-110 (0.5 to 2.0 μM) or SGI-1036 (0.5 and 1.0 μM) for 24 hours depleted protein levels of DNMT1 and EZH2 in the cultured and primary AML cells. SGI-110 and SGI-1036 promoted proteasomal degradation of DNMT1 and EZH2 since co-treatment with bortezomib significantly restored DNMT1 and EZH2 levels in the AML cells. Following treatment with SGI-110 or SGI-1036, bisulfite modification and methylation specific PCR demonstrated increase in unmethylated promoter DNA of p15 and JunB. This was associated with induction of the mRNA and protein levels of p15 and JunB, as well as caused inhibition of cell cycle progression (% of cells increased in G1 and increased in S phase) and colony growth in the soft agar. Treatment with 1.0 μM of SGI-110 or SGI-1036 also induced PARP cleavage activity of caspases and induced morphologic evidence of apoptosis in the AML cells. Co-treatment with 10 to 50 nM panobinostat enhanced SGI-110 or SGI-1036 mediated depletion of DNMT1 and EZH2, with more de-repression of the p15 and JunB and significant increase in apoptosis of AML cells. Collectively, these findings indicate that, SGI-110 and SGI-1036 deplete DNMT1 and EZH2 levels, as well as exert potent anti-AML activity. Additionally, combined epigenetic therapy consisting of SGI-110 or SGI-1036 in combination with panobinostat may represent a promising novel treatment of AML.
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Bloomfield, J. P., and B. P. Marchant. "Analysis of groundwater drought using a variant of the Standardised Precipitation Index." Hydrology and Earth System Sciences Discussions 10, no. 6 (June 14, 2013): 7537–74. http://dx.doi.org/10.5194/hessd-10-7537-2013.
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Abstract. A new index for standardising groundwater level time series and characterising groundwater droughts, the Standardised Groundwater level Index (SGI), is described. The SGI is a modification of the Standardised Precipitation Index (SPI) that accounts for differences in the form and characteristics of precipitation and groundwater level time series. The SGI is estimated using a non-parametric normal scores transform of groundwater level data for each calendar month. These monthly estimates are then merged to form a continuous index. The SGI has been calculated for 14 relatively long, up to 103 yr, groundwater level hydrographs from a variety of aquifers and compared with SPI for the same sites. The SPI accumulation period which leads to the strongest correlation between SPI and SGI, qmax, varies between sites. There is a positive linear correlation between qmax and a measure of the range of significant autocorrelation in the SGI series, mmax. For each site the strongest correlation between SPI and SGI is in the range 0.7 to 0.87, and periods of low values of SGI coincide with previously independently documented droughts. Hence SGI is taken to be a robust and meaningful index of groundwater drought. The maximum length of groundwater droughts defined by SGI is an increasing function of mmax, meaning that relatively long groundwater droughts are generally more prevalent at sites where SGI has a relatively long autocorrelation range. Based on correlations between mmax, average unsaturated zone thickness and aquifer hydraulic diffusivity, the source of autocorrelation in SGI is inferred to be dependent on aquifer flow and storage characteristics. For fractured aquifers, such as the Cretaceous Chalk, autocorrelation in SGI is inferred to be primarily related to autocorrelation in the recharge time series, while in granular aquifers, such as the Permo-Triassic Sandstones, autocorrelation in SGI is inferred to be primarily a function of intrinsic aquifer characteristics. These results highlight the need to take into account the hydrogeological context of groundwater monitoring sites when designing and interpreting data from groundwater drought monitoring networks.
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Bloomfield, J. P., and B. P. Marchant. "Analysis of groundwater drought building on the standardised precipitation index approach." Hydrology and Earth System Sciences 17, no. 12 (December 4, 2013): 4769–87. http://dx.doi.org/10.5194/hess-17-4769-2013.
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Abstract. A new index for standardising groundwater level time series and characterising groundwater droughts, the Standardised Groundwater level Index (SGI), is described. The SGI builds on the Standardised Precipitation Index (SPI) to account for differences in the form and characteristics of groundwater level and precipitation time series. The SGI is estimated using a non-parametric normal scores transform of groundwater level data for each calendar month. These monthly estimates are then merged to form a continuous index. The SGI has been calculated for 14 relatively long, up to 103 yr, groundwater level hydrographs from a variety of aquifers and compared with SPI for the same sites. The relationship between SGI and SPI is site specific and the SPI accumulation period which leads to the strongest correlation between SGI and SPI, qmax, varies between sites. However, there is a consistent positive linear correlation between a measure of the range of significant autocorrelation in the SGI series, mmax, and qmax across all sites. Given this correlation between SGI mmax and SPI qmax, and given that periods of low values of SGI can be shown to coincide with previously independently documented droughts, SGI is taken to be a robust and meaningful index of groundwater drought. The maximum length of groundwater droughts defined by SGI is an increasing function of mmax, meaning that relatively long groundwater droughts are generally more prevalent at sites where SGI has a relatively long autocorrelation range. Based on correlations between mmax, average unsaturated zone thickness and aquifer hydraulic diffusivity, the source of autocorrelation in SGI is inferred to be dependent on dominant aquifer flow and storage characteristics. For fractured aquifers, such as the Cretaceous Chalk, autocorrelation in SGI is inferred to be primarily related to autocorrelation in the recharge time series, while in granular aquifers, such as the Permo–Triassic sandstones, autocorrelation in SGI is inferred to be primarily a function of intrinsic saturated flow and storage properties of aquifer. These results highlight the need to take into account the hydrogeological context of groundwater monitoring sites when designing and interpreting data from groundwater drought monitoring networks.
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Moskowitz, Gordon B., and Irmak Olcaysoy Okten. "Spontaneous Goal Inference (SGI)." Social and Personality Psychology Compass 10, no. 1 (January 2016): 64–80. http://dx.doi.org/10.1111/spc3.12232.
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Kopylov, Uri, Michael Starr, Craig Watts, Serge Dionne, Marc Girardin, and Ernest G. Seidman. "Detection of Crohn Disease in Patients with Spondyloarthropathy: The SpACE Capsule Study." Journal of Rheumatology 45, no. 4 (February 15, 2018): 498–505. http://dx.doi.org/10.3899/jrheum.161216.
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Objective.Inflammatory bowel disease (IBD) is generally reported to be associated with spondylarthropathies (SpA) in 5%–15% of cases. Systematic colonoscopic assessment by protocol demonstrated mucosal inflammation characteristic of Crohn disease (CD) in up to one-third of patients with SpA. Video capsule endoscopy (CE) is a superior diagnostic tool to detect small bowel mucosal disease. Our study compared the accuracy of CE to standard colonoscopy for detection of inflammatory bowel lesions in patients with SpA, and to describe predictors of small bowel inflammation (SBI) in this cohort.Methods.Prospective cross-sectional study of adult patients followed for SpA. Patients were evaluated by CE and standard colonoscopy with biopsies. SBI was quantified using the Lewis Score. Additional screening tests included fecal calprotectin (FCP), C-reactive protein (CRP), and a diagnostic panel of serologic, inflammatory and genetic tests (SGI).Results.There were 64 patients recruited (53% female, mean age 42 ± 13 yrs). Chronic gastrointestinal (GI) symptoms were present in 57%. CE revealed significant SBI in 27/64 (42.2%), compared to 7/64 (10.9%) by standard colonoscopy (p = 0.035). Elevated FCP was associated with small bowel CD (OR 4.5, 95% CI 1.01–19.9; p = 0.042). No correlation was observed with presence of GI symptoms, CRP, or SGI results. Finding CD led to a change in management in 65.2% of cases.Conclusion.CE uncovered SBI consistent with CD in 42.2% of patients with SpA, with a significant incremental yield over colonoscopy of 31%. FCP levels were significantly correlated with CE results, while GI symptoms and SGI results were poor predictors of SBI.
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Barney, Brandon M., Svetomir Markovic, Nadia N. Laack, Robert C. Miller, Jann Nagina Sarkaria, Orlan Kenneth Macdonald, and Kenneth R. Olivier. "Increased bowel toxicity in patients treated with a vascular endothelial growth factor inhibitor (VEGF-i) following stereotactic body radiotherapy (SBRT)." Journal of Clinical Oncology 30, no. 15_suppl (May 20, 2012): e14507-e14507. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.e14507.
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e14507 Background: Serious gastrointestinal injury (SGI) is a rare but documented side effect that can occur independently with agents that affect the vascular endothelial growth factor (VEGF) receptor or with stereotactic body radiotherapy (SBRT). The risk of SGI in patients treated with the combination of SBRT sequentially followed by a VEGF inhibitor (VEGF-i) is not yet quantified. We explored the incidence of SGI in patients treated with SBRT with or without VEGF-i therapy at a single institution. Methods: From May 2008 to August 2011, 76 patients with 84 primary or metastatic intraabdominal lesions underwent SBRT (median dose, 50 Gy in 5 fractions). Twenty of these patients (26%) received a VEGF-i within two years of completing SBRT (bevacizumab, n=14; sorafenib, n=4; pazopanib, n=1; sunitinib, n=1). The most common site treated with SBRT was the liver (n=43, 57%), and the most common histology was colorectal adenocarcinoma (n=18, 24%). Other common histologies included melanoma of the skin (n=14, 18%) and non-small cell lung cancer (n=10, 13%). The incidence of SGI (CTCAE v4.0 grade 3 to 5 ulceration or perforation) after SBRT was obtained, and the relationship between SGI and VEGF-i was examined. Other factors that could potentially contribute to SGI, such as radiotherapy dose to bowel, were also analyzed. Results: Seven patients (9%) experienced SGI at a median 4.6 months (range, 3-17 months) after SBRT. All seven had received a VEGF-i prior to SGI and within 13 months of completing SBRT, and five received the VEGF-i within three months of SBRT. The six-month estimate of SGI in patients receiving a VEGF-i within three months of SBRT was 38%. No SGI was noted in the 63 patients not receiving VEGF-i therapy after SBRT. The Log-Rank test showed a significant correlation between SGI and VEGF-i therapy within three months of SBRT (p=0.0006) but not between SGI and maximum radiotherapy bowel dose (p=0.20). Conclusions: The combination of SBRT and VEGF-i therapy results in a much higher risk of SGI than would be expected with either treatment given independently. Local therapies other than SBRT should be considered if a patient is likely to be treated with a VEGF-i in the future.
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Kong, Shang, Dan Zhou, Qinghong Fan, Tingting Zhao, Chunguang Ren, and Hong Nie. "Salviae miltiorrhizae Liguspyragine Hydrochloride and Glucose Injection Protects against Myocardial Ischemia-Reperfusion Injury and Heart Failure." Computational and Mathematical Methods in Medicine 2022 (June 29, 2022): 1–12. http://dx.doi.org/10.1155/2022/7809485.
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Purpose. Myocardial ischemia-reperfusion (MIR) injury is a common stimulus for cardiac diseases like cardiac arrhythmias and heart failure and may cause high mortality rates. Salviae miltiorrhizae liguspyragine hydrochloride and glucose injection (SGI) has been widely used to treat myocardial and cerebral infarctions in China even though its pharmacological mechanisms are not completely clear. Methods. The protective effect and mechanism of SGI on MIR injury and heart failure were investigated through the H9c2 cell model induced by hypoxia/reoxygenation (H/R) and rapamycin, zebrafish model induced by H/R and isoprenaline, and rat MIR model. Results. SGI significantly reduced the infarct size and alleviated the impairment of cardiac functions in the MIR rat model and H/R zebrafish model and promoted cell viability of cardiomyocyte-like H9c2 cells under H/R condition. Consistently, SGI significantly downregulated the serum level of biomarkers for cardiac damage and attenuated the oxidative damage in the MIR and H/R models. We also found that SGI could downregulate the increased autophagy level in those MIR and H/R models since autophagy can contribute to the injurious effects of ischemia-reperfusion in the heart, suggesting that SGI may alleviate MIR injury via regulating the autophagy pathway. In addition, we demonstrated that SGI also played a protective role in the isoproterenol-induced zebrafish heart failure model, and SGI significantly downregulated the increased autophagy and SP1/GATA4 pathways. Conclusion. SGI may exert anti-MIR and heart failure by inhibiting activated autophagy and the SP1/GATA4 pathway.
