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Debona, Daniel, Angela Pivotto, Alexsandro J. Tetzlaff, Darlan F. Sartori, Luiz A. Borelli, Murilo S. de Oliveira, Lilian Y. Yamamoto, and Jociani Ascari. "Essential Oil of Baccharis dracunculifolia (Asteraceae) Decreases Alternaria Rot in Pitahaya." Journal of Agricultural Science 13, no. 7 (June 15, 2021): 10. http://dx.doi.org/10.5539/jas.v13n7p10.
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Alternaria rot, caused by Alternaria alternata, is one of the most destructive diseases of pitahaya (Hylocereus spp.). We investigated the effect of the essential oil of Baccharis dracunculifolia (Asteraceae) (EOB) in the control of A. alternata. Two studies were performed in Petri dishes containing potato dextrose agar medium amended with concentrations of the EOB ranging from 5 to 1,000 µg mL-1 (first study) and from 30 to 2,000 µg mL-1. The diameter of the fungal colony was recorded daily. These data were used to calculate the the area under the mycelial growth progress curve (AUMGPC) and mycelial growth index (MGI). In the third study, the control of Alternaria rot in pitahaya fruits by EOB was investigated by adding the EOB into an edible coat based on cassava starch and sorbitol which was prepared in Tween 20. Three treatments, containing EOB at 500, 1,000 or 2,000 µg mL-1, were assessed. Two additional treatments, one containing water and another containing only the edible coating served as controls. Pitahaya fruits were immersed in those solutions for 10 min, allowed to dry and inoculated with A. alternata 48 h later. The EOB was found to inhibit the mycelial growth and a negative and quadratic model best described the relationship of the EOB concentrations with MGI and AUMGPC. Results from the experiment performed with pitahaya fruits showed that Alternaria rot was decreased with increasing EOB concentrations. Therefore, EOB is a promising and ecofriendly method that may be included in the management of Alternaria rot in pitahya.
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Vicka, Vaidas, Elija Januskeviciute, Justina Krauklyte, Aiste Aleknaviciene, Donata Ringaitiene, Ligita Jancoriene, and Jurate Sipylaite. "Determinants of Increased Effort of Breathing in Non-Intubated Critical COVID-19 Patients." Medicina 58, no. 8 (August 21, 2022): 1133. http://dx.doi.org/10.3390/medicina58081133.
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Background and objectives: Acute respiratory distress syndrome (ARDS) is the most common complication occurring in COVID-19 patients admitted to the ICU. Given the increased respiratory work of these patients, it is necessary to evaluate their actual breathing efforts. The aim of this study is to report the incidence and determinants of increased effort of breathing (EOB) in critical COVID-19 patients. Materials and Methods: This was a retrospective study of COVID-19 patients admitted to the ICU during the year of 2020. Respiratory rate (RR) was chosen as an indicator of EOB. The cut-off value was set at more than 20 breaths per minute. ROC-AUC analysis was performed to identify the accuracy of the PaO2 and PaCO2 to determine increased EOB. Furthermore, multivariate regression analysis was performed to reveal the determinants of increased EOB. Results: 213 patients were included in the study. Mean RR in the population was 24.20 ± 6.28. 138 (64.8%) of the patients had increased EOB. The ROC-AUC analysis revealed the PaO2 (0.656 (CI 95%: 0.579–0.734, p < 0.001) as more accurate predictor of EOB than PaCO2 (0.584 (CI 95%: 0.505–0.662, p = 0.043). In the final multivariate model, the SpO2 (exp(B) = 0.922, CI 95%: 0.874–0.97 p = 0.033), PaO2/FiO2 ratio (exp(B) = 0.996, CI 95%: 0.922–1.000, p = 0.003) and PaO2 (exp(B) = 0.989 CI 95%: 0.982–0.996 p = 0.003) prevailed as independent predictors of increased EOB. Conclusions: To conclude, PaO2 was revealed as a more accurate predictor of increased EOB than PaCO2. Further investigation revealed the independent determinants of EOB: blood oxygen saturation, PaO2 and PaO2/FiO2 ratio.
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Wei, Jingwei, Hanyu Jiang, Mengsu Zeng, Meiyun Wang, Meng Niu, Dongsheng Gu, Huanhuan Chong, et al. "Prediction of Microvascular Invasion in Hepatocellular Carcinoma via Deep Learning: A Multi-Center and Prospective Validation Study." Cancers 13, no. 10 (May 14, 2021): 2368. http://dx.doi.org/10.3390/cancers13102368.
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Microvascular invasion (MVI) is a critical risk factor for postoperative recurrence of hepatocellular carcinoma (HCC). Preknowledge of MVI would assist tailored surgery planning in HCC management. In this multicenter study, we aimed to explore the validity of deep learning (DL) in MVI prediction using two imaging modalities—contrast-enhanced computed tomography (CE-CT) and gadoxetic acid-enhanced magnetic resonance imaging (EOB-MRI). A total of 750 HCCs were enrolled from five Chinese tertiary hospitals. Retrospective CE-CT (n = 306, collected between March, 2013 and July, 2019) and EOB-MRI (n = 329, collected between March, 2012 and March, 2019) data were used to train two DL models, respectively. Prospective external validation (n = 115, collected between July, 2015 and February, 2018) was performed to assess the developed models. Furthermore, DL-based attention maps were utilized to visualize high-risk MVI regions. Our findings revealed that the EOB-MRI-based DL model achieved superior prediction outcome to the CE-CT-based DL model (area under receiver operating characteristics curve (AUC): 0.812 vs. 0.736, p = 0.038; sensitivity: 70.4% vs. 57.4%, p = 0.015; specificity: 80.3% vs. 86.9%, p = 0.052). DL attention maps could visualize peritumoral high-risk areas with genuine histopathologic confirmation. Both DL models could stratify high and low-risk groups regarding progression free survival and overall survival (p < 0.05). Thus, DL can be an efficient tool for MVI prediction, and EOB-MRI was proven to be the modality with advantage for MVI assessment than CE-CT.
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Fehrenbach, Uli, Siyi Xin, Alexander Hartenstein, Timo Alexander Auer, Franziska Dräger, Konrad Froböse, Henning Jann, et al. "Automatized Hepatic Tumor Volume Analysis of Neuroendocrine Liver Metastases by Gd-EOB MRI—A Deep-Learning Model to Support Multidisciplinary Cancer Conference Decision-Making." Cancers 13, no. 11 (May 31, 2021): 2726. http://dx.doi.org/10.3390/cancers13112726.
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Background: Rapid quantification of liver metastasis for diagnosis and follow-up is an unmet medical need in patients with secondary liver malignancies. We present a 3D-quantification model of neuroendocrine liver metastases (NELM) using gadoxetic-acid (Gd-EOB)-enhanced MRI as a useful tool for multidisciplinary cancer conferences (MCC). Methods: Manual 3D-segmentations of NELM and livers (149 patients in 278 Gd-EOB MRI scans) were used to train a neural network (U-Net architecture). Clinical usefulness was evaluated in another 33 patients who were discussed in our MCC and received a Gd-EOB MRI both at baseline and follow-up examination (n = 66) over 12 months. Model measurements (NELM volume; hepatic tumor load (HTL)) with corresponding absolute (ΔabsNELM; ΔabsHTL) and relative changes (ΔrelNELM; ΔrelHTL) between baseline and follow-up were compared to MCC decisions (therapy success/failure). Results: Internal validation of the model’s accuracy showed a high overlap for NELM and livers (Matthew’s correlation coefficient (φ): 0.76/0.95, respectively) with higher φ in larger NELM volume (φ = 0.80 vs. 0.71; p = 0.003). External validation confirmed the high accuracy for NELM (φ = 0.86) and livers (φ = 0.96). MCC decisions were significantly differentiated by all response variables (ΔabsNELM; ΔabsHTL; ΔrelNELM; ΔrelHTL) (p < 0.001). ΔrelNELM and ΔrelHTL showed optimal discrimination between therapy success or failure (AUC: 1.000; p < 0.001). Conclusion: The model shows high accuracy in 3D-quantification of NELM and HTL in Gd-EOB-MRI. The model’s measurements correlated well with MCC’s evaluation of therapeutic response.
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You, Myung-Won, Hyoung Jung Kim, Hyeong-Seok Lim, So Yeon Kim, Jae Ho Byun, Kyung Won Kim, Dae Wook Hwang, and Young-Joo Lee. "Assessment of Liver Function Using Pharmacokinetic Parameters of Gd-EOB-DTPA: Experimental Study in Rat Hepatectomy Model." Contrast Media & Molecular Imaging 2018 (2018): 1–7. http://dx.doi.org/10.1155/2018/6321316.