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Brown, Valerie I., Cecilia Sheen, Jessica Hulitt, Theresa Ryan, Laura DiNardo, David Barrett, David T. Teachey, David J. Bearss, Gregory I. Berk, and Stephan A. Grupp. "Inhibiting PIM-1 Is Effective in Vitro and in Vivo against ALL: A Novel Mechanistic and Potentially Clinically Relevant Druggable Target." Blood 112, no. 11 (November 16, 2008): 1922. http://dx.doi.org/10.1182/blood.v112.11.1922.1922.
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Abstract The outcome for patients with acute lymphoblastic leukemia (ALL) has improved greatly over the past three decades. However, the prognosis remains dismal for those with relapsed or refractory ALL despite intensified therapy. Biologically targeted agents, such as signal transduction inhibitors (STIs) have shown promise in treating leukemia. We have reported that mTOR inhibitors (MTIs) such as rapamycin (rap), RAD-001, and CCI- 779 show activity in models of murine and human ALL. However, acquired resistance to STIs remains a concern. Furthermore, the presence of cytokines such as IL-7 and TSLP can promote survival, induce STAT5 phosphorylation, and reverse the inhibitory effects of MTIs in ALL cells. We hypothesize that IL-7-mediated signaling promotes ALL cell survival and potentially contributes to MTI resistance by upregulating alternative survival pathways, such as the JAK/STAT pathway. We have evaluated the effects of inhibiting PIM-1 kinase, a known downstream target of STAT5. Using the PIM-1 inhibitor SGI- 1776 (generously provided by SuperGen, Inc.), we have found that SGI-1776 profoundly inhibited proliferation in vitro, with an IC50 of approximately 1 mM for murine and 2.5 mM for human ALL cell lines. Greater than 90% inhibition was seen at concentrations of 5 and 10 mM in murine and human ALL lines, respectively. Furthermore, a combination of 1 mM SGI-1776 and 1 ng/ml rap resulted in further inhibition than either agent alone. Because PIM-1 is regulated at the transcription level, we measured changes in PIM-1 specific mRNA levels via real time PCR after 24 hour treatment with combinations of SGI-1776, rap and IL-7 (2 ng/ml). As seen in the Table, in each treatment condition SGI-1776 significantly decreased PIM-1 mRNA. As expected, IL-7 increased PIM-1 expression. Interestingly, inhibition of mTOR signaling via rap also resulted in an apparent compensatory increase in PIM-1 mRNA, which was in turn antagonized by SGI-1776. TABLE: fold change in PIM-1 mRNA by RT-PCR Untreated SGI-1776 IL7 IL7+SGI Rap Rap+SGI Rap+IL7 Rap+IL7+SGI 1 0.1 17 1 3 0.4 22 6.5 To evaluate SGI-1776 in a clinically relevant in vivo model, NOD/SCID mice xenografted with human primary ALL cells from several samples were treated with SGI-1776 alone, SGI-1776 + rap or drug vehicle. SGI-1776 (200 mg/kg/dose daily x 5 per week by gavage) alone or with rap decreased in vivo tumor proliferation over time as compared to untreated mice. At this dose of SGI-1776, the treated mice exhibited significant side effects, including weight loss, hunched appearance with scruffy coats, decreased appetite and decreased activity. Because of this toxicity, we were not able to detect a difference in survival as a result of observed decreases in ALL burden; however these toxicities were alleviated with a reduction of SGI-1776 to 100 mg/kg/dose, and survival studies at the better-tolerated dose are ongoing. These data show that, alone and in combination with rapamycin, the PIM-1 inhibitor SGI-1776 demonstrates activity in vitro and in vivo against human ALL. Together these data suggest that PIM-1 activation can act as a mechanism of cytokine mediated MTI resistance, making PIM-1 an attractive therapeutic target for ALL.
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Vitoreli, Gislaine Aparecida, and Luiz Cesar Ribeiro Carpinetti. "Análise da integração dos sistemas de gestão normalizados ISO 9001 e OHSAS 18001: estudo de casos múltiplos." Gestão & Produção 20, no. 1 (March 2013): 204–17. http://dx.doi.org/10.1590/s0104-530x2013000100015.
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Para atender às demandas do ambiente, as organizações implementam diversos sistemas de gestão. Com isso, dificuldades relacionadas ao seu gerenciamento paralelo podem surgir, o que leva as empresas a integrar estes sistemas em um único Sistema de Gestão Integrado (SGI). Dado este cenário, os pesquisadores buscam elaborar modelos que visam facilitar a implementação do SGI, a integração da documentação, além de investigar os benefícios e dificuldades dessa implementação. Entretanto, as pesquisas não mostram como a integração dos sistemas de gestão normalizados acontece nas organizações, assim uma investigação deste processo se torna interessante de forma a contribuir para a pesquisa sobre SGI. Com foco nos sistemas de gestão normalizados ISO 9001 e OHSAS 18001, o objetivo deste trabalho é analisar a integração desses sistemas de gestão sob três variáveis de pesquisa: o processo de implementação do SGI, a integração dos requisitos das normas e a estrutura de gestão do SGI. Para a condução desta pesquisa foi utilizado como método o estudo de caso. Como resultados, foram observadas diversas semelhanças no processo de implementação do SGI e na documentação desenvolvida pelas organizações para a sua implementação. Identificou-se ainda, que o tamanho da organização pode influenciar na estrutura de gestão estabelecida para o gerenciamento do SGI.
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Saito, Yasuhiko, and Tadashi Isa. "Organization of Interlaminar Interactions in the Rat Superior Colliculus." Journal of Neurophysiology 93, no. 5 (May 2005): 2898–907. http://dx.doi.org/10.1152/jn.01051.2004.
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Our previous studies have shown that when slices of the rat superior colliculus (SC) are exposed to a solution containing 10 μM bicuculline and a low concentration of Mg2+ (0.1 mM), most neurons in the intermediate gray layer (stratum griseum intermediale; SGI), wide-field vertical (WFV) cells in the optic layer (stratum opticum; SO), and a minor population of neurons in the superficial gray layer (stratum griseum superficiale; SGS) exhibit spontaneous depolarization and burst firing, which are synchronous among adjacent neurons. These spontaneous and synchronous depolarizations were thought to share common mechanisms with presaccadic burst activity in SGI neurons. In the present study, we explored the site responsible for generation of synchronous depolarization of SGI neurons by performing dual whole cell recordings under different slice conditions. A pair of SGI neurons recorded in a small rectangular piece of the SGI punched out from the SC slice showed synchronous depolarization but far less frequently than those recorded in a small rectangular piece including SGS and SO. This suggests that the superficial layers are needed for triggering synchronous depolarization in the SGI. Furthermore, we recorded spontaneous depolarizations in pairs of neurons belonging to the different layers. Analysis of their synchronicity revealed that WFV cells in the SO exhibit synchronous depolarizations with both SGS and SGI neurons, and the onset of spontaneous depolarization in WFV cells precedes those of neurons in other layers. Further, when SGS and SGI neurons exhibit synchronous depolarizations, SGI neurons usually precede the SGS neurons. These observations give further evidence to the existence of interlaminar interaction between superficial and deeper layers of the SC. In addition, it is suggested that WFV cells can trigger burst activity in other layers of the SC and that there is an excitatory signal transmission from the deeper layers to the superficial layers.
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Lu, Dingyan, Yubin Zhang, Weina Xue, Jia Sun, Chang Yang, Changhu Lin, Yongjun Li, and Ting Liu. "Shenxiong Glucose Injection Protects H9c2 Cells From CoCl2-Induced Oxidative Damage via Antioxidant and Antiapoptotic Pathways." Natural Product Communications 15, no. 4 (April 2020): 1934578X2092005. http://dx.doi.org/10.1177/1934578x20920054.
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Cardiovascular disease has become one of the main diseases that endanger humans, and oxidative damage plays an important role in this. Shenxiong glucose injection (SGI) is a common clinical treatment in China for the treatment of this condition. To understand further the protective effects and related mechanisms of SGI on cardiovascular diseases, H9c2 cells were treated with SGI at different concentrations (0.5%, 1%, 2% [v/v]) before hypoxic damage was induced by treatment with CoCl2). In CoCl2-induced H9c2 cells, SGI treatment increased cell viability and the activity of superoxide dismutase, glutathione peroxidase, catalase, elevated mitochondrial membrane potential, and decreased the rate of cellular apoptosis, lactic dehydrogenase release, and the content of malondialdehyde and reactive oxygen species, while also upregulating Bcl-2 expression and downregulating Bax, Cyt-c, and cleaved caspase-3 expression. Together, these results suggested that SGI has a protective effect on CoCl2-induced damage, and its mechanism may be related to increased antioxidant and antiapoptosis capacity in H9c2 cells. This study provides the basis for further research and potential practical applications of SGI.
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Scholl, Jason, Rajashree Joshi-Hangal, Roger Inloes, Chongtie Shi, Pietro Taverna, Gavin S. Choy, Sanjeev Redkar, and Mohammad Azab. "SGI-110, a Novel Second Generation Potent DNA Methylation Inhibitor, In Development for the Treatment of MDS and AML. Preclinical Safety, Pharmacokinetics, and DNA Methylation Results of a Low Volume Subcutaneous (SC) Formulation." Blood 116, no. 21 (November 19, 2010): 1872. http://dx.doi.org/10.1182/blood.v116.21.1872.1872.
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Abstract Abstract 1872 SGI-110, is a novel second generation DNA methylation inhibitor that is currently in Phase I/II clinical study for treatment of myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). SGI-110 is a dinucleotide of decitabine and guanosine developed to be more biologically stable than decitabine by making it less prone to deamination by cytidine deaminase, thus offering a promising alternative to current hypomethylating agents approved in MDS. SGI-110 demonstrated potent activity in vivo using different routes of administration (Chuang JC, et al, Mol Cancer Ther, 2010; 9:1443-50). We report here the results of a novel SGI-110 non-aqueous formulation intended for clinical use. The clinical formulation can be administered in small volumes subcutaneously (SC) up to a concentration of 100 mg/mL. We evaluated 2 regimens: daily SC × 5 days (in rats, and rabbits); and weekly SC (once weekly in rabbits, and cynomolgus monkeys; and twice weekly in rats). Both regimens are intended for 28-day cycles. The 5-day regimen was well tolerated up to a dose of 1.5 mg/kg/day × 5 in the most sensitive species (rabbit) which is equivalent to 18 mg/m2/day × 5 in humans. The weekly regimen was also well tolerated up to 1.5 mg/kg weekly × 3 in rabbits, and up to 3 mg/kg weekly × 3 in monkeys (equivalent to 36 mg/m2 weekly × 3 in humans). Rats tolerated much higher doses (30 mg/kg/day × 5; and 20 mg/kg twice weekly × 4 weeks). The main toxicity was myelosuppression in all species. The relative bioavailability of SGI-110 dosed SC is close to 100%. In vivo, SGI-110 rapidly converts to decitabine in rats, and rabbits, with much slower conversion in monkeys compared to other species, possibly sustaining efficacy for longer duration. Dose proportional pharmacokinetics and no significant accumulation of both SGI-110 and decitabine levels were evident after SC treatment in both the 5-day and the weekly regimens. We studied changes in LINE-1 DNA methylation in rats and monkeys after SGI-110 SC administration. Changes in LINE-1 DNA methylation after SGI-110 SC weekly × 4 in rats at tolerated doses of 12.5, 25 and 30 mg/kg/week were evident during the first recovery week (Day 31) and were dose-dependent. Maximum methylation reduction was observed with 30 mg/kg/week of SGI-110. These data in rats suggest a delayed pharmacodynamic effect. In monkeys, SGI-110 was administered at 3 mg/kg/week SC for 3 weeks (Days 1, 8 and 15). Reduction in LINE-1 DNA methylation became evident by Day 8, reached a maximum reduction of 10–15% by Day 15–22, and was maintained until Day 29. LINE-1 methylation levels were significantly reduced from baseline levels (p< 0.05) from Days 8–29. On Day 1, an average Cmax of 33.4 ng/mL at a Tmax of 1 hr and AUC of 120 ng*hr/mL were achieved for decitabine compared to Cmax of 184 ng/mL at a Tmax of 1 hr and AUC of 381 ng*hr/mL for SGI-110. On Day 15, an increase in the average SGI-110 AUC to 592 ng*hr/mL was observed suggesting some accumulation. All other pharmacokinetic parameters for decitabine and SGI-110 were similar to those on Day 1. Compared to other animal species tested, levels of SGI-110 were consistently and substantially higher in monkey plasma across studies. SGI-110 was well tolerated in monkeys at this dose with only mild reversible myelosuppresion and no deaths. In conclusion, based on the non-human primate monkey data, this uniquely developed low volume non-aqueous SC formulation of SGI-110 may allow sustained efficacy with less frequent weekly dosing offering a new alternative to MDS and AML patients. SGI-110 is being studied in a first-in-human study. This study is a randomized Phase I/II, dose escalation, multicenter study of two subcutaneous regimens (daily on Days 1–5, and weekly × 3 on Days 1, 8, 15, both given in a 28-day cycle) in relapsed or refractory MDS, and relapsed, refractory, or elderly AML patients. Disclosures: Scholl: SuperGen: Employment. Joshi-Hangal:SuperGen: Employment. Inloes:SuperGen: Employment. Shi:SuperGen: Employment. Taverna:SuperGen, Inc.: Employment. Choy:SuperGen, Inc.: Employment. Redkar:SuperGen: Employment. Azab:SuperGen: Employment.
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Chen, Lisa S., Sanjeev Redkar, David Bearss, William G. Wierda, and Varsha Gandhi. "Pim kinase inhibitor, SGI-1776, induces apoptosis in chronic lymphocytic leukemia cells." Blood 114, no. 19 (November 5, 2009): 4150–57. http://dx.doi.org/10.1182/blood-2009-03-212852.
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Abstract Pim kinases are involved in B-cell development and are overexpressed in B-cell chronic lymphocytic leukemia (CLL). We hypothesized that Pim kinase inhibition would affect B-cell survival. Identified from a screen of imidazo[1,2-b]pyridazine compounds, SGI-1776 inhibits Pim-1, Pim-2, and Pim-3. Treatment of CLL cells with SGI-1776 results in a concentration-dependent induction of apoptosis. To elucidate its mechanism of action, we evaluated the effect of SGI-1776 on Pim kinase function. Unlike in replicating cells, phosphorylation of traditional Pim-1 kinase targets, phospho-Bad (Ser112) and histone H3 (Ser10), and cell-cycle proteins were unaffected by SGI-1776, suggesting an alternative mechanism in CLL. Protein levels of total c-Myc as well as phospho-c-Myc(Ser62), a Pim-1 target site, were decreased after SGI-1776 treatment. Levels of antiapoptotic proteins Bcl-2, Bcl-XL, XIAP, and proapoptotic Bak and Bax were unchanged; however, a significant reduction in Mcl-1 was observed that was not caused by caspase-mediated cleavage of Mcl-1 protein. The mechanism of decline in Mcl-1 was at the RNA level and was correlated with inhibition of global RNA synthesis. Consistent with a decline in new RNA synthesis, MCL-1 transcript levels were decreased after treatment with SGI-1776. These data suggest that SGI-1776 induces apoptosis in CLL and that the mechanism involves Mcl-1 reduction.
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Sulistyarini, Wahyu Dewi, Suyatmi, Amalia Indra Kusuma, Ririn Saniah Dwiyanti Abdullah, and Efrida Mia Siska. "IMPLEMENTASI INTERVENSI SPRITUAL GUIDED IMAGERY (SGI) TERHADAP KECEMASAN PADA PASIEN KANKER PAYUDARA YANG MENJALANI KEMOTERAPI: STUDI KASUS DAN STUDI LITERATUR." Jurnal Ilmiah Keperawatan (Scientific Journal of Nursing) 8, no. 2 (June 30, 2022): 427–37. http://dx.doi.org/10.33023/jikep.v8i2.1178.
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Pendahuluan : Kanker dan kemoterapi adalah suatu keadaan yang memicu perasaan gelisah, cemas dan takut akan bayang-bayang proses pengobatan dan perawatan yang panjang serta kematian yang menghantui setiap saat. Salah satu intervensi keperawatan yang dapat dilakukan sebagai penatalksanaan cemas yakni dengan Spiritual Guided Imagery (SGI). Tujuan: penelitian ini adalah untuk mengetahui perbedaan tingkat kecemasan pasien kanker payudara yang menjalani kemoterapi dengan pendekatan intervensi SGI. Metode: studi kasus dengan pendekatan Asuhan Keperawatan dengan melibatkan 2 responden dengan dilengkapi studi literatur dari berbagai database artikel yakni Pubmed, Science Direct, Wiley Online, Proquest dan Google Scholar yang dipublikasikan dari tahun 2015 sampai 2021. Pengumpulan data menggunakan asuhan keperawatan yang meliputi Pengkajian, Diagnosa Keperawatan, Intervensi, Implementasi dan Evaluasi. Instrument pengumpulan data menggunakan format Pengkajian Asuhan Keperawatan Paliatif sesuai ketentuan yang berlaku dan menggunakan kuesioner State- Traite Anxiety Inventory (STAI) untuk mengevaluasi tingkat kecemasan. Terapi yang diberikan adalah SGI dan dievaluasi dalam waktu 3 hari. Hasil: Evaluasi intervensi Keperawatan SGI menunjukkan bahwa terdapat perubahan skala kecemasan dari sedang menjadi ringan. Kesimpulan: SGI dapat mengatasi kecemasan sedang pada pasien kanker payudara. SGI dapat dilakukan sebagai salah satu intervensi keperawatan mandiri dalam menurunkan gejala kecemasan yang dirasakan oleh pasien kanker terutama yang sedang menjalani proses pengobatan kemoterapi
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Jueliger, Simone, John F. Lyons, Joern Lewin, Mohammad Azab, and Pietro Taverna. "Identification of Novel Methylation Biomarkers to Predict Clinical Response to SGI-110, a Second Generation Hypomethylating Agent (HMA), in Patients with Acute Myeloid Leukaemia (AML)." Blood 124, no. 21 (December 6, 2014): 1050. http://dx.doi.org/10.1182/blood.v124.21.1050.1050.
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Abstract Introduction: SGI-110 is second generation HMA formulated as a dinucleotide of decitabine (DAC) and deoxyguanosine delivered as a small volume, pharmaceutically stable SQ injection allowing longer half-life and more extended decitabine exposure than DAC IV infusion. SGI-110 differentiated pharmacokinetic profile resulted in potent hypomethylation and clinical responses in previously treated MDS and AML patients in the phase 1 trial (Kantarjian et al. 2012). Here, we have identified novel DNA-methylation biomarker candidates that may be predictive of response to SGI-110 using Differential Methylation Hybridisation (DMH) profiling of the NCI-60 cell line panel (Fassbender A et al, Methods Mol Biol 2010). Cell lines were stratified based on SGI-110 EC50 values from Colony Forming Assay and degree of LINE-1 (Long Interspersed Nucleotide Elements) demethylation post-SGI-110 treatment. The stratification was used to classify cell lines into SGI-110 sensitive and resistant and to generate 249 genomic methylation sites as candidate biomarkers of response to SGI-110. Candidate markers from this analysis will now be compared in DNA samples derived from whole blood from treatment naïve and relapsed/refractory AML patients that were classified into responders and non-responders after treatment with SGI-110 in our phase 2 clinical study. Methods: DMH was used for unbiased profiling of methylated loci throughout the genome. Briefly, the genome is cleaved into a defined fragment library using methylation unspecific restriction enzymes, followed by PCR-adapter ligation. In a second step, the fragments are digested by methylation-sensitive restriction enzymes cutting only at unmethylated restriction sites, while methylated fragments and fragments that do not have any restriction site were protected from the restriction digestion. The methylated fragments and the control fragments are then selectively amplified by PCR and the PCR product is labeled and hybridized to Epigenomics' proprietary DMH microarray. Direct Bisulfite Sequencing (DBS) is used to assess the DNA-methylation pattern of marker candidates at CpG level. Regions with CpGs of interest are amplified to generate PCR products that are directly sequenced using a 4 dye labelled ddNTP Sanger sequencing. Quantitative DNA methylation of CpG region with a lengths of up to 550 bp are derived from the resulting trace files using the ESME software (Lewin J et al, Bioinformatics. 2004 Nov 22;20(17):3005-12). Results: Using this method, we have seen a clear correlation of high sensitivity to SGI-110 with high LINE-1 methylation level. Five (leukemia) cell lines classified as sensitive to SGI-110 by EC50 values were among the 6 cell lines with the highest LINE-1 methylation (> 73% methylation) while resistant cell lines showed a LINE-1 methylation < 70%. A high degree of correlation was observed between LINE-1 methylation and genome-wide DNA-Methylation measured by DMH in over 50k genomic sites and supported the role of LINE-1 as a useful indicator for sensitivity to SGI-110 and global DNA methylation. Fifty genomic fragments that better characterized sensitive and resistant cell lines were selected for further validation. The differential DNA-methylation discriminating between SGI-110 sensitive and resistant cancer cell lines (n=18) was validated by DBS analysis at CpG level in genomic fragments. We will present data obtained from the DBS evaluation of methylation in these validated methylation marker candidates in up to 45 AML blood samples that were classified into responders and non-responders after treatment with SGI-110 in a phase 2 clinical trial. Conclusions: We identified DNA methylation patterns associated to sensitivity and resistance to the novel HMA SGI-110. The validated methylation biomarker discovery process based on DMA and DBS approaches may help to identify and characterise specific subgroups of AML patients that could preferentially respond to SGI-110. Disclosures Jueliger: Astex Pharmaceuticals: Employment. Lyons:Astex Pharmaceuticals: Employment. Lewin:Epitenomics AG: Employment. Azab:Astex Pharmaceuticals, Inc.: Employment. Taverna:Astex Pharmaceuticals, Inc.: Employment.
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Ahmed, Kausar Begam Riaz, Roberto H. Nussenzveig, Andrew T. Chen, Josef T. Prchal, Charles J. Parker, Eric Gourley, Paul Severson, et al. "Preclinical Characterization of the JAK-2 Inhibitor, SGI-1252." Blood 112, no. 11 (November 16, 2008): 2629. http://dx.doi.org/10.1182/blood.v112.11.2629.2629.
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Abstract Discovery of somatic mutation of JAK-2 (G1849T that produces JAK-2V617F) in the hematopoietic cells of patients with Philadelphia chromosome negative myeloproliferative disorders (Ph−MPDs) was a watershed event that not only provided new insights into the pathobiology of polycythemia vera, essential thrombocytosis and primary myelofibrosis but also identified a potential target for therapy. Herein we report the results of preclinical studies designed to characterize the activity of a novel inhibitor of JAK-2. The compound, SGI-1252, developed by SuperGen (Dublin, CA) incorporates with high affinity into the ATP-binding site of JAK-2. SGI-1252 was tested against a panel of 75 kinases and was found to have significant activity against only FLT-3, TYK-2 and the SRC family members, ABL, LCK, YES, in addition to JAK-2 and JAK-1. SGI-1252 has an IC50 for JAK-2 of 5.4 nM with an IC50 for JAK-2V617F of 19.7 nM. The inhibitor also effectively blocks the activity of JAK-1 (IC50 14.8 nM) but has little JAK-3 inhibitory activity (IC50 1,700 nM). SGI-1252 is a potent inhibitor of STAT-5 phosphorylation (EC50 76.2 nM) and was also found to block the JAK-2 dependent expression of the anti-apoptotic protein, BCL-XL (EC50 778 nM). Drug treatment of a murine cell line (FDCP) transfected with either human wild-type JAK-2 or JAK-2G1849Tgenerated IC50 values of 83 nM and 108 nM, respectively, and SGI-1252 treatment of human cell lines, HEL, UKE-1 and SET-2, that express mutant JAK2 in different copy numbers, gave IC50 values of 472 nM, 83 nM and 63 nM, repectively. When tested in ex-vivo expanded native human erythroid progenitor cells from 17 patients with Ph−MPDs (10 PV and 7 MF), SGI-1252 showed an IC50 of ~100 nM, regardless of the JAK-2V617F allele burden. Using a flow cytometric assay, SGI-1252 was shown to induce apoptotic cell death in a concentration dependent manner. Luminex technology allows for concurrent quantitative analysis of multiple proteins from the same tissue source, and this technology was used to investigate simultaneously the effects of SGI-1252 on total and phospho ERK1/2, total and phospho STAT3, phospho STAT5, caspase 3, cleaved PARP and GAPDH (control) in untreated and drug treated cells at IC50 and IC80 concentrations. Significant in vivo efficacy of SGI-1252 was also observed using HEL and MV-4-11 xenograft models when compared to treatment with vehicle or daunorubicin. Using a murine model, we found that SGI-1252 has high oral bioavailability and is well tolerated with a five-day repeat maximum dose of at least 900 mg/kg. Together, these studies demonstrate that SGI-1252 is a potent inhibitor of JAK-2 dependent proliferation in both JAK-2V617F positive cell lines and in ex vivo expanded erythroid progenitors derived from patients with JAK-2V617F positive Ph−MPDs. Moreover, our studies show that the effects of SGI-1252 are mediated by blocking both JAK-2 dependent anti-apoptoic pathways and JAK-2 dependent proliferative pathways. Using the orally available form of the compound, pharmacokinetic, pharmacodynamic and toxicity studies in mice suggest that serum concentration of the drug well above the predicted therapeutic range can be achieved without significant hematological toxicity. Based on these preclinical experiments, SGI-1252 appears to be an excellent candidate for phase I/II studies in patients with Ph−MPDs.