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Objectives. To determine whether the pharmacokinetic parameters of Gd-EOB-DTPA can identify the difference in liver function in a rat hepatectomy model. Methods. A total of 56 eight-week-old male Sprague-Dawley rats were divided into the following groups: control group without hepatectomy (n=16), 70% hepatectomy group (n=14), and 90% hepatectomy group (n=26). On postoperative day 2, Gd-EOB-DTPA (0.1 mmol/kg) was injected intravenously and serial blood samples were obtained. Pharmacokinetic analysis was performed using a noncompartmental method. Statistical analysis was performed using one-way analysis of variance and post hoc pairwise group comparisons. Results. After excluding 6 rats that died unexpectedly, blood samples were obtained from 16, 14, and 20 rats in the control group, 70% hepatectomy group, and 90% hepatectomy group. There was a significant increase in area under the concentration-time curve from time zero to the time of the last measurable concentration between the 70% and 90% hepatectomy group (P<0.001). The volume of distribution at steady state was significantly decreased between the control and 70% hepatectomy group (P<0.001). The clearance was significantly different in all pairwise group comparisons (P<0.001). Conclusions. The vascular clearance of Gd-EOB-DTPA can identify the difference in liver function in a rat hepatectomy model.
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Tanpowpong, Natthaporn, and Teerasak Phewplung. "Brief communication (Original). Correlation between liver signal intensity in hepatobiliary phase of Gd-EOB-DTPA enhancement and liver function reserves." Asian Biomedicine 8, no. 3 (June 1, 2014): 411–15. http://dx.doi.org/10.5372/1905-7415.0803.308.
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Abstract Background: Gadolinium diethylenetriamine-pentaacetic acid (Gd-EOB-DTPA) is a developed agent with preferential uptake by hepatocytes. A rapid and specific hepatocyte uptake with biliary excretion was observed of approximately 50% of the injected dose. The amount of contrast uptake is thought to be related to reserve liver function. Objectives: To evaluate correlation between liver signal intensity in the hepatobiliary phase of Gd-EOB-DTPA and reserved liver function by using the model score for end-stage liver disease (MELD). Methods:All patients who underwent magnetic resonance (MR) imaging with Gd-EOB-DTPA were retrospectively collected. The patients with serum creatinine level higher than 1.5 mg/dL or patients without available data to estimate MELD score were excluded. Thirty-six patients were enrolled. A signal-to-noise ratio (SNR) in the liver parenchyma on a fat-suppressed three dimensional fast spoiled-gradient recalled echo sequence images before and 20 minutes after contrast injection were measured and calculated on PACS by two radiologists. The MELD score was determined and interobserver reliability was estimated. Results: Among 36 patients, we found a negative relationship between the percentage enhancement and the MELD score (P < 0.01, r = 0.545). The SNR at 20 minutes after Gd-EOB-DTPA injection also had a negative relationship with the MELD score with statistical significance (P < 0.01, r = 0.460). Interobserver reliability was 0.675. Conclusion: The percentage enhancement in hepatobiliary phase of Gd-EOB-DTPA can predict reserved liver function.
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Huang, Mengqi, Bing Liao, Ping Xu, Huasong Cai, Kun Huang, Zhi Dong, Ling Xu, et al. "Prediction of Microvascular Invasion in Hepatocellular Carcinoma: Preoperative Gd-EOB-DTPA-Dynamic Enhanced MRI and Histopathological Correlation." Contrast Media & Molecular Imaging 2018 (2018): 1–9. http://dx.doi.org/10.1155/2018/9674565.
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Objective. To investigate the imaging features observed in preoperative Gd-EOB-DTPA-dynamic enhanced MRI and correlated with the presence of microvascular invasion (MVI) in hepatocellular carcinoma (HCC) patients. Methods. 66 HCCs in 60 patients with preoperative Gd-EOB-DTPA-dynamic enhanced MRI were retrospectively analyzed. Features including tumor size, signal homogeneity, tumor capsule, tumor margin, peritumor enhancement during mid-arterial phase, peritumor hypointensity during hepatobiliary phase, signal intensity ratio on DWI and apparent diffusion coefficients (ADC), T1 relaxation times, and the reduction rate between pre- and postcontrast enhancement images were assessed. Correlation between these features and histopathological presence of MVI was analyzed to establish a prediction model. Results. Histopathology confirmed that MVI were observed in 17 of 66 HCCs. Univariate analysis showed tumor size (p=0.003), margin (p=0.013), peritumor enhancement (p=0.001), and hypointensity during hepatobiliary phase (p=0.004) were associated with MVI. A multiple logistic regression model was established, which showed tumor size, margin, and peritumor enhancement were combined predictors for the presence of MVI (α=0.1). R2 of this prediction model was 0.353, and the sensitivity and specificity were 52.9% and 93.0%, respectively. Conclusion. Large tumor size, irregular tumor margin, and peritumor enhancement in preoperative Gd-EOB-DTPA-dynamic enhanced MRI can predict the presence of MVI in HCC.
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Lee, Yi-Hsueh, Menq-Rong Wu, and Jong-Kai Hsiao. "Organic Anion Transporting Polypeptide 1B1 Is a Potential Reporter for Dual MR and Optical Imaging." International Journal of Molecular Sciences 22, no. 16 (August 16, 2021): 8797. http://dx.doi.org/10.3390/ijms22168797.
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Membrane proteins responsible for transporting magnetic resonance (MR) and fluorescent contrast agents are of particular importance because they are potential reporter proteins in noninvasive molecular imaging. Gadobenate dimeglumine (Gd-BOPTA), a liver-specific MR contrast agent, has been used globally for more than 10 years. However, the corresponding molecular transportation mechanism has not been validated. We previously reported that the organic anion transporting polypeptide (OATP) 1B3 has an uptake capability for both MR agents (Gd-EOB-DTPA) and indocyanine green (ICG), a clinically available near-infrared (NIR) fluorescent dye. This study further evaluated OATP1B1, another polypeptide of the OATP family, to determine its reporter capability. In the OATP1B1 transfected 293T transient expression model, both Gd-BOPTA and Gd-EOB-DTPA uptake were confirmed through 1.5 T MR imaging. In the constant OAPT1B1 and OATP1B3 expression model in the HT-1080 cell line, both HT-1080-OAPT1B1 and HT-1080-OATP1B3 were observed to ingest Gd-BOPTA and Gd-EOB-DTPA. Lastly, we validated the ICG uptake capability of both OATP1B1 and OATP1B3. OAPT1B3 exhibited a superior ICG uptake capability to that of OAPT1B1. We conclude that OATP1B1 is a potential reporter for dual MR and NIR fluorescent molecular imaging, especially in conjunction with Gd-BOPTA.
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Bilton, Shawna, and Zhi Sheng. "DDDR-12. THE ROLE OF CASEIN KINASE 1 EPSILON IN TEMOZOLOMIDE SENSITIVITY IN GLIOBLASTOMA STEM CELLS." Neuro-Oncology 24, Supplement_7 (November 1, 2022): vii101. http://dx.doi.org/10.1093/neuonc/noac209.377.
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Abstract A major hurdle in effectively treating glioblastoma is the resistance to current chemotherapy temozolomide (TMZ), exhibited intrinsically in glioblastoma stem cells (GSCs). GSCs are a population of tumor cells that are self-renewing, highly resilient and capable of forming genetically heterogeneous and difficult-to-treat tumors. Therefore, overcoming TMZ resistance holds significant promise in the treatment of glioblastoma. Casein kinase 1 ε (CK1ε) has been identified as a stem cell factor that is important for GSCs to self-renew. However, whether CK1ε confers TMZ resistance in GSCs remains elusive. METHODS To test the role of CK1ε in the chemoresistance of GSCs, we treated GSC adherent cell lines with TMZ, CK1ε inhibitor IC261, and a combination of TMZ plus IC261. Cell viability was assessed with MTS viability assay or CellTiter-Blue viability assay. RESULTS Cell viability was significantly decreased in GSCs treated with 0.8μM IC261 combined with 100μM TMZ as compared to cells treated with either 0.8μM IC261 or 100μM TMZ alone (p < 0.05). We assessed synergistic drug effects using the Bliss independence model to yield Excess Over Bliss (EOB) scores. EOB > 0% indicates a synergistic effect; EOB = 0% indicates additive effect; and EOB < 0% indicates antagonistic effect. Cells treated with 0.8μM IC261 together with 100μM TMZ yielded EOB of > 0%. CONCLUSIONS Previous work has identified CK1ε as an important stem cell factor in the survival GSCs, but there lacked studies testing the role of CK1ε in TMZ chemoresistance in vitro. We demonstrate synergistic inhibition of cell viability in GSCs treated with CK1ε inhibitor IC261 in combination with TMZ. Based on these results, CK1ε is suggested to play an important role in the chemoresistance of GSCs to TMZ.
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Mattson, J. K., A. T. DeVries, S. M. McGuire, J. Krebs, E. E. Louis, and N. M. Loskutoff. "247 SUCCESSFUL ARTIFICIAL INSEMINATION IN THE CORN SNAKE (ELAPHE GUTATTA), USING FRESH AND COOLED SEMEN." Reproduction, Fertility and Development 19, no. 1 (2007): 240. http://dx.doi.org/10.1071/rdv19n1ab247.