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Chen, Lisa S., Sanjeev Redkar, Pietro Taverna, Jorge E. Cortes, and Varsha Gandhi. "Mechanisms of cytotoxicity to Pim kinase inhibitor, SGI-1776, in acute myeloid leukemia." Blood 118, no. 3 (July 21, 2011): 693–702. http://dx.doi.org/10.1182/blood-2010-12-323022.
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Abstract Pim kinases are Ser/Thr kinases with multiple substrates that affect survival pathways. These proteins are overexpressed in acute myeloid leukemia (AML) blasts and we hypothesized that Pim kinase inhibition would affect AML cell survival. Imidazo[1,2-b]pyridazine compound, SGI-1776 inhibits Pim-1, Pim-2 and Pim-3, and was evaluated in AML-cell line, -xenograft model, and -primary blasts. Treatment of AML cells with SGI-1776 results in a concentration-dependent induction of apoptosis and we investigated its effect on Pim kinase functions. Phosphorylation of traditional Pim kinase targets, c-Myc(Ser62) and 4E-BP1 (Thr36/Thr47), were both decreased in actively cycling AML cell lines MV-4-11, MOLM-13 and OCI-AML-3. Levels of antiapoptotic proteins Bcl-2, Bcl-xL, XIAP, and proapoptotic Bak and Bax were unchanged; however, a significant reduction in Mcl-1 was observed. This was correlated with inhibition of global RNA and protein synthesis and MCL-1 transcript decline after SGI-1776 treatment. These data suggest that SGI-1776 mechanism in AML involves Mcl-1 protein reduction. Consistent with cell line data, xenograft model studies with mice bearing MV-4-11 tumors showed efficacy with SGI-1776. Importantly, SGI-1776 was also cytotoxic in AML primary cells, irrespective of FLT3 mutation status and resulted in Mcl-1 protein decline. Pim kinase inhibition may be a new strategy for AML treatment.
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Branford, Susan, Junia V. Melo, and Timothy P. Hughes. "Selecting optimal second-line tyrosine kinase inhibitor therapy for chronic myeloid leukemia patients after imatinib failure: does the BCR-ABL mutation status really matter?" Blood 114, no. 27 (December 24, 2009): 5426–35. http://dx.doi.org/10.1182/blood-2009-08-215939.
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Abstract Preclinical studies of BCR-ABL mutation sensitivity to nilotinib or dasatinib suggested that the majority would be sensitive. Correspondingly, the initial clinical trials demonstrated similar response rates for CML patients after imatinib failure, irrespective of the mutation status. However, on closer examination, clinical evidence now indicates that some mutations are less sensitive to nilotinib (Y253H, E255K/V, and F359V/C) or dasatinib (F317L and V299L). T315I is insensitive to both. Novel mutations (F317I/V/C and T315A) are less sensitive/insensitive to dasatinib. We refer to these collectively as second-generation inhibitor (SGI) clinically relevant mutations. By in vitro analysis, other mutations confer a degree of insensitivity; however, clinical evidence is currently insufficient to define them as SGI clinically relevant. Here we examine the mutations that are clearly SGI clinically relevant, those with minimal impact on response, and those for which more data are needed. In our series of patients with mutations at imatinib cessation and/or at nilotinib or dasatinib commencement, 43% had SGI clinically relevant mutations, including 14% with T315I. The frequency of SGI clinically relevant mutations was dependent on the disease phase at imatinib failure. The clinical data suggest that a mutation will often be detectable after imatinib failure for which there is compelling clinical evidence that one SGI should be preferred.
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Chen, Lisa S., William G. Wierda, Sanjeev Redkar, David J. Bearss, and Varsha Gandhi. "Pim Kinase Inhibitor, SGI-1776, Induces Apoptosis in CLL Lymphocytes." Blood 112, no. 11 (November 16, 2008): 4199. http://dx.doi.org/10.1182/blood.v112.11.4199.4199.
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Abstract We report investigational studies of a Pim-1 kinase inhibitor, SGI-1776, as a therapeutic agent for the treatment of chronic lymphocytic leukemia (CLL). Pim family proteins are serine/threonine kinase inhibitors of apoptosis, and elevated expression of Pim kinases have been detected in hematological malignancies and in certain solid tumors. Three Pim kinases have been identified to date, Pim-1, -2 and -3. Pim-1 has been shown to synergize with c-Myc in tumorigenesis, and increased expression of the human Pim-2 gene is observed in CLL and non-Hodgkin lymphomas. Specifically, Pim-1 and Pim-2 have been shown to be required for efficient pre–B-cell transformation by v-Abl oncogene. Small molecule SGI-1776 was evaluated using Ambit Biosciences’ KINOMEscan and was found to have IC50s in the nanomolar range for Pim-1, Pim-2, and Pim-3 using the Millipore IC50 Profiler. SGI-1776 was screened against a panel of kinases utilizing radiolabeled biochemical assays, and was found to be highly selective for Pim kinases without any effects on CDKs, Chk1, IKK, JNK, Abl, Raf, MAP kinases and protein kinase A and B. Specifically, the IC50 were measured as follows: Pim-1 (7 nM), Pim-2 (363 nM) and Pim-3 (69 nM.) The other two enzymes affected at nM concentration of SGI-1776 were Flt-2 and haspin. Using primary samples obtained from patients with CLL, we evaluated the potential for SGI-1776 to induce cell death. In vitro incubation of primary CLL cells (n=7), with 1, 3, and 10 μM SGI-1776 for 24 h resulted in an average increase in apoptosis of 10%, 22% and 38% respectively, compared with untreated cells. SGI-1776-induced apoptosis was observed in heterogeneous patient populations, and there was disparity in the expression levels of traditional CLL prognostic markers including ZAP-70, b2-microglobulin, IgVH mutation status, Rai stage and number of prior treatments. To elucidate its mechanism of action, we evaluated the effect of SGI-1776 on Pim kinase function. Phosphorylation of traditional Pim-1 kinase targets, phospho-Bad (Ser112) and histone H3 (Ser10) were not affected by SGI-1776 treatment in CLL, unlike in replicating cell types, suggesting an alternative mechanism in CLL. We then evaluated the potential inhibition of c-Myc driven transcription by measuring total RNA synthesis. Following treatment with 3 or 10 μM SGI-1776, there was a decrease in total RNA synthesis to approximately 50% of control, measured using a radioactive uridine incorporation assay (n = 3). There was also a reduction in Mcl-1 and c-Myc protein level, both of which have short transcript half-lives. The reduction in Mcl-1 protein was not due to apoptosis or cleavage by caspases, since Mcl-1 reduction occurred in the presence of caspase inhibitor ZVAD, nor was there an increase in cleaved Mcl-1. In contrast, there was no change in anti-apoptotic proteins Bcl-2, XIAP, survivin, stabilization of p53 or p21. Taken together, SGI-1776 consistently induced apoptosis in CLL cells. Although its mechanism of action is not fully elucidated, inhibition of RNA synthesis and reduction of Mcl-1 and c-Myc protein levels are associated with SGI-1776-induced apoptosis.
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Reichhardt, Caleb C., Tevan J. Brady, Reganne K. Briggs, Laura A. Smith, Brett Bowman, Matthew D. Garcia, Aaron Thomas, and Kara J. Thornton. "98 Comparing the effectiveness of anabolic implants in Santa Gertrudis sired steers versus Angus steers." Journal of Animal Science 98, Supplement_4 (November 3, 2020): 80. http://dx.doi.org/10.1093/jas/skaa278.146.
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Abstract This research compared the use of implants in Bos indicus influenced animals versus Bos taurus in a feedlot setting. Twenty steers were blocked by weight and breed in a 2 x 2 factorial design examining two different breeds: Angus (AN; n = 10) or Santa Gertrudis influenced (SGI; n = 10), and two implant strategies: no implant (CON; n = 10) or a combined implant (CI; n = 10). Steers were randomly placed into pens equipped with GrowSafe® bunks, fed the same ration, and weighed and ultrasounded on days 0, 28, 56, 84, and 112. Blood was collected on days 0, 2, 10, 28, 56, 84, and 112. Backfat measurements (BF), weights, and blood urea nitrogen (BUN) were determined. Data were analyzed using repeated measures and the ProcMixed procedure of SAS, looking at the main effects of breed, implant, and breed*implant. There were no initial differences (P > 0.05) in weight between any of the main effects. The main effects of breed, implant, and breed*implant demonstrate that AN gained more (P < 0.05) weight than SGI, CI gained more (P < 0.05) weight than CON, and the AN that received a CI had increased weight gain when compared to the AN CON, SGI CON and SGI CI. There was no difference (P > 0.05) in weight gain between the SGI that received a CI vs CON, nor was there a difference (P > 0.05) between the CON SGI and AN. There was a treatment*breed interaction for BF (P < 0.05), with AN tending to put on more BF than SGI CON (P < 0.08). A breed*treatment interaction was also observed when analyzing BUN (P < 0.05). This research provides preliminary evidence suggesting that anabolic implants are not as effective in Bos indicus influenced animals when compared to Bos taurus animals.
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Ren, Jiangzhuo, Fengzhang Ren, Fengjun Li, Linkai Cui, Yi Xiong, and Alex A. Volinsky. "Effects of Microstructure, Mechanical and Physical Properties on Machinability of Graphite Cast Irons." Metals 10, no. 2 (February 21, 2020): 285. http://dx.doi.org/10.3390/met10020285.
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Flake (FGI) and spheroidal (SGI) graphite cast irons are often used to produce workpieces, which often need to be machined. Machinability differences under various machining methods are the basis for choosing machining equipment and technology. In this work, FGI and SGI were used to produce tractor front brackets, and the machinability of both materials under turning and drilling processes was compared. The machinability (turning and drilling ability) has been evaluated in terms of machining load, chips shape, surface roughness, and tool temperature. The influence of materials microstructure and thermal conductivity on the machinability was analyzed. In the turning process, the cutting force and its standard deviation of the FGI were larger than the SGI due to the higher volume fraction of pearlite. The surface roughness was similar in both materials. In the drilling process, the even action of the friction and cutting force on the bit turned into similar drilling loads for both materials. Higher friction and lower thermal conductivity caused a higher bit temperature in SGI drilling compared to FGI. The chip breaking was worse in SGI drilling, where the longer chips scratched the internal surface of the holes, resulting in the higher surface roughness.
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Cosenza, Apoena Canuto. "A Sociedade Geográfica Italiana e seu papel no projeto colonialista para a África, entre 1870 a 1889. Uma introdução à análise quantitativa." Sankofa (São Paulo) 6, no. 12 (December 6, 2013): 74. http://dx.doi.org/10.11606/issn.1983-6023.sank.2013.88943.
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Este artigo tem como objetivo apresentar uma leitura quantitativa da visão da Sociedade Geográfica Italiana (SGI) sobre a África. A SGI, desde de sua fundação, pretendeu ser uma fomentadora das políticas italianas de exploração econômica da África. Uma análise quantitativa sobre os temas dos artigos e notas divulgadas nos boletins da SGI, entre 1870 e 1889, podem ajudar a entender quais eram os interesses de parcelas da burguesia sobre o continente Africano. Ainda, permite perceber aspectos sobre como aquela sociedade influenciou (ou foi influenciada) pelas conquistas coloniais italianas.