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The purpose of this investigation was to develop a non-invasive technique to artificially inseminate snakes using the corn snake, Elaphe gutatta, as the model representative for this taxon. Semen was collected by first applying pressure to the lower abdomen in a continuous distal motion toward the cloaca to remove any feces or urates. The cloaca was then gently washed using phosphate-buffered saline, and a more localized pressure was applied to each side of the vent to evert the hemipenes and, subsequently, the ejaculate. The semen was collected using a sterile transfer pipette and placed into 70 to 90 �L of medium (TL-HEPES solution; Cambrex Bio Science, Inc., Baltimore, MD, USA04–616F) in a sterile microcentrifuge tube, and then analyzed for overall motility, rate of forward progression (RFP, 0–5), and concentration. Based on a previously reported procedure, 10 females were inseminated with either fresh (n = 5) or cooled semen (n = 5; refrigerated for 3 days) one week after recovering from a hibernation period required to stimulate reproduction in this species. The overall sperm motility and concentration for females inseminated with fresh or cooled semen was 92%, 9.6 million sperm mL-1; and 85%, 6.1 million sperm mL-1, respectively. Immediately prior to insemination, the same method for expressing feces and urates in the males was applied to the females. The insemination dose (50 �L semen per oviduct) was drawn into a 1-mL latex- and silicone-free tuberculin syringe (Norm-Ject; VWR, Batavia, IL, USA) that was connected to a feeding/dosing needle (EJAY International, Issaquah, WA, USA) with a ball tip to prevent any potential damage during the insemination. The tip of the needle was then moved around the inner tissue of the vent to relax the cloaca, and the insertion continued until resistance was found indicating the vicinity of the oviducts. The extended semen was carefully deposited on both sides, and then the needle was slowly withdrawn. The offspring were tested for parentage to verify the success of the insemination. Blood was collected from the dorsal aorta posterior to the cloaca and stored in 10 mM Tris at 4�C. The DNA was extracted using a phenyl : chloroform : isoamyl alcohol (PCI) extraction method. Eight microsatellite loci were used for the paternity exclusion analysis: Eob�1, Eob�3, Eob�10, Eob�13, Eob�16, Eob�34, Eob�366, and Eob�373 (IDT, Coraville, IA, USA). All males and females in the collection were tested, and parental candidates were excluded if 2 or more allele mismatches occurred. From the total number of females inseminated, 3 females laid 51 eggs. Two females inseminated with cooled semen laid 36 eggs, of which 5 eggs were hatched, and the remaining were either unfertilized (n = 25) or non-viable (n = 6). All 5 hatched eggs were laid by one of the females. The third female inseminated with fresh semen laid 15 eggs, resulting in 5 hatching and 10 unfertilized eggs. The parentage test validated the AI a success as the alleles correlated between the adults and the offspring. In conclusion, artificial insemination was successful using both freshly collected and cooled (3 days) semen. Further studies are underway to improve the success rate in order to maximize the efficiency of this technology, and thus assist in the genetic preservation of endangered snake species.
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Segers, J??r??me, G??raldine Le Duc, Catherine Laumonier, Ir??ne Tropr??s, Luce Vander Elst, and Robert N. Muller. "Evaluation of Gd-EOB-DTPA Uptake in a Perfused and Isolated Mouse Liver Model." Investigative Radiology 40, no. 9 (September 2005): 574–82. http://dx.doi.org/10.1097/01.rli.0000174474.43772.58.
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Mi, Xu, Gan, Chen, Qiao, and Zhu. "How to Motivate Employees’ Environmental Citizenship Behavior through Perceived Interpersonal Circle Power? A New Perspective from Chinese Circle Culture." Sustainability 11, no. 17 (August 21, 2019): 4549. http://dx.doi.org/10.3390/su11174549.
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Employees’ spontaneous environmental citizenship behavior (ECB) is a key factor in facilitating the low-carbon transition of enterprises. However, little research has focused on the impact of interpersonal interactions on ECB. To explore how ECB is affected by special interpersonal circles in Chinese organizations, we propose a new concept: perceived interpersonal circle power (PICP). From the two dimensions of PICP, leader-oriented perceived interpersonal circle power (PICP-L) and colleague-oriented perceived interpersonal circle power (PICP-C), we establish a mechanism model to explore the effect of PICP on ECB. A structural equation model was used to test our hypotheses through 332 questionnaires, and the results show that PICP-L and PICP-C differ significantly in the directions and strengths of their effects on ECB. PICP-C has a direct positive driving effect on environmental engagement behavior (EEB) and environmental helping behavior (EHB). High PICP-C can also encourage EEB via affective organizational commitment (AOC). Conversely, PICP-L has no significant effect on EEB. More unexpectedly, PICP-L has a significant negative influence on EHB. This study provides a new direction for future theoretical research on ECB, as well as a new opportunity for policy-making and enterprise management practices to promote employees’ ECB.
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Cavaliere, Alessandra, Katrin C. Probst, Stephen J. Paisey, Christopher Marshall, Abdul K. H. Dheere, Franklin Aigbirhio, Christopher McGuigan, and Andrew D. Westwell. "Radiosynthesis of [18F]-Labelled Pro-Nucleotides (ProTides)." Molecules 25, no. 3 (February 6, 2020): 704. http://dx.doi.org/10.3390/molecules25030704.
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Phosphoramidate pro-nucleotides (ProTides) have revolutionized the field of anti-viral and anti-cancer nucleoside therapy, overcoming the major limitations of nucleoside therapies and achieving clinical and commercial success. Despite the translation of ProTide technology into the clinic, there remain unresolved in vivo pharmacokinetic and pharmacodynamic questions. Positron Emission Tomography (PET) imaging using [18F]-labelled model ProTides could directly address key mechanistic questions and predict response to ProTide therapy. Here we report the first radiochemical synthesis of [18F]ProTides as novel probes for PET imaging. As a proof of concept, two chemically distinct radiolabelled ProTides have been synthesized as models of 3′- and 2′-fluorinated ProTides following different radiosynthetic approaches. The 3′-[18F]FLT ProTide was obtained via a late stage [18F]fluorination in radiochemical yields (RCY) of 15–30% (n = 5, decay-corrected from end of bombardment (EoB)), with high radiochemical purities (97%) and molar activities of 56 GBq/μmol (total synthesis time of 130 min.). The 2′-[18F]FIAU ProTide was obtained via an early stage [18F]fluorination approach with an RCY of 1–5% (n = 7, decay-corrected from EoB), with high radiochemical purities (98%) and molar activities of 53 GBq/μmol (total synthesis time of 240 min).
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Liu, Xiaolin, Zhoujian Cao, and Zong-Hong Zhu. "A higher-multipole gravitational waveform model for an eccentric binary black holes based on the effective-one-body-numerical-relativity formalism." Classical and Quantum Gravity 39, no. 3 (January 6, 2022): 035009. http://dx.doi.org/10.1088/1361-6382/ac4119.
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Abstract We have previously constructed a waveform model, S E O B N R E , for spinning binary black hole (BBH) moving along eccentric orbit based on effective-one-body (EOB) formalism. In the current paper, we update S E O B N R E waveform model in the following three respects. Firstly, we update the EOB dynamics from S E O B N R v 1 to S E O B N R v 4 . Secondly we properly treat the Schott term which has been ignored in previous S E O B N R E . Thirdly, we construct a new factorized waveform including (l, |m|) = (2, 2), (2, 1), (3, 3), (4, 4) modes based on EOB formalism, which is valid for spinning BBHs in general equatorial orbit. Following our previous S E O B N R E waveform model, we call our new waveform model S E O B N R E H M . The (l, |m|) = (2, 2) mode waveform of S E O B N R E H M can fit the original S E O B N R v 4 waveform very well in the case of a quasi-circular orbit. We have validated S E O B N R E H M waveform model through comparing the waveform against the Simulating eXtreme Spacetimes (SXS) catalog. The comparison is done for BBH with total mass in (20, 200)M ⊙ using Advanced LIGO designed sensitivity. For the quasi-circular cases we have compared our (2, 2) mode waveforms to the 281 numerical relativity (NR) simulations of BBH along quasi-circular orbits. All of the matching factors are bigger than 98%. For the elliptical cases, 24 NR simulations of BBH along an elliptic orbit are used. For each elliptical BBH system, we compare our modeled gravitational polarizations against the NR results for different combinations of the inclination angle, the initial orbit phase and the source localization in the sky. We use the minimal matching factor respect to the inclination angle, the initial orbit phase and the source localization to quantify the performance of the higher modes waveform. We found that after introducing the higher modes, the minimum of the minimal matching factor among the 24 tested elliptical BBHs increases from 90% to 98%. Our S E O B N R E H M waveform model can match all tested 305 SXS waveforms better than 98% including highly spinning (χ = 0.99) BBH, highly eccentric (e ≈ 0.6 at reference frequency Mf 0 = 0.002) BBH and large mass ratio (q = 10) BBH.