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Sutherland Owens, Ashley N., Euripedes C. Miguel, and Neal R. Swerdlow. "Sensory Gating Scales and Premonitory Urges in Tourette Syndrome." Scientific World JOURNAL 11 (2011): 736–41. http://dx.doi.org/10.1100/tsw.2011.57.
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Sensory and sensorimotor gating deficits characterize both Tourette syndrome (TS) and schizophrenia. Premonitory urges (PU) in TS can be assessed with the University of Sao Paulo Sensory Phenomena Scale (USP-SPS) and the Premonitory Urge for Tics Scale (PUTS). In 40 subjects (TS: n = 18; healthy comparison subjects [HCS]: n = 22), we examined the relationship between PU scores and measures of sensory gating using the USP-SPS, PUTS, Sensory Gating Inventory (SGI), and Structured Interview for Assessing Perceptual Anomalies (SIAPA), as well symptom severity scales. SGI, but not SIAPA, scores were elevated in TS subjects (p < 0.0003). In TS subjects, USP-SPS and PUTS scores correlated significantly with each other, but not with the SGI or SIAPA; neither PU nor sensory gating scales correlated significantly with symptom severity. TS subjects endorse difficulties in sensory gating and the SGI may be valuable for studying these clinical phenomena.
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Natarajan, Karthika, Mehmet Burcu, and Maria R. Baer. "Inhibition of the Serine/Threonine Kinase Pim-1 Has Anti-Proliferative Effects In Acute Myeloid Leukemia (AML) and Sensitizes Multidrug Resistant Cells to Chemotherapy." Blood 116, no. 21 (November 19, 2010): 1832. http://dx.doi.org/10.1182/blood.v116.21.1832.1832.
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Abstract Abstract 1832 Poster Board I-812 The serine/threonine kinase Pim-1, encoded by a proto-oncogene originally identified as the proviral integration site in Moloney murine leukemia virus lymphomagenesis, phosphorylates and thereby increases expression of multiple cellular proteins, including the pro-apoptotic protein BAD, the cell cycle regulatory proteins p21, p27, Cdc25A and Cdc25C, the transcription factors SOCS-1, RUNX3 and c-myc and, as we recently demonstrated, the drug resistance-associated ATP-binding cassette (ABC) proteins P-glycoprotein (Pgp, ABCB1) and breast cancer resistance protein (BCRP, ABCG2). Pim-1 is synthesized in an active form by virtue of its hinge structure, and its activity is therefore regulated solely by its level of expression. Pim-1 is overexpressed downstream of FLT3 in AML cells with FLT3-ITD, but less is known about its expression and role in AML with wild-type (wt) FLT3. We studied Pim-1 expression and the effects of Pim-1 inhibition on AML cell survival, proliferation, apoptosis and chemosensitivity. Cell lines studied included HL60, K562, U937, Kasumi-1 and EOL-1 FLT3-wt cells and MV4-11 and MOLM-14 FLT3-ITD cells, as well as Pgp+ HL60/VCR and BCRP+ 8226/MR20 and parental 8226 myeloma cells as a model for BCRP-mediated drug resistance. Expression of Pim-1 and of phospho-BAD at S112, a measure of Pim-1 activity, was studied by Western blot analysis, normalized to GAPDH expression. Effects of the Pim-1 inhibitor SGI-1776 (SuperGen, Inc., Dublin, CA) on survival, cell cycle, apoptosis and colony growth were measured in WST-1 cell survival, flow cytometric cell cycle and apoptosis, and methylcellulose colony formation assays, respectively. SGI-1776 inhibits Pim-1 at a concentration of 7 +/− 1.8 nM, but is more than 90% bound to human plasma protein, so that its Pim-1 inhibitory concentration in cell culture-based assays is in μM range. Of note, SGI-1776 also inhibits FLT3 in this concentration range. Pim-1 was expressed in all cell lines studied, and expression of Pim-1 and of phopho-BAD did not differ between FLT3-ITD and FLT3-wt cells, nor between drug-resistant and parental cells. SGI-1776 decreased viable cell numbers in 96-hour WST-1 cell viability assays, with IC50's of 5 to 7 μM in FLT-wt cells, while IC50's were 20 and 65 nM, respectively, in MV4-11 and MOLM-14 FLT3-ITD cells. SGI-1776 IC50's did not differ between Pgp+ or BCRP+ cells and parental cells. In FLT3-wt cells, SGI-1776 had no effect on cell cycle at concentrations up to 5 μM, and caused apoptosis at 10 μM, while in FLT3-ITD cells, G1 arrest and apoptosis occurred at 100 nM. HL60 colony formation was completely inhibited by 5 μM SGI-1776, while MOLM-14 colony formation inhibition occurred at 500 nM. Finally, SGI-1776 sensitized multidrug resistant, but not parental, cells to multidrug resistance protein substrate, but not non-substrate, drugs. SGI-1776 at 1 μM decreased the IC50 of the Pgp substrate chemotherapy drug daunorubicin in Pgp+ HL60/VCR cells 7-fold, but had no effect on daunorubicin IC50 in HL60 cells, nor on IC50 of the non-Pgp substrate cytarabine in either cell line. SGI-1776 at 1 μM also decreased the IC50 of the BCRP substrate chemotherapy drug mitoxantrone in BCRP+ 8226/MR20 cells 7-fold. SGI-1776 at 1 μM doubled the percentage of apoptotic cells among HL60/VCR, but not HL60, cells exposed to daunorubicin and 8226/MR20 cells exposed to mitoxantrone. Finally, SGI-1776 at 1 μM decreased HL60/VCR colony formation in the presence of daunorubicin, but not cytarabine, but had no effect in HL60 cells, and also decreased 8226/MR20 colony formation in the presence of mitoxantrone, but not cytarabine. Thus the Pim-1 inhibitor SGI-1776 has anti-proliferative effects in AML cells with wt FLT3 as well FLT3-ITD, and sensitizes Pgp+ and BCRP+ multidrug resistant cells to chemotherapy. These data support clinical trials of SGI-1776 in AML with wt FLT3 as well FLT3-ITD, as a single agent and in combination with chemotherapy in multidrug resistant AML. Disclosures: No relevant conflicts of interest to declare.
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JONSSON, Magnus, Sara LINSE, Birgitta FROHM, Åke LUNDWALL, and Johan MALM. "Semenogelins I and II bind zinc and regulate the activity of prostate-specific antigen." Biochemical Journal 387, no. 2 (April 5, 2005): 447–53. http://dx.doi.org/10.1042/bj20041424.
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In semen, the gel proteins SgI and SgII (semenogelins I and II) are digested by PSA (prostate-specific antigen), resulting in liquefaction and release of motile spermatozoa. Semen contains a high concentration of Zn2+, which is known to inhibit the protease activity of PSA. We characterized the binding of Zn2+ to SgI and SgII and found evidence that these proteins are involved in regulating the activity of PSA. Intact SgI and SgII and synthetic semenogelin peptides were used in the experiments. Binding of Zn2+ was studied by radioligand blotting, titration with a zinc (II) fluorophore chelator and NMR analysis. A chromogenic substrate was used to measure the enzymatic activity of PSA. SgI and SgII bound Zn2+ with a stoichiometry of at least 10 mol (mol of protein)−1 and with an average dissociation constant of approx. 5 μM per site. Moreover, Zn2+-inhibited PSA was activated by exposure to SgI or SgII. Since both proteins have high affinity for Zn2+ and are the dominating proteins in semen, they probably represent the major Zn2+ binders in semen, one function of which may be to regulate the activity of PSA. The system is self-regulating, and PSA is maintained in an active state by its substrate.
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Pierens, Arnaud. "On the non-axisymmetric fragmentation of rings generated by the secular gravitational instability." Monthly Notices of the Royal Astronomical Society 504, no. 3 (January 23, 2021): 4522–32. http://dx.doi.org/10.1093/mnras/stab183.
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ABSTRACT Ringed structures have been observed in a variety of protoplanetary discs. Among the processes that might be able to generate such features, the Secular Gravitational Instability (SGI) is a possible candidate. It has also been proposed that the SGI might lead to the formation of planetesimals during the non-linear phase of the instability. In this context, we employ two-fluid hydrodynamical simulations with self-gravity to study the non-axisymmetric, non-linear evolution of ringed perturbations that grow under the action of the SGI. We find that the non-linear evolution outcome of the SGI depends mainly on the initial linear growth rate. For SGI growth rates smaller than typically σ ${\lesssim}$ 10−4–10−5 Ω, dissipation resulting from dust feedback introduces a m = 1 spiral wave in the gas, even for Toomre gas stability parameters Qg > 2 for which non-axisymmetric instabilities appear in a purely gaseous disc. This one-armed spiral subsequently traps dust particles until a dust-to-gas ratio ϵ ∼ 1 is achieved. For higher linear growth rates, the dust ring is found to undergo gravitational collapse until the bump in the surface density profile becomes strong enough to trigger the formation of dusty vortices through the Rossby Wave Instability (RWI). Enhancements in dust density resulting from this process are found to scale with the linear growth rate, and can be such that the dust density is higher than the Roche density, leading to the formation of bound clumps. Fragmentation of axisymmetric rings produced by the SGI might therefore appear as a possible process for the formation of planetesimals.
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Natarajan, Karthika, Jasjeet Bhullar, Suneet Shukla, Mehmet Burcu, Suresh V. Ambudkar, and Maria R. Baer. "The Pim Kinase Inhibitor SGI-1776 Chemosensitizes Multidrug Resistant Cells by Both Inhibiting Drug Transport by ABCB1 and ABCG2 and Decreasing ABCB1 and ABCG2 Surface Expression On Cells That Overexpress Pim-1." Blood 120, no. 21 (November 16, 2012): 2462. http://dx.doi.org/10.1182/blood.v120.21.2462.2462.
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Abstract Abstract 2462 Overexpression of the ATP-binding cassette (ABC) cellular drug efflux proteins ABCB1 and ABCG2 on acute myeloid leukemia (AML) cells is associated with inferior chemotherapy outcomes. Nevertheless, inhibitors of drug transport have not improved treatment outcomes in clinical trials. The serine/threonine kinase Pim-1, encoded by a proto-oncogene originally identified as the proviral integration site in Moloney murine leukemia virus lymphomagenesis, is expressed in AML and is implicated in regulation of multiple key cellular processes, as well as drug resistance. Our group has shown that Pim-1 phosphorylates ABCB1 and ABCG2 and promotes their translocation to the cell surface, where they mediate drug efflux. The imidazo[1,2-b]pyridazine small molecule SGI-1776 (Tolero Pharmaceuticals, Inc. Salt Lake City, UT) is the first Pim kinase inhibitor to have entered clinical testing. SGI-1776 has been shown to sensitize ABCB1-overexpressing drug-resistant cells to ABCB1 substrate cancer chemotherapy drugs, but chemosensitization was found to be associated with direct inhibition of drug transport mediated by ABCB1. Moreover, while silencing of Pim-1 expression with siRNA was found to sensitize ABCG2-overexpressing cells to ABCG2 substrate chemotherapy drugs, the effects of SGI-1776 on resistance mediated by ABCG2 have not been studied. Therefore we studied the Pim-1-dependent and -independent effects of SGI-1776 on chemosensitivity of cells overexpressing ABCB1 and ABCG2. SGI-1776 at the Pim-1-inhibitory and non-cytotoxic concentration of 1 μM decreased the IC50s of ABCB1 and ABCG2 substrate drugs including daunorubicin and mitoxantrone 2- to 4-fold in leukemia and myeloma cell lines overexpressing ABCB1 and ABCG2, but had no effect on the IC50 of the non-substrate drug cytarabine, and no effect in parental cells. SGI-1776 also increased apoptosis of ABCB1- and ABCG2-overexpressing leukemia and myeloma cells exposed to ABCB1 and ABCG2 substrate chemotherapy drugs, respectively, and decreased their colony formation in the presence of substrate, but not non-substrate, chemotherapy drugs, with no effect on parental cells. We found that SGI-1776 decreased ABCB1 and ABCG2 surface expression, measured by flow cytometry, on K562/ABCB1 (p=0.013) and K562/ABCG2 (p=0.0038) leukemia cells, respectively, both of which express Pim-1 at high levels, without decrease in total cellular ABCB1 and ABCG2 expression, measured by Western blot analysis. In contrast, SGI-1776 had no effect on ABCB1 and ABCG2 surface expression on HL60/VCR leukemia and 8226/MR20 myeloma cells, which express ABCB1 and ABCG2, respectively, but express Pim-1 at lower levels. Thus SGI-1776 decreased ABCB1 and ABCG2 surface expression on cells that overexpress Pim-1, consistent with decreased cell surface translocation of ABCB1 and ABCG2 as a result of inhibition of Pim-1, but also chemosensitized cells expressing ABCB1 and ABCG2 in the absence of effects on ABCB1 and ABCG2 cell surface expression. We found that SGI-1776 indeed inhibited uptake of fluorescent substrates of both ABCB1 and ABCG2, measured by flow cytometry, in a concentration-dependent manner. We further determined that SGI-1776 inhibited ABCB1 and ABCG2 photoaffinity labeling with the transport substrate [125I]-IAAP and stimulated ABCB1 and ABCG2 ATPase activity, consistent with binding to drug-binding sites of ABCB1 and ABCG2 and inhibition of substrate transport by both proteins. Thus SGI-1776 both inhibits drug transport by ABCB1 and ABCG2 and decreases ABCB1 and ABCG2 surface expression on cells that overexpress Pim-1. Pim-1 is thought to be a clinically promising therapeutic target in AML and other malignancies, and other Pim kinase inhibitors are in preclinical and clinical development. Subsequent clinically applicable Pim kinase inhibitors should be characterized with regard to interactions with ABCB1 and ABCG2. In particular, while therapeutic strategies based on inhibition of drug transport mediated by ABCB1 with competitive inhibitors including PSC-833, zosuquidar and cyclosporin A have largely been clinically unsuccessful, inhibition of ABCB1 and ABCG2 cell surface translocation by Pim kinase inhibitors may have therapeutic implications. Disclosures: No relevant conflicts of interest to declare.