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Chudakov, D. B., O. D. Kotsareva, D. S. Tsaregorotseva, E. I. Kashirina, and G. V. Fattakhova. "Effect of β-alanine on humoral immune response in low-dose allergy model." Medical Immunology (Russia) 23, no. 1 (March 1, 2021): 127–36. http://dx.doi.org/10.15789/1563-0625-eob-2008.
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At the present time, the efforts of many research groups around the world are aimed at finding new factors triggering the allergic sensitization process linked with IgE synthesis to harmless allergens. According to the recent data, production of tissue cytokines is induced in tissue cells by alarmins, thus, in turn, eliciting pro-allergic immune response. Previously we have shown that β-alanine could be a potential alarmin capable to stimulate production of tissue cytokines. The aim of this work was to determine the impact of β-alanine on humoral immune response in low-dose allergy model. BALB/c mice were immunized by recombinant Asp f 2 protein or commercial ovalbumin (OVA) in the withers 3 times a week with or without β-alanine supplementation. To determine the mechanism of β-alanine effect, α-L-alanine, an isomer which is not MrgD receptor ligand, and β-aminoisobutyrate with β-alanine-like affinity to MrgD ligand, were compared. According to our data, β-alanine stimulated specific IgE and IgG1 production in a short-term course (7 immunizations) and enhanced antibody affinity after long-term (14 immunizations) protocol in the case of low-immunogenic protein Asp f 2. In the case of high-immunogenic OVA protein, the impact of β-alanine was significant only upon antibody affinity. Hence, β-alanine accelerates specific IgE production in the case of low-immunogenic protein. The impact of β-alanine on specific IgE production was not linked to specific MrgD receptor activation, because β-aminoisobutyrate, which is the other ligand of this receptor, did not have a similar effect upon humoral immune response. The effect of β-alanine on IgG1 production seems also independent of MrgD receptor, since the common proteinogenic amino acid α-L-alanine also enhanced specific IgG1 production. The effect of β-alanine on humoral immune response could be linked to its non-specific action, e.g., due to its ability to induce oxidative stress through blocking taurine transporter, or due to its ability to stimulate cellular metabolism.
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HÖGEMANN, DAGMAR, ANDREAS BAUMANN, DIRK ROCKER, AUGUSTINUS BADER, and MICHAEL GALANSKI. "In Vitro Model of the Human Liver Parenchyma to Study Hepatotoxic Side Effects of Dy-EOB-DTPA." Investigative Radiology 35, no. 6 (June 2000): 373–79. http://dx.doi.org/10.1097/00004424-200006000-00006.
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Feng, Shi-Ting, Yingmei Jia, Bing Liao, Bingsheng Huang, Qian Zhou, Xin Li, Kaikai Wei, et al. "Preoperative prediction of microvascular invasion in hepatocellular cancer: a radiomics model using Gd-EOB-DTPA-enhanced MRI." European Radiology 29, no. 9 (January 28, 2019): 4648–59. http://dx.doi.org/10.1007/s00330-018-5935-8.
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Granata, Vincenza, Roberta Fusco, Federica De Muzio, Carmen Cutolo, Mauro Mattace Raso, Michela Gabelloni, Antonio Avallone, et al. "Radiomics and Machine Learning Analysis Based on Magnetic Resonance Imaging in the Assessment of Colorectal Liver Metastases Growth Pattern." Diagnostics 12, no. 5 (April 29, 2022): 1115. http://dx.doi.org/10.3390/diagnostics12051115.
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To assess Radiomics and Machine Learning Analysis in Liver Colon and Rectal Cancer Metastases (CRLM) Growth Pattern, we evaluated, retrospectively, a training set of 51 patients with 121 liver metastases and an external validation set of 30 patients with a single lesion. All patients were subjected to MRI studies in pre-surgical setting. For each segmented volume of interest (VOI), 851 radiomics features were extracted using PyRadiomics package. Nonparametric test, univariate, linear regression analysis and patter recognition approaches were performed. The best results to discriminate expansive versus infiltrative front of tumor growth with the highest accuracy and AUC at univariate analysis were obtained by the wavelet_LHH_glrlm_ShortRunLowGray Level Emphasis from portal phase of contrast study. With regard to linear regression model, this increased the performance obtained respect to the univariate analysis for each sequence except that for EOB-phase sequence. The best results were obtained by a linear regression model of 15 significant features extracted by the T2-W SPACE sequence. Furthermore, using pattern recognition approaches, the diagnostic performance to discriminate the expansive versus infiltrative front of tumor growth increased again and the best classifier was a weighted KNN trained with the 9 significant metrics extracted from the portal phase of contrast study, with an accuracy of 92% on training set and of 91% on validation set. In the present study, we have demonstrated as Radiomics and Machine Learning Analysis, based on EOB-MRI study, allow to identify several biomarkers that permit to recognise the different Growth Patterns in CRLM.
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Sun, X., X. Jiang, X. Li, L. Bu, and D. Wang. "Gd-EOB-DTPA MRI Imaging and Apoptosis Research in Orthotopic Rats Model of Hepatocellular Carcinoma after Stereotactic Radiotherapy." International Journal of Radiation Oncology*Biology*Physics 105, no. 1 (September 2019): E229. http://dx.doi.org/10.1016/j.ijrobp.2019.06.1993.
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Zheng, Rencheng, Chunzi Shi, Chengyan Wang, Nannan Shi, Tian Qiu, Weibo Chen, Yuxin Shi, and He Wang. "Imaging-Based Staging of Hepatic Fibrosis in Patients with Hepatitis B: A Dynamic Radiomics Model Based on Gd-EOB-DTPA-Enhanced MRI." Biomolecules 11, no. 2 (February 18, 2021): 307. http://dx.doi.org/10.3390/biom11020307.
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Accurate grading of liver fibrosis can effectively assess the severity of liver disease and help doctors make an appropriate diagnosis. This study aimed to perform the automatic staging of hepatic fibrosis on patients with hepatitis B, who underwent gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance imaging with dynamic radiomics analysis. The proposed dynamic radiomics model combined imaging features from multi-phase dynamic contrast-enhanced (DCE) images and time-domain information. Imaging features were extracted from the deep learning-based segmented liver volume, and time-domain features were further explored to analyze the variation in features during contrast enhancement. Model construction and evaluation were based on a 132-case data set. The proposed model achieved remarkable performance in significant fibrosis (fibrosis stage S1 vs. S2–S4; accuracy (ACC) = 0.875, area under the curve (AUC) = 0.867), advanced fibrosis (S1–S2 vs. S3–S4; ACC = 0.825, AUC = 0.874), and cirrhosis (S1–S3 vs. S4; ACC = 0.850, AUC = 0.900) classifications in the test set. It was more dominant compared with the conventional single-phase or multi-phase DCE-based radiomics models, normalized liver enhancement, and some serological indicators. Time-domain features were found to play an important role in the classification models. The dynamic radiomics model can be applied for highly accurate automatic hepatic fibrosis staging.
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Bäumler, Wolf, Philipp Wiggermann, Lukas Lürken, Marco Dollinger, Christian Stroszczynski, Lukas P. Beyer, and Andreas Schicho. "Early Detection of Local Tumor Progression after Irreversible Electroporation (IRE) of Hepatocellular Carcinoma Using Gd-EOB-DTPA-Based MR Imaging at 3T." Cancers 13, no. 7 (March 30, 2021): 1595. http://dx.doi.org/10.3390/cancers13071595.
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This single-center retrospective study was conducted to improve the early detection of local tumor progression (LTP) after irreversible electroporation (IRE) of a hepatocellular carcinoma (HCC) using gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB-DTPA)-based 3T MR imaging and to identify helpful signal characteristics by comparing 23 patients with and 60 patients without LTP. To identify the differences in the sensitivity of MRI sequences, the specificity, positive prediction value, negative prediction value (NPV) and diagnostic odds ratio were calculated. A chi-squared test, two-tailed student’s t-test and binary logistic regression model were used to detect distinct patient characteristics and variables for the prediction of LTP. LTP was mostly detected in the peripheral ablation zone (82.6%) within the first six months (87.0%). The central LTP ablation area presented more hypointensities in T1 p.v. (sensitivity: 95.0%; NPV: 90.0%) and in T1 d.p. (sensitivity: 100.0%; NPV: 100.0) while its peripheral part showed more hyperintensities in T2 BLADE (sensitivity: 95.5%; NPV: 80.0%) and in diffusion sequences (sensitivity: 90.0%). Liver cirrhosis seems to be an unfavorable prognosticator for LTP (p = 0.039). In conclusion, LTP mostly occurs in the peripheral ablation zone within six months after IRE. Despite often exhibiting atypical Gd-EOB-DTPA MR signal characteristics, T2 BLADE and diffusion sequences were helpful for their detection in the peripheral zone while T1 p.v. and T1 d.p. had the highest sensitivity in the central zone.
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Luo, Yong, Wei Ren, Yongmei Huang, Qiunong He, Qiongyan Wu, Xi Zhou, and Yao Mao. "Feedforward Control Based on Error and Disturbance Observation for the CCD and Fiber-Optic Gyroscope-Based Mobile Optoelectronic Tracking System." Electronics 7, no. 10 (September 29, 2018): 223. http://dx.doi.org/10.3390/electronics7100223.
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In the mobile optoelectronic tracking system (MOTS) based on charge-coupled device (CCD) and fiber-optic gyroscope (FOG), the tracking performance (TP) and anti-disturbance ability (ADA) characterized by boresight error are of equal importance. Generally, the position tracking loop, limited by the image integration time of CCD, would be subject to a non-negligible delay and low-sampling rate, which could not minimize the boresight error. Although the FOG-based velocity loop could enhance the ADA of the system, it is still insufficient in the case of some uncertain disturbances. In this paper, a feedforward control method based on the results of error and disturbance observation was proposed. The error observer (EOB) based on the CCD data and model output essentially combined the low-frequency tracking feedforward and closed-loop disturbance observer (DOB), which could simultaneously enhance the low-frequency TP and ADA. In addition, in view of the poor low-frequency performance of the FOG due to drift and noise that may result in the inaccuracy of the observed low-frequency disturbance, the FOG-based DOB was used to improve the relatively high-frequency ADA. The proposed method could make EOB and DOB complementary and help to obtain a high-precision MOTS, for in practical engineering, we give more attention to the low-frequency TP and full-band ADA. Simulations and experiments demonstrated that the proposed method was valid and had a much better performance than the traditional velocity and position double-loop control (VPDC).
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Vossen, Josephina A., Manon Buijs, Jean-Francois H. Geschwind, Eleni Liapi, Veronica Prieto Ventura, Kwang Hun Lee, David A. Bluemke, and Ihab R. Kamel. "Diffusion-Weighted and Gd-EOB-DTPA-Contrast-Enhanced Magnetic Resonance Imaging for Characterization of Tumor Necrosis in an Animal Model." Journal of Computer Assisted Tomography 33, no. 4 (July 2009): 626–30. http://dx.doi.org/10.1097/rct.0b013e3181953df3.
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Forsgren, Mikael Fredrik, Olof Dahlqvist Leinhard, Nils Dahlström, Gunnar Cedersund, and Peter Lundberg. "Physiologically Realistic and Validated Mathematical Liver Model Revels Hepatobiliary Transfer Rates for Gd-EOB-DTPA Using Human DCE-MRI Data." PLoS ONE 9, no. 4 (April 18, 2014): e95700. http://dx.doi.org/10.1371/journal.pone.0095700.
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Chen, Shuling, Shiting Feng, Jingwei Wei, Fei Liu, Bin Li, Xin Li, Yang Hou, et al. "Pretreatment prediction of immunoscore in hepatocellular cancer: a radiomics-based clinical model based on Gd-EOB-DTPA-enhanced MRI imaging." European Radiology 29, no. 8 (January 21, 2019): 4177–87. http://dx.doi.org/10.1007/s00330-018-5986-x.
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Le Tiec, Alexandre. "The overlap of numerical relativity, perturbation theory and post-Newtonian theory in the binary black hole problem." International Journal of Modern Physics D 23, no. 10 (September 2014): 1430022. http://dx.doi.org/10.1142/s0218271814300225.
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Inspiralling and coalescing binary black holes are promising sources of gravitational radiation. The orbital motion and gravitational-wave emission of such system can be modeled using a variety of approximation schemes and numerical methods in general relativity: The post-Newtonian (PN) formalism, black hole perturbation theory (BHP), numerical relativity (NR) simulations and the effective one-body (EOB) model. We review recent work at the multiple interfaces of these analytical and numerical techniques, emphasizing the use of coordinate-invariant relationships to perform meaningful comparisons. Such comparisons provide independent checks of the validity of the various calculations, they inform the development of a universal, semi-analytical model of the binary dynamics and gravitational-wave emission and they help to delineate the respective domains of validity of each approximation method. For instance, several recent comparisons suggest that perturbation theory may find applications in a broader range of physical problems than previously thought, including the radiative inspiral of intermediate mass-ratio and comparable-mass black hole binaries.
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Zhang, Shuai, Guizhi Xu, Chongfeng Duan, Xiaoming Zhou, Xin Wang, Haiyang Yu, Lan Yu, et al. "Radiomics Analysis of MR Imaging with Gd-EOB-DTPA for Preoperative Prediction of Microvascular Invasion in Hepatocellular Carcinoma: Investigation and Comparison of Different Hepatobiliary Phase Delay Times." BioMed Research International 2021 (January 7, 2021): 1–8. http://dx.doi.org/10.1155/2021/6685723.
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Purpose. To investigate whether the radiomics analysis of MR imaging in the hepatobiliary phase (HBP) can be used to predict microvascular invasion (MVI) in patients with hepatocellular carcinoma (HCC). Method. A total of 130 patients with HCC, including 80 MVI-positive patients and 50 MVI-negative patients, who underwent MR imaging with Gd-EOB-DTPA were enrolled. Least absolute shrinkage and selection operator (LASSO) regression was applied to select radiomics parameters derived from MR images obtained in the HBP 5 min, 10 min, and 15 min images. The selected features at each phase were adopted into support vector machine (SVM) classifiers to establish models. Multiple comparisons of the AUCs at each phase were performed by the Delong test. The decision curve analysis (DCA) was used to analyze the classification of MVI-positive and MVI-negative patients. Results. The most predictive features between MVI-positive and MVI-negative patients included 9, 8, and 14 radiomics parameters on HBP 5 min, 10 min, and 15 min images, respectively. A model incorporating the selected features produced an AUC of 0.685, 0.718, and 0.795 on HBP 5 min, 10 min, and 15 min images, respectively. The predictive model for HBP 5 min, 10 min and 15 min showed no significant difference by the Delong test. DCA indicated that the predictive model for HBP 15 min outperformed the models for HBP 5 min and 10 min. Conclusions. Radiomics parameters in the HBP can be used to predict MVI, with the HBP 15 min model having the best differential diagnosis ability.
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Granata, Vincenza, Roberta Fusco, Federica De Muzio, Carmen Cutolo, Sergio Venanzio Setola, Federica Dell’Aversana, Alessandro Ottaiano, et al. "EOB-MR Based Radiomics Analysis to Assess Clinical Outcomes following Liver Resection in Colorectal Liver Metastases." Cancers 14, no. 5 (February 27, 2022): 1239. http://dx.doi.org/10.3390/cancers14051239.
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The aim of this study was to assess the efficacy of radiomics features obtained by EOB-MRI phase in order to predict clinical outcomes following liver resection in Colorectal Liver Metastases Patients, and evaluate recurrence, mutational status, pathological characteristic (mucinous) and surgical resection margin. This retrospective analysis was approved by the local Ethical Committee board of National Cancer of Naples, IRCCS “Fondazione Pascale”. Radiological databases were interrogated from January 2018 to May 2021 in order to select patients with liver metastases with pathological proof and EOB-MRI study in pre-surgical setting. The cohort of patients included a training set (51 patients with 61 years of median age and 121 liver metastases) and an external validation set (30 patients with single lesion with 60 years of median age). For each segmented volume of interest by 2 expert radiologists, 851 radiomics features were extracted as median values using PyRadiomics. non-parametric test, intraclass correlation, receiver operating characteristic (ROC) analysis, linear regression modelling and pattern recognition methods (support vector machine (SVM), k-nearest neighbors (KNN), artificial neural network (NNET), and decision tree (DT)) were considered. The best predictor to discriminate expansive versus infiltrative front of tumor growth was HLH_glcm_MaximumProbability extraxted on VIBE_FA30 with an accuracy of 84%, a sensitivity of 83%, and a specificity of 82%. The best predictor to discriminate tumor budding was Inverse Variance obtained by the original GLCM matrix extraxted on VIBE_FA30 with an accuracy of 89%, a sensitivity of 96% and a specificity of 65%. The best predictor to differentiate the mucinous type of tumor was the HHL_glszm_ZoneVariance extraxted on VIBE_FA30 with an accuracy of 85%, a sensitivity of 46% and a specificity of 95%. The best predictor to identify tumor recurrence was the LHL_glcm_Correlation extraxted on VIBE_FA30 with an accuracy of 86%, a sensitivity of 52% and a specificity of 97%. The best linear regression model was obtained in the identification of the tumor growth front considering the height textural significant metrics by VIBE_FA10 (an accuracy of 89%; sensitivity of 93% and a specificity of 82%). Considering significant texture metrics tested with pattern recognition approaches, the best performance for each outcome was reached by a KNN in the identification of recurrence with the 3 textural significant features extracted by VIBE_FA10 (AUC of 91%, an accuracy of 93%; sensitivity of 99% and a specificity of 77%). Ours results confirmed the capacity of radiomics to identify as biomarkers, several prognostic features that could affect the treatment choice in patients with liver metastases, in order to obtain a more personalized approach.