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Chung, Woonbok, Pietro Taverna, John F. Lyons, Yong Hao, Mohammad Azab, Hagop M. Kantarjian, Patricia Kropf, and Jean-Pierre Issa. "Determinants Of Demethylation and Clinical Response In AML Patients Treated With SGI-110, a Novel Subcutaneous (SQ) Hypomethylating Agent (HMA) In a Phase 1 Study." Blood 122, no. 21 (November 15, 2013): 1442. http://dx.doi.org/10.1182/blood.v122.21.1442.1442.
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Abstract Introduction SGI-110 is a dinucleotide of decitabine and deoxyguanosine and is a potent inhibitor of DNA methylation in-vitro and in-vivo. A Phase 1 study established the biologically effective dose of SGI-110 in MDS/AML patients as 60 mg/m2 SQ daily x 5 and demonstrated clinical responses that correlated with hypomethylation induction. Here, we analyze AML patients treated at pharmacologically effective doses of SGI-110 to explore determinants of hypomethylation and response. Methods We studied patients with relapsed/refractory AML treated at therapeutic dose ranges of SGI-110 (36 mg/m2-125 mg/m2). DNA methylation pre/post treatment (for pharmacodynamics [PD]) was measured by bisulfite-pyrosequencing for the LINE-1 repetitive element and the INS6 CpG island gene promoter which is highly methylated in all somatic tissues. Gene expression at baseline and after treatment was measured by qPCR. Results We analyzed samples from 27 patients with AML. Median age was 64, (range, 29–86), 18 were Males (67%), 13 (48%) had poor risk cytogenetics at study entry and 59% had prior exposure to a hypomethylating agent. Overall, peak LINE-1 demethylation generally occurred on Day 8 and correlated strongly with INSL6 demethylation (R=0.95, p<0.001). In individual patients, peak LINE-1 demethylation ranged from +1% to -39%. We next examined baseline expression of a panel of genes (CDA, P15, P21, DNMT3B, DNMT3A, DNMT1, CTCF) as possible predictors of SGI-110 response. High expression of DNMT3b (but not DNMT1) was associated with a trend for reduced demethylation (R=-0.20, p>0.05). Unsupervised classification grouped the patients into four clusters: A (N=2), B (N=6), C (N=10), and D (N=9). Cluster D is characterized by high DNMT3b expression, low P15 expression, low CDA expression and reduced demethylation (demethylation average -10.9% in cluster D compared to -22.7% in clusters B and C, p=0.06). Next, we examined SGI-110 mediated induction of gene expression for the P15, P21, DNMT3B and CTCF genes. P15 was significantly induced in patients who were treated on the daily x 5 regimen (p=0.03) but not in patients receiving the weekly x 3 regimen. In this group of 14 patients with induced P15, P15 induction peaked on Day 8 and averaged a 2.4-fold increase. P15 induction was associated with a trend for increased demethylation on Day 8 (R=0.28) and on Day 29 (R=0.37), p>0.05 for both. Of the 27 patients, 5 showed major clinical responses (2 CR, 3 CRi/CRp). LINE-1 and INSL6 demethylation averaged -21.1% and -16.4% in responders compared to -13.1% and -11.3% in non-responders. A three gene classifier score (low CDA, low P15 and high DNMT3B) was associated with low LINE-1 demethylation (R=0.43, p=0.025) as well as resistance to SGI-110 (mean score 6.2 in non-responders compared to 0.5 in responders, p=0.047). Finally, peak induction of P15 was similar in responders and non-responders, but sustained induction (at Day 29) was higher in responders (3.1 fold) than in non-responders (1.0 fold). While a genetic signature of response could not be identified among those 8 genes that were examined by exome sequencing, mutations in IDH1 or IDH2 were identified in 5 patients. One of these patients was positive for substitution R132H of IDH1 (described to induce epigenetic alterations and may predict poor clinical outcome in AML) and achieved a CR in response to SGI-110 treatment. The TP53 polymorphism NM_000546:c.C215G:p.P72R, (associated with differential response to chemotherapy in AML), was identified in 9 subjects, 3 of whom responded to SGI-110. Conclusions At therapeutic doses of SGI-110, we identified a gene expression signature (high DNMT3B, low P15, and low CDA) that differentiates responders from non-responders to SGI-110 and we find trends for associations between demethylation and response, as well as sustained P15 induction and response. These associations will be further investigated in the ongoing Phase 2 study of SGI-110 in AML. Disclosures: Chung: Astex Pharmaceuticals Inc.: Research Funding. Off Label Use: SGI-110. Taverna:Astex Pharmaceuticals Inc.: Employment. Lyons:Astex Pharmaceuticals Inc.: Employment. Hao:Astex Pharmaceuticals Inc.: Employment. Azab:Astex Pharmaceuticals Inc.: Employment. Kantarjian:Astex Pharmaceuticals Inc.: Research Funding. Kropf:Astex Pharmaceuticals Inc.: Research Funding. Issa:Astex Pharmaceuticals Inc.: Honoraria, Research Funding.
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Dessì, Ugo. "Soka Gakkai International in Post-Apartheid South Africa." Religions 11, no. 11 (November 11, 2020): 598. http://dx.doi.org/10.3390/rel11110598.
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This paper analyzes the activities of Soka Gakkai International (SGI) in South Africa, a largely Christian country with the presence of very strong African Independent and Pentecostal churches, where Buddhism has mostly attracted the attention of a small minority of white middle-class people interested in meditational practices. By focusing on SGI South Africa, which has been able to reach out to a significant number of black, and, to a lesser extent, Coloured and Indian/Asian members, this ethnographic study aims to contribute to the understanding of Buddhism’s interplay with a broader cross-section of post-apartheid South African society, and, secondarily, to add to the existing literature on this Japanese new religious movement overseas. After a brief overview of the historical development of SGI in South Africa, my analysis focuses on SGI South Africa’s main ritual, social, and missionary activities; its interplay with local religions; its attempts to establish a meaningful link with South African culture; and, finally, on the religious experiences and narratives of SGI’s South African members.
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Bloomfield, J. P., B. P. Marchant, S. H. Bricker, and R. B. Morgan. "Regionalisation of groundwater droughts using hydrograph classification." Hydrology and Earth System Sciences Discussions 12, no. 6 (June 8, 2015): 5293–341. http://dx.doi.org/10.5194/hessd-12-5293-2015.
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Abstract. Groundwater drought is a spatially and temporally variable phenomenon. Here we describe the development and application of a method to regionalize and quantify groundwater drought based on categorisation of Standardised Groundwater level Index (SGI) time series. The categorisation scheme uses non-hierarchical k-means cluster analysis. This has been applied to 74 SGI time series for the period January 1983 to August 2012 for a case study from Lincolnshire, UK. Six SGI time series clusters have been identified. For each cluster a correlation can be established between the mean SGI and a mean Standardised Precipitation Index (SPI) associated with an optimal SPI accumulation period, qmax. Based on a comparison of SPI time series for each cluster and SPI estimated for the whole study area, it is inferred that the clusters are largely independent of heterogeneity in the diving meteorology across the study region and are primarily a function of catchment and hydrogeological factors. This inference is supported by the observation that the majority of sites in each cluster are associated with one of three principal aquifers in the study region. The groundwater drought characteristics of the three largest clusters (CL1, CL2 and CL4 that constitute ~80% of the sites) have been analyzed. There is a common linear relationship between drought magnitude and duration for each of three clusters. However, there are differences in the character of the groundwater drought events between the three clusters as a function of autocorrelation of the mean SGI time series for each cluster. For example, CL1 has a relatively short period of significant SGI autocorrelation compared with CL2 (15 and 23 months respectively); CL1 has more than twice the number of drought episodes (39 episodes) than CL2 (15 episodes), and the average and maximum duration of droughts in CL1 (4.6 and 27 months) are less than half those of CL2 (11.3 and 61 months). The drought characteristics of CL4 are intermediate between those of CL1 and CL2. Differences in characteristics between the three clusters are also seen in their response to three major multi-annual droughts that occurred during the analysis period. For example, sites in CL2 with the longest SGI autocorrelation experience the greatest magnitude droughts and are the slowest to recover from drought, with groundwater drought conditions typically persisting at least six months longer than at sites in the other two clusters. Membership of the clusters reflects differences in the autocorrelation of the SGI time series that in turn is shown to be related to unsaturated zone thickness at individual boreholes. This last observation emphasises the importance of catchment and aquifer characteristics as (non-trivial) controls on groundwater drought hydrographs.
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Golding, Michelle, Pragya Srivastava, Golda Collamat, Smitha R. James, Adam R. Karpf, Michael J. Nemeth, and Elizabeth A. Griffiths. "SGI-110, a Novel Hypomethylating Agent, Induces the WNT Inhibitor Secreted Frizzled Related Protein-2 (SFRP2), and Down Regulates β-Catenin in Acute Myeloid Leukemia (AML) Cells." Blood 120, no. 21 (November 16, 2012): 1290. http://dx.doi.org/10.1182/blood.v120.21.1290.1290.