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Strotzer, Quirin David, Hinrich Winther, Kirsten Utpatel, Alexander Scheiter, Claudia Fellner, Michael Christian Doppler, Kristina Imeen Ringe, et al. "Application of A U-Net for Map-Like Segmentation and Classification of Discontinuous Fibrosis Distribution in Gd-EOB-DTPA-Enhanced Liver MRI." Diagnostics 12, no. 8 (August 11, 2022): 1938. http://dx.doi.org/10.3390/diagnostics12081938.
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We aimed to evaluate whether U-shaped convolutional neuronal networks can be used to segment liver parenchyma and indicate the degree of liver fibrosis/cirrhosis at the voxel level using contrast-enhanced magnetic resonance imaging. This retrospective study included 112 examinations with histologically determined liver fibrosis/cirrhosis grade (Ishak score) as the ground truth. The T1-weighted volume-interpolated breath-hold examination sequences of native, arterial, late arterial, portal venous, and hepatobiliary phases were semi-automatically segmented and co-registered. The segmentations were assigned the corresponding Ishak score. In a nested cross-validation procedure, five models of a convolutional neural network with U-Net architecture (nnU-Net) were trained, with the dataset being divided into stratified training/validation (n = 89/90) and holdout test datasets (n = 23/22). The trained models precisely segmented the test data (mean dice similarity coefficient = 0.938) and assigned separate fibrosis scores to each voxel, allowing localization-dependent determination of the degree of fibrosis. The per voxel results were evaluated by the histologically determined fibrosis score. The micro-average area under the receiver operating characteristic curve of this seven-class classification problem (Ishak score 0 to 6) was 0.752 for the test data. The top-three-accuracy-score was 0.750. We conclude that determining fibrosis grade or cirrhosis based on multiphase Gd-EOB-DTPA-enhanced liver MRI seems feasible using a 2D U-Net. Prospective studies with localized biopsies are needed to evaluate the reliability of this model in a clinical setting.
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Korkusuz, Huedayi, Lea L. Knau, Wolfgang Kromen, Verena Bihrer, Daniel Keese, Albrecht Piiper, and Thomas J. Vogl. "Different signal intensity at Gd-EOB-DTPA compared with Gd-DTPA-enhanced MRI in hepatocellular carcinoma transgenic mouse model in delayed phase hepatobiliary imaging." Journal of Magnetic Resonance Imaging 35, no. 6 (January 20, 2012): 1397–402. http://dx.doi.org/10.1002/jmri.23584.
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Petrash, E. A., M. A. Shorikov, E. V. Mikhaylova, and A. L. Nikulina. "Differential Diagnosis of Benign and Malignant Level Tumors in Children by Quantitative MRI with Intracellular Contrast Agent." Journal of oncology: diagnostic radiology and radiotherapy 4, no. 3 (October 1, 2021): 56–63. http://dx.doi.org/10.37174/2587-7593-2021-4-3-56-63.
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Purpose: Тo determine the possibilities of quantitative assessment of mpMRI with EOB-DTPA in the differential diagnosis of benign and malignant tumors in children.Material and methods: 30 patients (male — 17, female — 13) with 83 tumors underwent MRI. Age ranged from 5 months to 20 years. All children underwent MRI on 3T or 1.5T MR-scanners using body coil. Fat saturated T1WI were performed before and after hepatotropic MR-contrast agent (gadoxetic acid) injection in arterial, portal, venous and delayed phases (1, 5, 20, 40 min). Tumors were divided into 2 groups: benign (52) and malignant (31). In this work we use only pre- and postcontrast T1WI. Diagnosis was confirmed histologically (all malignant and a part of benign FLL) and long-term MRI follow-up studies (for benign). To eliminate influence of external factors we used coefficients for each MR-program, the signal was normalized to intact liver parenchyma, spleen, abdominal aorta and v. cava inferior, also normalization to native series has been performed. Coefficients were compared for malignant and benign tumors using Student’s t-test, significantly different parameters were further used to build mathematical model by constructing a logistic regression with step-by-step selection of the most informative values.Results: Regression model is presented by formula. The model is informative and statistically significant (p < 0.001). If A>0.5 tumors has a malignant nature if А ≤ 0.5–benign. Model sensitivity and specificity are 0.862 and 0.925, respectively.Conclusion: Our model could be an excellent assistance in differentiation of benign and malignant focal liver lesions and reduces diagnostic path, effects the proper patients management.
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MORIYAMA, Yuki, Shigeyoshi SAITO, Shuichiro KOBAYASHI, Ryota OGIHARA, Daichi KOTO, Akihiro KITAMURA, Taro MATSUSHITA, Motoko NISHIURA, and Kenya MURASE. "Evaluation of Concanavalin A-induced Acute Liver Injury in Rats using an Empirical Mathematical Model and Dynamic Contrast-enhanced MR Imaging with Gd-EOB-DTPA." Magnetic Resonance in Medical Sciences 11, no. 1 (2012): 53–60. http://dx.doi.org/10.2463/mrms.11.53.
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Saito, Shigeyoshi, Yuki Moriyama, Shuichiro Kobayashi, Ryota Ogihara, Daichi Koto, Akihiro Kitamura, Taro Matsushita, Motoko Nishiura, and Kenya Murase. "Assessment of liver function in thioacetamide-induced rat acute liver injury using an empirical mathematical model and dynamic contrast-enhanced MRI with Gd-EOB-DTPA." Journal of Magnetic Resonance Imaging 36, no. 6 (June 18, 2012): 1483–89. http://dx.doi.org/10.1002/jmri.23726.
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Ma, Chunmei, Ailian Liu, Yuanyuan Wang, Xiaoling Geng, Li Hao, Qingwei Song, Bo Sun, Heqing Wang, and Gang Zhao. "The hepatocyte phase of Gd-EOB-DTPA-enhanced MRI in the evaluation of hepatic fibrosis and early liver cirrhosis in a rat model: An experimental study." Life Sciences 108, no. 2 (July 2014): 104–8. http://dx.doi.org/10.1016/j.lfs.2014.05.016.
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Zhou, Zhi-Peng, Li-Ling Long, Li-Juan Huang, Teng-Fei Yang, and Zhong-Kui Huang. "Gd-EOB-DTPA-enhanced MRI T1 mapping for assessment of liver function in rabbit fibrosis model: comparison of hepatobiliary phase images obtained at 10 and 20 min." La radiologia medica 122, no. 4 (January 9, 2017): 239–47. http://dx.doi.org/10.1007/s11547-016-0719-1.
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Dong, Haoyu, Shijie Liu, Shi Han, Zhouyu Fu, and Dongmei Zhang. "TableSense: Spreadsheet Table Detection with Convolutional Neural Networks." Proceedings of the AAAI Conference on Artificial Intelligence 33 (July 17, 2019): 69–76. http://dx.doi.org/10.1609/aaai.v33i01.330169.
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Spreadsheet table detection is the task of detecting all tables on a given sheet and locating their respective ranges. Automatic table detection is a key enabling technique and an initial step in spreadsheet data intelligence. However, the detection task is challenged by the diversity of table structures and table layouts on the spreadsheet. Considering the analogy between a cell matrix as spreadsheet and a pixel matrix as image, and encouraged by the successful application of Convolutional Neural Networks (CNN) in computer vision, we have developed TableSense, a novel end-to-end framework for spreadsheet table detection. First, we devise an effective cell featurization scheme to better leverage the rich information in each cell; second, we develop an enhanced convolutional neural network model for table detection to meet the domain-specific requirement on precise table boundary detection; third, we propose an effective uncertainty metric to guide an active learning based smart sampling algorithm, which enables the efficient build-up of a training dataset with 22,176 tables on 10,220 sheets with broad coverage of diverse table structures and layouts. Our evaluation shows that TableSense is highly effective with 91.3% recall and 86.5% precision in EoB-2 metric, a significant improvement over both the current detection algorithm that are used in commodity spreadsheet tools and state-of-the-art convolutional neural networks in computer vision.
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Zech, Christoph J., Bernhard Vos, Anders Nordell, Matthias Urich, Lennart Blomqvist, Josy Breuer, Maximilian F. Reiser, and Hanns-Joachim Weinmann. "Vascular Enhancement in Early Dynamic Liver MR Imaging in an Animal Model: Comparison of Two Injection Regimen and Two Different Doses Gd-EOB-DTPA (Gadoxetic Acid) With Standard Gd-DTPA." Investigative Radiology 44, no. 6 (June 2009): 305–10. http://dx.doi.org/10.1097/rli.0b013e3181a24512.
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Jongerius, Ilse, Jörg Köhl, Manoj K. Pandey, Maartje Ruyken, Kok P. M. van Kessel, Jos A. G. van Strijp, and Suzan H. M. Rooijakkers. "Staphylococcal complement evasion by various convertase-blocking molecules." Journal of Experimental Medicine 204, no. 10 (September 24, 2007): 2461–71. http://dx.doi.org/10.1084/jem.20070818.
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To combat the human immune response, bacteria should be able to divert the effectiveness of the complement system. We identify four potent complement inhibitors in Staphylococcus aureus that are part of a new immune evasion cluster. Two are homologues of the C3 convertase modulator staphylococcal complement inhibitor (SCIN) and function in a similar way as SCIN. Extracellular fibrinogen-binding protein (Efb) and its homologue extracellular complement-binding protein (Ecb) are identified as potent complement evasion molecules, and their inhibitory mechanism was pinpointed to blocking C3b-containing convertases: the alternative pathway C3 convertase C3bBb and the C5 convertases C4b2aC3b and C3b2Bb. The potency of Efb and Ecb to block C5 convertase activity was demonstrated by their ability to block C5a generation and C5a-mediated neutrophil activation in vitro. Further, Ecb blocks C5a-dependent neutrophil recruitment into the peritoneal cavity in a mouse model of immune complex peritonitis. The strong antiinflammatory properties of these novel S. aureus–derived convertase inhibitors make these compounds interesting drug candidates for complement-mediated diseases.
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Manavalan, John S., Ipsita Pal, Aidan Pursley, George A. Ward, Tomoko Smyth, Martin Sims, David J. Feith, Thomas P. Loughran, Owen A. O'Connor, and Enrica Marchi. "Tolinapant (ASTX660), a Non-Peptidomimetic Antagonist of cIAP1/2 and XIAP, and the HDAC Inhibitor Romidepsin Are Synergistic in in Vitro Models of T Cell Lymphoma." Blood 138, Supplement 1 (November 5, 2021): 4356. http://dx.doi.org/10.1182/blood-2021-153451.
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Abstract Background: The PTCL are a heterogeneous group of non-Hodgkin lymphomas originating from mature T-lymphocytes. They are aggressive diseases, often resistant to conventional chemotherapy. Despite the fact that a number of new agents have been approved, treatment paradigms tailored to the biology of the disease have yet to emerge. Tolinapant (ASTX660) is a potent antagonist of both cellular and X-linked inhibitors of apoptosis proteins (cIAP1/2 and XIAP), and is presently in phase I/II trials in patients with advanced solid tumors and lymphomas (NCT02503423). IAP antagonists enhance tumor necrosis factor (TNF) receptor superfamily mediated apoptosis (Ward GA, et al. Mol Cancer Ther. 2018), are potent anti-tumor immune enhancers and induce markers of immunogenic cell death such as damage associated molecular patterns (DAMPs; Ye W, et al, Oncoimmunology, 2020). Objectives: We explored the sensitivity of a range of T-cell lymphoma (TCL) cell lines to tolinapant. We establish the synergy coefficient between tolinapant and the HDAC inhibitor, romidepsin, and interrogated the molecular basis of their synergistic interaction. Methods: A panel of human T-cell lymphoma cell lines were tested in proliferation assays (CellTiterGlo) for sensitivity to tolinapant in the presence or absence of 10ng/ml of TNF alpha. For combination studies, with tolinapant and romidepsin, each drug was tested at the IC10 and IC40 concentrations in the presence or absence of TNF alpha. Synergy scores using the Excess over Bliss (EOB) model were calculated using SynergyFinder (Aleksandr Ianevski et al; Nucleic Acids Research, 2020). Additionally, the effects of tolinapant and romidepsin on the IAPs and caspases were analyzed by western blots. TNFR1 receptor expression and induction of DAMPs were also analyzed by flow cytometry. Results: TCL Lines demonstrated varying sensitivities to tolinapant in the presence or absence of TNF alpha. The most sensitive cell lines, ALK+ ALCL and SUP-M2, had IC50 concentrations ranging from 200nM ± 100nM to 20nM ± 1nM in the absence or presence of TNF alpha, respectively, at 24, 48 and 72hrs, while a resistant CTCL cell line HH had an IC50 concentration of over 20mM, even in the presence of TNF alpha. Interestingly, using western blot analysis, we found that the presence of TNF alpha increased the levels of cIAP1 in the tolinapant sensitive SUP-M2 cell line, but not in the resistant HH cell line. However, there was a concentration dependent decrease in cIAP1 but not in XIAP in both cell lines treated with tolinapant. Flow cytometry analysis demonstrated that tolinapant increases the expression of TNFR1 and DAMPs in a dose dependent manner on the sensitive SUP-M2, but not in the resistant HH cells. In combination experiments, using the EOB model, tolinapant plus romidepsin was found to be synergistic in the absence of TNF alpha, at 36hrs, in both the sensitive cell line SUP-M2 and the resistant cell line HH. In the presence of TNF alpha, synergism was seen only in the sensitive cell line SUP-M2 and antagonistic in the HH cell line (Fig. 3). In the tolinapant plus romidepsin treated samples, cIAP1 levels decreased in the SUP-M2 cell line, in the absence of TNF alpha, however, addition of TNF alpha did not alter the levels of cIAP1 in the SUP-M2 cells. The cIAP1 levels decreased in the HH cells treated with the combination, in both the presence or absence of TNF alpha (Figure). Our findings indicate that the synergy of the tolinapant plus romidepsin is not dependent on the presence of TNF alpha. Conclusion: Tolinapant has demonstrated potent cytotoxic effects against a broad range of TCL lines both as a monotherapy and in combination with the HDAC Inhibitor, romidepsin. In in vitro studies, T cell lymphoma cell lines demonstrated varying sensitivity to tolinapant with certain cell lines being more resistant, even in the presence of TNF alpha. Interestingly, the addition of romidepsin appeared to overcome the intrinsic resistance to tolinapant in the absence of TNF alpha. These data provide the rationale to continue to explore the combination of tolinapant and romidepsin in vivo and to investigate additional combinations with T-cell specific agents (e.g. pralatrexate, belinostat, azacitidine and decitabine). Figure 1 Figure 1. Disclosures Smyth: Astex Pharmaceuticals: Current Employment. Sims: Astex Pharmaceuticals: Current Employment. Loughran: Kymera Therapeutics: Membership on an entity's Board of Directors or advisory committees; Bioniz Therapeutics: Membership on an entity's Board of Directors or advisory committees; Keystone Nano: Membership on an entity's Board of Directors or advisory committees; Dren Bio: Membership on an entity's Board of Directors or advisory committees. Marchi: Kyowa Kirin: Honoraria; Myeloid Therapeutics: Honoraria; Astex: Research Funding; BMS: Research Funding; Merck: Research Funding; Kymera Therapeutics: Other: Scientific Advisor.
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Vulin, Domagoj, Marko Gaćina, and Valentina Biličić. "SLIM-TUBE SIMULATION MODEL FOR CO2 INJECTION EOR." Rudarsko-geološko-naftni zbornik 33, no. 2 (2018): 37–48. http://dx.doi.org/10.17794/rgn.2018.2.4.
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Li, Dan, Gabriel G. Katul, and Sergej S. Zilitinkevich. "Closure Schemes for Stably Stratified Atmospheric Flows without Turbulence Cutoff." Journal of the Atmospheric Sciences 73, no. 12 (November 21, 2016): 4817–32. http://dx.doi.org/10.1175/jas-d-16-0101.1.
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Abstract Two recently proposed turbulence closure schemes are compared against the conventional Mellor–Yamada (MY) model for stably stratified atmospheric flows. The Energy- and Flux-Budget (EFB) approach solves the budgets of turbulent momentum and heat fluxes and turbulent kinetic and potential energies. The Cospectral Budget (CSB) approach is formulated in wavenumber space and integrated across all turbulent scales to obtain flow variables in physical space. Unlike the MY model, which is subject to a “critical gradient Richardson number,” both EFB and CSB models allow turbulence to exist at any gradient Richardson number and predict a saturation of flux Richardson number () at sufficiently large . The CSB approach further predicts the value of and reveals a unique expression linking the Rotta and von Kármán constants. Hence, all constants in the CSB model are nontunable and stability independent. All models agree that the dimensionless sensible heat flux decays with increasing . However, the decay rate and subsequent cutoff in the MY model appear abrupt. The MY model further exhibits an abrupt cutoff in the turbulent stress normalized by vertical velocity variance, while the CSB and EFB models display increasing trends. The EFB model produces a rapid increase in the ratio of turbulent potential energy and vertical velocity variance as is approached, suggesting a strong self-preservation mechanism. Vertical anisotropy in the turbulent kinetic energy is parameterized in different ways in MY and EFB, but this consideration is not required in CSB. Differences between EFB and CSB model predictions originate from how the vertical anisotropy is specified in the EFB model.
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Huang, Yung-Fu, and Kuang-Hua Hsu. "AN EOQ MODEL WITH NONINSTANTANEOUS RECEIPT UNDER SUPPLIER CREDITS." Journal of the Operations Research Society of Japan 50, no. 1 (2007): 1–13. http://dx.doi.org/10.15807/jorsj.50.1.