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Abstract Abstract 1290 Introduction: SGI-110 (Astex Pharmaceuticals, Inc.) is a dinucleotide hypomethylating agent whose active metabolite is decitabine (DAC). This drug demonstrates superior pharmacokinetics relative to the parent drug as a result of resistance to modification by cytidine deaminase, and is being investigated in myeloid malignancy in the phase I/II setting. We and others have demonstrated that WNT inhibitory genes including SFRP2 are epigenetically silenced in AML and that exposure to DNA methyltransferase inhibitors such as 5-Azacitidine (AZA) and DAC can re-express these genes and down-regulate β-catenin signaling in AML cell lines. We hypothesized that treatment with SGI-110 would have a similar effect upon the epigenetically silenced WNT inhibitor SFRP2 and further would down-regulate β-catenin signaling in AML cells in vitro. Methods: The AML cell lines HL60 and U937 were cultured in vitro using standard techniques and treated with phosphate buffered saline, 0.1, 1 or 5 μM SGI-110, 2μM AZA or 0.5μM DAC. Results presented are pooled data from a minimum of three biological replicates. Samples were harvested on day 5 and viable cells, DNA, RNA and protein obtained. β-catenin levels and cellular localization were quantified using imaging flow cytometry (ImageStream), DNA was extracted and bisulfite converted for analysis of gene specific and global DNA methylation by pyrosequencing (LINE-1, SFRP2), RNA was converted to cDNA for analysis by RT-PCR, and protein was obtained to confirm ImageStream results by Western blot. Nuclear translocation of β-catenin, indicative of its signaling activity, was assessed in individual cells by ImageStream using a similarity score: a log-transformed Pearson's correlation coefficient between the digitized images of immunostained β-catenin and a nuclear stain (DAPI). Shifts in the population (n=5,000) distributions of this similarity score were assessed by a resolution metric (Fishers discriminant ratio, Rd). Results: Treatment of AML cell lines with 5μM SGI-110 was toxic, and in line with previous experiments in AML cell lines, above the IC90. Treatment at the lowest dose of SGI-110 had minimal effects upon viability, methylation, and mRNA and protein expression in both cell lines tested. Treatment with SGI-110 at the 1μM dose resulted in reductions in LINE-1 methylation in HL60 cells by 21% (from 82% to 61%), compared to 8% with AZA (to 74%) and 20% with DAC (to 62%). In U937 cells, LINE-1 methylation decreased by 40% (from 67% to 27%) after SGI-110 treatment compared to a 25% reduction with AZA (to 42%) and a 30% reduction with DAC (to 36%). SFRP2 methylation in HL60 and U937 decreased from 86 and 88% at baseline to 66 and 60% with SGI-110 at the 1μM dose, compared to 68% with AZA and to 61% with DAC. Expression of SFRP2 mRNA was observed following treatment with 1μM SGI-110 and with DAC, but was limited following AZA treatment. ImageStream analysis of total cellular β-catenin in HL-60 and U937 cells demonstrated 2.4-fold and 1.2-fold reductions in total β-catenin following 1μM SGI-110 treatment. These results were similar to those seen with DAC (1.8-fold and 1.3-fold in HL-60 and U937 cells respectively). AZA treatment appeared to have a greater effect on total β-catenin in U937 cells (1.3-fold reduction) than in HL-60 cells (0.84-fold reduction). Western blot confirmed reductions in β-catenin protein. We also observed decreased nuclear translocation of β-catenin after treatment of HL-60 and U937 cells with 1 μM SGI-110 (Rd = −0.58 and −0.21 respectively; the negative sign indicates a change in cellular distribution from the nucleus to the cytoplasm). Changes were comparable to those observed with DAC (Rd = −0.75 and −0.26 in HL-60 and U937 cells respectively). AZA treatment of U937 cells resulted in a shift in cellular distribution (Rd = −0.20) similar to that for DAC and SGI-110 but had no effect on β-catenin distribution in HL-60 cells (Rd= 0.00). Conclusions: SGI-110 is a novel DNMT inhibitor which demonstrates robust effects on LINE-1 methylation, SFRP2 mRNA expression, and β-catenin level and localization consistent with epigenetically mediated re-expression of the WNT inhibitor SFRP2. Both upregulated β-catenin signaling and SFRP2 methylation have been demonstrated to correlate with inferior survival in patients with myeloid malignancies. Re-expression of epigenetically silenced WNT inhibitory genes such as SFRP2 may abrogate β-catenin signaling in AML cells. Disclosures: Karpf: Astex Pharmaceuticals: Research Funding. Griffiths:Celgene: Honoraria; Astex Pharmaceuticals: Research Funding.
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Seo and Lee. "Spatio-Temporal Groundwater Drought Monitoring Using Multi-Satellite Data Based on an Artificial Neural Network." Water 11, no. 9 (September 19, 2019): 1953. http://dx.doi.org/10.3390/w11091953.
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Drought is a complex phenomenon caused by lack of precipitation that affects water resources and human society. Groundwater drought is difficult to assess due to its complexity and the lack of spatio-temporal groundwater observations. In this study, we present an approach to evaluate groundwater drought based on relatively high spatial resolution groundwater storage change data. We developed an artificial neural network (ANN) that employed satellite data (Gravity Recovery and Climate Experiment (GRACE) and Tropical Rainfall Measuring Mission (TRMM)) as well as Global Land Data Assimilation System (GLDAS) models. The Standardized Groundwater Level Index (SGI) was calculated by normalizing ANN-predicted groundwater storage changes from 2003 to 2015 across South Korea. The ANN-predicted 25 km groundwater storage changes correlated well with both the in situ and the water balance equation (WBE)-estimated groundwater storage changes, with mean correlation coefficients of 0.87 and 0.64, respectively. The Standardized Precipitation–Evapotranspiration Index (SPEI), having an accumulation time of 1–6 months, and the Palmer Drought Severity Index (PDSI) were used to validate the SGI. The results showed that the SGI had a pattern similar to that of SPEI-1 and SPEI-2 (1- and 2-month accumulation periods, respectively), and PDSI. However, the SGI performance fluctuated slightly due to its relatively short study period (13 years) as compared to SPEI and PDSI (more than 30 years). The SGI, which was developed using a new approach in this study, captured the characteristics of groundwater drought, thus presenting a framework for the assessment of these characteristics.
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Saito, Yasuhiko, and Tadashi Isa. "Laminar Specific Distribution of Lateral Excitatory Connections in the Rat Superior Colliculus." Journal of Neurophysiology 92, no. 6 (December 2004): 3500–3510. http://dx.doi.org/10.1152/jn.00033.2004.
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Premovement activities in neurons in the intermediate gray layer [stratum griseum intermediale (SGI)] of the mammalian superior colliculus (SC) are essential for initiation of orienting behaviors such as saccades. Our previous study demonstrated that burst activities are induced by synchronous activation of SGI neurons communicating within a local excitatory network, which depends on NMDA-receptor–dependent synaptic transmission and release from GABAA inhibition. Furthermore, dual whole cell recordings from adjacent neurons in SGI revealed that application of 10 μM bicuculline (Bic) and reduction of extracellular Mg2+ concentration (to 0.1 mM) induce spontaneous depolarization that is synchronous between neuron pairs, suggesting the recruitment of a large number of neurons communicating through intense excitatory connections. In the present study, we investigated the properties of synchronous depolarization and the fundamental structure of the lateral excitatory network that recruits a neuronal population in SC to synchronous activation, by analyzing the synchronicity of spontaneous depolarization induced in the presence of Bic plus low Mg2+. We found that 1) spontaneous depolarization exhibits bidirectional horizontal propagation among the SGI neuron pairs; 2) induction of spontaneous depolarization is not caused by activation of intrinsic voltage-dependent conductances; 3) neurons exposed to low Mg2+ alone exhibit spontaneous depolarization, although in this case the depolarization is less synchronous; and 4) neurons exposed to Bic alone exhibit synchronous depolarization, but less frequently than those exposed to both Bic and low Mg2+. Analysis of the synchronicity of spontaneous depolarization indicates that the distribution of lateral excitatory connections is markedly different among layers of SC; the SGI neurons form extensive lateral excitatory connections, whereas they are sparse or limited within subsets of neurons in the stratum griseum superficiale (SGS). Wide-field vertical neurons in the stratum opticum have features intermediate between neurons in the SGS and SGI. Such differences in the structure of lateral excitatory connections may reflect the different way signal processing is achieved in each layer of SC.
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Kelly, Kevin R., Kelli Oberheu, Ernest Medina, Claudia M. Espitia, Devalingam Mahalingam, Pietro Taverna, Gavin S. Choy, Steffan T. Nawrocki, Francis J. Giles, and Jennifer S. Carew. "Targeting Pim Kinase Activity with the Novel Small Molecule Inhibitor SGI-1776 Significantly Augments the Efficacy of Cytarabine In Models of Acute Myeloid Leukemia." Blood 116, no. 21 (November 19, 2010): 3253. http://dx.doi.org/10.1182/blood.v116.21.3253.3253.
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Abstract Abstract 3253 Drug resistance is a major cause of treatment failure for patients with acute myeloid leukemia (AML) and novel strategies that circumvent resistance mechanisms are urgently needed. The Pim kinases (PIM1, PIM2, PIM3) are a small family of proto-oncogenes within the CAMK superfamily with essential roles in the regulation of signal transduction cascades that promote cell survival, proliferation, and drug resistance. Accordingly, overexpression of Pim kinases has been reported in a wide range of malignancies including AML. However, the specific role of Pim kinases as regulators of sensitivity to standard agents utilized in AML therapy remains to be elucidated. We hypothesized that inhibiting Pim kinase activity would significantly increase the efficacy of the standard of care drug cytarabine by disrupting signaling events that enable cells to resist cytotoxic stress. In order to investigate a potential role for Pim kinases as mediators of cytarabine resistance, we first evaluated their expression levels in paired HL-60 cell lines that are sensitive and resistant to cytarabine. Our results showed that the levels of Pim-1 are significantly higher in cytarabine-resistant HL-60 cells compared with their sensitive counterparts. Consistent with this observation, treatment of cultured AML cell lines and primary AML blasts with cytarabine led to a dose-dependent increase in Pim-1 expression as assessed by quantitative RT-PCR and immunoblotting. SGI-1776 is novel small molecule inhibitor of Pim kinase activity that has entered Phase I clinical trials. To further test our hypothesis, we investigated the in vitro efficacy of SGI-1776 in a panel of 9 human AML cell lines. SGI-1776 led to a dose-dependent reduction in viability in all cell lines evaluated. Subsequent experiments showed that SGI-1776 impaired clonogenic survival, diminished cell proliferation as determined by BrdU incorporation, and induced apoptotic cell death. These effects were associated with a significant reduction in the phosphorylation of the Pim kinase substrate and apoptotic regulator Bad as well as an increase in the expression of the cyclin-dependent kinase inhibitor, p27. We next investigated whether inhibiting Pim signaling with SGI-1776 could augment the efficacy of cytarabine. Treatment of AML cells with the combination of cytarabine and SGI-1776 led to significantly greater inhibition of clonogenic survival and induction of apoptosis over what was achieved by either single agent. To validate the therapeutic utility of this combination, vehicle, cytarabine, SGI-1776, or cytarabine and SGI-1776 were administered to mice bearing MOLM-13 AML xenografts for 21 days. Treatment with the combination of these two agents was very well tolerated and significantly increased the efficacy of single agent cytarabine therapy. Immunohistochemical analyses of specimens from mice treated with this regimen revealed that SGI-1776 diminished Bad phosphorylation and cooperated with cytarabine in vivo to promote activation of caspase-3 and inhibit tumor cell proliferation as quantified by the expression of proliferating cell nuclear antigen (PCNA). Collectively, our data demonstrate that antagonizing Pim kinase activity represents a new strategy to increase the therapeutic efficacy of cytarabine. A clinical trial evaluating the safety and efficacy of this combination for patients with AML that are refractory to standard treatments is warranted. Disclosures: Taverna: SuperGen, Inc.: Employment. Choy:SuperGen, Inc.: Employment.
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Mohebbi, Mehrnaz, Mohammad Farhadi, Ahmad Daneshi, and Saeid Mahmoudian. "Toward An Exploration of Habituating to Tinnitus: Perspectives on Sensory Gating." Journal of the American Academy of Audiology 30, no. 10 (November 2019): 896–903. http://dx.doi.org/10.3766/jaaa.18038.
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AbstractSome tinnitus participants habituate to their tinnitus, but some others do not and complain of its annoyance so much. It has been suggested that tinnitus is a habituation deficit. Habituation and the ability to ignore a sensory input depend on the normal function of filtering mechanism of sensory gating.The purpose of this study was to compare behavioral aspects of sensory gating in normal and tinnitus participants to search for the reason why some tinnitus participants habituate to their tinnitus but some others do not.This investigation was an observational case–control study.There were 60 tinnitus participants who were categorized into two tinnitus groups (30 compensated tinnitus participants and 30 decompensated tinnitus participants) based on the complaint of tinnitus annoyance, visual analog scale (VAS) for tinnitus loudness, annoyance, and awareness, scores on Tinnitus Questionnaire (TQ), and Tinnitus Handicap Inventory (THI). Also, there were 30 normal hearing participants without tinnitus as the normal control group.Sensory Gating Inventory (SGI), TQ, THI, and VAS was obtained from all participants. THI, TQ, VAS, and SGI total scores and their factors were compared among the groups. Correlations between SGI scores with THI, TQ, and VAS score were calculated.The results showed that SGI total score and the scores of its four factors were significantly higher in decompensated tinnitus participants compared with compensated tinnitus participants and normal controls. Also, there was a positive correlation between SGI perceptual modulation factor and TQ emotional distress factor and with the VAS for loudness in decompensated tinnitus group.These results suggested that tinnitus associated with behavioral aspects of sensory gating and decompensated tinnitus may be a result of deficient sensory gating.
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Azevêdo, J. A. G., S. C. Valadares Filho, D. S. Pina, E. Detmann, L. G. R. Pereira, R. F. D. Valadares, H. J. Fernandes, L. F. Costa e Silva, and P. B. Benedeti. "Nutritional diversity of agricultural and agro-industrial by-products for ruminant feeding." Arquivo Brasileiro de Medicina Veterinária e Zootecnia 64, no. 5 (October 2012): 1246–55. http://dx.doi.org/10.1590/s0102-09352012000500024.
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Fifty-seven by-products were collected from regions throughout Brazil. Chemical composition, in vitro neutral detergent fiber digestibility (IVNDFD), and total digestible nutrients (TDN) were determined with the objective of grouping by-products with similar nutritional characteristics. The by-products belonging to group one (G1) presented the highest content of neutral detergent fiber exclusive of ash and nitrogenous compounds [aNDFom(n)] and lowest energy content, with 42.5% and 38.8% of IVNDFD and TDN, respectively. A new cluster analysis was carried in order to better characterize G2 by-products, six subgroups (SGs) were established (SG1 to SG6). SG1 by-products had the highest and the lowest values for lignin and TDN, respectively. SG2 by-products had the highest aNDFom(n) value, with TDN and IVNDFD values greater than 600 and 700g/kg, respectively, and crude protein (CP) value below 200g/kg in dry matter (DM). Among all the subgroups, SG3 had the highest TDN (772g/kg) and IVNDFD (934g/kg) values and the lowest lignin (23g/kg in DM) value. The ether extract was what most influenced the hierarchical establishment of residual grouping in SG4. SG5 by-products had the highest concentration of non-fibrous carbohydrate. Different from the other subgroups, SG6 by-products had the highest value of available CP.
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Marahleh, G., A. R. I. Khede ., and S. Al-Goussous . "Fatigue Crack Propagation in SGI and CGI." Journal of Applied Sciences 5, no. 6 (May 15, 2005): 1004–11. http://dx.doi.org/10.3923/jas.2005.1004.1011.
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Challis, John RG. "SGI 2012: Advances in Reproductive Health Research." Women's Health 8, no. 4 (July 2012): 363–65. http://dx.doi.org/10.2217/whe.12.30.
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Zarantonello, Sergio E. "SGI parallel technology for graphics and visualization." Applied Numerical Mathematics 30, no. 1 (May 1999): 113–23. http://dx.doi.org/10.1016/s0168-9274(98)00088-9.
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Tyagi, Ruchi. "Stakeholder Mapping and Corporate Social Responsibility." Journal of Global Economy 17, no. 1 (April 17, 2021): 21–40. http://dx.doi.org/10.1956/jge.v17i1.616.
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The purpose of this paper is whom do Sports Goods Industry (SGI) consider as their stakeholder, which stakeholders they give priority to others and why. The present study is exploratory. A list of sports goods manufacturers in Meerut was procured from the Federation of sports goods manufacturers. The total number of manufacturers as per the list was 356. With the help of a simple random sampling technique, 50 were selected for a pilot study, and 100 for the final study. The required information obtained using a structured interview schedule. There are nine interest groups identified by the SGI Meerut. These are - customers, suppliers, competitors, governments, partners, communities, owners, investors and labor. Out of the recognized interest groups in SGI Meerut, customers top the list of preference. There is a need of accommodating stakeholders concerns in business.
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Fiskus, Warren C., Kathleen M. Buckley, Rekha Rao, Yongchao Wang, Atul Joshi, Daniel G. Chong, Anand Jillella, et al. "Synergistic Activity of Co-Treatment with PIM1 Kinase Inhibitor SGI-1776 and Histone Deacetylase Inhibitor Panobinostat or Heat Shock Protein 90 Inhibitor AUY922 against Human CML and Myeloproliferative Neoplasm (MPN) Cells." Blood 114, no. 22 (November 20, 2009): 2651. http://dx.doi.org/10.1182/blood.v114.22.2651.2651.
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Abstract Abstract 2651 Poster Board II-627 The oncoprotein PIM1 is a cytoplasmic serine/threonine kinase, which is overexpressed and implicated in the pathogenesis of hematologic malignancies. PIM1 activity promotes cell survival and proliferation, and is a downstream mediator of cytokine receptor signaling involving the JAK/STATs. PIM1 phosphorylates and inactivates Bad, which enhances the anti-apoptotic functions of Bcl-2. PIM1 also mediates the phosphorylation and inactivation of cell cycle inhibitors p21 and p27, thereby promoting progression through G1 and G2/M phases of the cell cycle. PIM1 phosphorylates serine 10 on histone H3, and has been shown to phosphorylate and stabilize Myc, thereby collaborating in Myc-induced transformation. Further, PIM1 is known to phosphorylate 4EBP1 on the same residues (threonine 37 and 46) as mTOR kinase. It can also phosphorylate eIF4B, thereby maintaining high levels of protein translation. PIM1 is known to be chaperoned as a heat shock protein 90 client protein. In the present studies, we demonstrate that treatment with the PIM kinase inhibitor SGI-1776 (SuperGen Inc.) dose-dependently (500 nM to 2.0 μM) depleted p-BAD (Ser112), p-p70S6K, p-4EBP1, p-Ser10 Histone H3 and c-Myc levels, while inducing p27 and p21 expression, in the cultured human CML-BC K562 and erythroleukemia HEL92.1.7 (with homozygous JAK2-V617F mutation). Treatment with SGI-1776 induced apoptosis of K562 and HEL92.1.7 (HEL) cells as well as Ba/F3-hEpoR-JAK2-V617F but not Ba/F3-hEpoR cells. Similar effects of SGI-1776 were observed in primary CML-BC and MPN (myeloproliferative neoplasm) cells. Treatment with the non-geldanamycin analogue hsp90 inhibitor AUY922 (Novartis Pharma) or with the pan-HDAC inhibitor panobinostat (PS) (Novartis Pharma) disrupted the chaperone association of PIM1 with hsp90 and increased binding to hsp70, thereby promoting the proteasomal degradation of PIM1 in K562 and HEL cells. Treatment with PS (20–100 nM) also depleted PIM1 mRNA as measured by qPCR. Co-treatment with SGI-1776 (0.5 to 2.0 μM) and clinically achievable concentrations of AUY922 (e.g., 25 nM) caused greater depletion of pBAD (Ser112), pp70S6K, p4EBP1, cyclin B1, c-Raf, c-Myc, and AKT and synergistically induced apoptosis of K562 and HEL92.1.7 cells (combination indices < 1.0). As compared to treatment with either agent alone, co-treatment with SGI-1776 and AUY922 or PS also exerted greater cytotoxicity against primary CML-BC and MF-MPN cells. Importantly, co-treatment with PS significantly enhanced SGI-1776-induced apoptosis of purified primary CD34+CD38-Lin- hematopoietic stem cells expressing JAK2-V617F derived from a patient with primary myelofibrosis. Taken together, these pre-clinical findings indicate that simultaneously depleting PIM kinase levels by AUY922 or PS and inhibiting PIM1 kinase activity with SGI-1776 induces synergistic apoptosis against cultured and primary CML-BC and MPN cells. Additionally, our findings suggest that co-treatment with PS and SGI-1776 may be an effective treatment strategy against hematopoietic stem cells expressing JAK2-V617F in patients with MF-MPN. Disclosures: Atajada: Novartis: Employment. Quadt:Novartis: Employment. Bhalla:Merck: Honoraria; Novartis: Honoraria, Research Funding.
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Onuchina, Ol'ga, and Irina Korneva. "ADAPTIVE CAPACITY AND STABILITY OF BREEDING POPULATIONS OF RED CLOVER UNDER CONDITIONS OF THE KIROV REGION." Adaptive Fodder Production 2020, no. 4 (December 28, 2020): 30–38. http://dx.doi.org/10.33814/afp-2222-5366-2020-4-30-38.
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The results of the assessment of breeding populations of red clover according to the parameters of adaptive capacity and stability of the characteristic "yield of the dry mass" are presented. The experiments were laid on two types of soils, contrasting in the content of H+ ions и Al3+ ions. The meteorological conditions also significantly varied (drought in 2016 and over wetting in 2017). Parameters of adaptive capacity and stability of populations, environmental parameters as the base for the selection were counted according to A.V. Kilchevsky and L.V. Khotyleva method, regression coefficient of the genotype on the b1 environment was counted according to S.A. Eberhart and W.A. Russell method. Statistically high general adaptive capacity (GAAi = 3.10 t/ha), stability (σ2САСi = 0.64; Sgi = 6.68%) and the greatest breeding value (BVGi = 8.63) were identified in the tetraploid standard Kudesnik. Picked out, promising for adaptive breeding, diploid populations SGPA-53 and P-4/03, showing at an average GAAi (0.26 and –0.07 t/ha, respectively) the high stability (σ2CACi = 0.32–0.66; Sgi = 6.48–8.87%) and the breeding value (BVGi = 5.74–6.42). It is of interest to hybridize a low-productive (GAAi = –1.14 t/ha), but the most stable (σ2CACi = 0.08; Sgi = 3.62%, Kgi = 0.14) population P-15k. Correlation analysis revealed no significant relation between GAAi and stability parameters, which does not exclude the possibility of combining high productivity and environmental sustainability in one variety. A statistically high relation between the parameters Sgi and σ2CACi, Sgi and Kgi, (r = 0.86), bi and σ2CACi, bi and Kgi (r = 0.79) was established, indicating that these characteristics provide relatively close information on the population stability. The stress alumina background in 2017 and the medium acid ground (Sek – 40.88 and 35.33%; Pk – 0.37 and 0.32, respectively) were characterized by the highest differentiating ability and predictability.
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Gadžo, Amra, Sanel Halilbegović, Alma Osmanović Đaković, and Adisa Hodžić. "Predicting Auditor’s Opinion on Financial Statements of Public Enterprises Based on Indicators of the Beneish M-score Model." Journal of Forensic Accounting Profession 2, no. 2 (December 1, 2022): 1–13. http://dx.doi.org/10.2478/jfap-2022-0006.
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Abstract Considering the burning problem of corruption and non-transparency of public enterprises in the Federation of Bosnia and Herzegovina (FBiH), the paper aims to investigate whether the Beneish M-score model can be used to predict inaccurate financial statements. Where, the cause of inaccurate financial statements are intentional or unintentional errors. On a sample of 200 financial statements of public enterprises and related audit reports issued by the Audit Office of the Institutions in FBiH, we made a link between the Beneish M score model with its partial indicators (DSRI, GMI, AQI, SGI, DEPI, SGAI, LVGI, TATA) and four types of opinions: positive, opinion with distraction, negative and refraining from giving opinions. The research was conducted using descriptive statistics and an artificial neural network with the “scaled conjugate gradient backpropagation (trainscg)” algorithm for pattern recognition and classification. The research results show that it is possible on the basis of 8 partial indicators (DSRI, GMI, AQI, SGI, DEPI, SGAI, LVGI, TATA) i.e. 24 balance sheet position for their calculation, predict the auditor’s opinion on the quality of financial statements of public companies with an accuracy ranging between 98 and 100% in repeated procedures. The results of the research have their practical usefulness and can serve to researchers, creditors, customers, suppliers and state auditors in planning resources and priorities for performing financial audits at public companies in the FBiH.
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Fumeaux, Thierry, Antje Heise, Martin Balmer, and Luca Lavina. "Smarter Intensive Care Medicine: Choosing Wisely®, less is more, appropriate is better … and so what?" Therapeutische Umschau 78, no. 7 (September 2021): 389–94. http://dx.doi.org/10.1024/0040-5930/a001286.
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Zusammenfassung. Die Top-9-Liste der Schweizerischen Gesellschaft für Intensivmedizin (SGI) wurde 2017 veröffentlicht. Welchen Stand hat diese Initiative in Bezug auf ihre Umsetzung auf den Schweizer Intensivstationen? Welches sind ihre Auswirkungen auf die Patientenversorgung und auf die Kosten der Intensivmedizin? Welche evidenzbasierten, neueren Entwicklungen rechtfertigen eine Aktualisierung der Liste und welche Massnahmen sind erforderlich, um diese Initiative erfolgreich in den kommenden Jahren fortzusetzen? Der folgende Artikel gibt einen aktuellen Überblick über die «Choosing Wisely®»-Initiative der SGI.