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Lue, Jennifer Kimberly, John S. Manavalan, Christine Klaus, Rahul Kanik, Andre M. Grilo, Alice McDonald, Jared Gollob, Duncan Walker, Owen A. O'Connor, and Nello Mainolfi. "Targeting MYD88-Mutant DLBCL with IRAKIMiDs: A Comparison to IRAK4 Kinase Inhibition and Evaluation of Synergy with Rational Combinations." Blood 136, Supplement 1 (November 5, 2020): 12. http://dx.doi.org/10.1182/blood-2020-135898.
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Introduction: MYD88 mutations are found in 25% of DLBCL and are associated with an inferior survival. MYD88 is an adapter molecule, forming the core of the Myddosome complex. MYD88 mutations constitutively activate pathways such as NFқB, leading to lymphomagenesis. Essential to the Myddosome-dependent signaling pathway is the recruitment of IRAK4 which complexes with MYD88 to activate downstream effects. Targeting IRAK4 is therefore a rational therapeutic approach in MYD88-mutant lymphomas. First-in-class IRAKIMiDs, novel heterobifunctional degraders that target IRAK4 as well as the IMiD substrates Ikaros and Aiolos to enable the inhibition of both the NFkB and IRF4 pathways activated by MYD88 mutations, demonstrate potent efficacy in MYD88-mutant lymphomas (KTX-475, KTX-582, Walker D et al. AACR 2020). Herein, we compare the activity of IRAKIMiDs to IRAK4 kinase inhibitors and IMiDs alone in MYD88-mutant DLBCL, and evaluate rational combinations of IRAKIMiDs and other active agents in DLBCL for synergy. Methods: MYD88-mutant (n=4) and wild type (n=4) DLBCL cell lines were exposed to a panel of single agents (KTX-475, KTX-582, BAY1830839, CA-4948, CC-220, lenalidomide, pomalidomide, ibrutinib, umbralisib, venetoclax) in order to establish the drug concentration:cytotoxicity effect relationship. Cell viability was assessed using Celltiter-Glo assay at 24-hour intervals. IC50 values were computed. MYD88-mutant DLBCL cells were co-exposed to combinations of KTX-475 with venetoclax, ibrutinib, or umbralisib at concentrations representing their respective IC10-40 in order to determine synergy using the excess over bliss (EOB) method. Venetoclax, ibrutinib, and umbralisib were selected for combinational studies in order to target adverse pathways known to be associated in DLBCL biology. To confirm IRAK4 degradation, western blot and flow cytometry was performed. Apoptosis was evaluated with flow cytometry. Pre-treatment RNA-seq libraries were developed for the purpose of identifying GSEA and mutational analysis to predict response to IRAKIMiDs. Results: Exposure to IRAKIMiDs led to potent activity in MYD88-mutated DLBCL with IC50s in the low nanomolar range. IRAK4 degradation occured in a dose- and time-dependent manner and was observed as early as four hours after exposure. IRAKIMiDs induced superior cytotoxicity compared to two IRAK4 kinase inhibitors, including CA-4948 (Curis), which is currently under clinical investigation for relapsed/refractory NHL, as determined by lower IC50s in all cell lines. IRAKIMiD IC50s were also lower compared to pomalidomide, lenalidomide, and CC-220. KTX-475 was selected for synergy assessments based on IC50 values. Synergy was observed after exposure to KTX-475 in conjunction with venetoclax, ibrutinib, or umbralisib as determined by EOB >0 in the MYD88-mutant OCI-LY10 model, with maximum values peaking at 72-96 hours. After dual drug exposure, IRAK4 degradation was validated by flow cytometry demonstrating that the addition of venetoclax, ibrutinib or umbralisib to KTX-475 did not impair IRAK4 degradation capabilities. RNA-seq interpretation is currently underway. Conclusions: Collectively, our results demonstrate that dual-function degraders targeting both IRAK4 and the IMiD substrates Ikaros and Aiolos can serve as a potential therapeutic option for poor prognosis MYD88-mutant DLBCL. Our data thus far demonstrate improved efficacy of IRAKIMiDs compared to IRAK4 kinase inhibitors or IMiDs alone in vitro, as well as synergy with other active agents in combination regimens. A promising lead IRAKIMiD candidate has been identified, with initiation of a first-in-human clinical trial in B-cell lymphomas planned for 2021. Disclosures Lue: Daiichi Sankyo: Honoraria; AstraZeneca: Speakers Bureau; Astex Pharmaceuticals: Honoraria; Kymera Therapeutics: Honoraria, Research Funding; Kura Oncology: Honoraria. Klaus:Kymera Therapeutics: Current Employment, Current equity holder in publicly-traded company. Kanik:Kymera Therapeutics: Current Employment, Current equity holder in publicly-traded company. McDonald:Kymera Therapeutics: Current Employment, Current equity holder in publicly-traded company. Gollob:Kymera Therapeutics: Current Employment, Current equity holder in publicly-traded company. Walker:Kymera Therapeutics: Current Employment, Current equity holder in publicly-traded company. O'Connor:Kymera Therapeutics: Current equity holder in private company, Honoraria, Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Current Employment, Current equity holder in publicly-traded company; Servier: Consultancy; Mundipharma: Other: Consulting; Astex Pharmaceuticals: Honoraria, Research Funding; Merck: Research Funding; Nomocan: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Other: Data Safety Monitoring Committee, Research Funding. Mainolfi:Kymera Therapeutics: Current Employment, Current equity holder in publicly-traded company.
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Deng, Changchun, Mark Lipstein, Luigi Scotto, Xavier O. Jirau Serrano, Michael Mangone, Shirong Li, Jeremie Vendome, et al. "Silencing c-Myc Translation As a Therapeutic Strategy through Targeting PI3K Delta and CK1 Epsilon in Hematological Malignancies." Blood 128, no. 22 (December 2, 2016): 291. http://dx.doi.org/10.1182/blood.v128.22.291.291.
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Abstract Introduction: c-Myc is a master transcription factor and one of the most frequently altered genes across a vast array of human cancers including diffuse large B-cell lymphoma (DLBCL), and is thus an attractive therapeutic target . However, no direct inhibitor of c-Myc has been successfully developed for the treatment of any cancer. The c-Myc protein has a short half-life of less than 30 minutes , and the complex secondary structures in the 5' untranslated region (UTR) of MYC mRNA make its translation highly dependent on the eukaryotic translation initiation factor 4F (eIF4F) . eIF4F exists as a complex comprised of the eIF4E, eIF4A, and eIF4G subunits. eIF4E can be sequestered by 4E-BP1, which acts as a "brake" for initiation of mRNA translation . Hyper-phosphorylation of 4E-BP1, caused by upstream signals such as mTORC1, leads to release of eIF4E from 4E-BP1, assembly of the eIF4F complex, and robust mRNA translation. Surprisingly, neither FDA approved mTORC1 inhibitors nor the investigational mTORC1/mTORC2 inhibitor MLN0128 has demonstrated adequate activity in aggressive lymphoma. The therapeutic effects of mTOR inhibition in c-Myc driven aggressive lymphoma remain poorly understood. Recognizing phosphoinositide 3-kinase (PI3K) and the proteasome pathway are both involved in activating mTOR, we hypothesized that co-targeting the PI3K and proteasome pathways might synergistically inhibit translation of c-Myc. Since both PI3K and proteasome are proven drug targets in blood cancer, such co-targeting strategy may be expeditiously studied in clinical trials for c-Myc driven aggressive lymphoma. Methods: Cytotoxicity was studied in lymphoma cell lines and primary lymphoma cells using Cell TiterGlo (Promega®). The Bliss additivism model was used to determine the expected inhibition of cell growth and the excess over Bliss (EOB) values. EOB values above 0 indicate synergy, with higher values indicating higher levels of synergy. Expression of c-Myc was investigated at the translation and transcription levels, using a combination of Western blot, qPCR, and a bi-cistronic luciferase reporter we developed to study cap dependent translation. Gene expression profiling (GEP) studies were conducted using RNAseq, and analyzed by the Fisher t-test and running enrichment score (RES) between different treatment groups. Mechanisms of synergy were determined through interrogating the effects of small molecule inhibitors and shRNA targeting regulators of various regulators of 4E-BP1. Structural studies of TGR-1202 were performed by in silico docking, and validated by synthesis of novel analogs of TGR-1202. Activity of TGR-1202 on CK1 epsilon was studied by kinome profiling (Reaction Biology®), cell free kinase assay of CK1e (Promega®), and cell based assay of CK1e autophosphorylation. Results: We found that a novel PI3K delta isoform inhibitor TGR-1202, but not the approved PI3Kd inhibitor idelalisib, was highly synergistic with the proteasome inhibitor carfilzomib in lymphoma, leukemia, and myeloma cell lines and primary lymphoma and leukemia cells (Figure 1). TGR-1202 and carfilzomib (TC) synergistically inhibited phosphorylation of eIF4E-binding protein 1 (4E-BP1), leading to suppression of c-Myc translation and silencing of c-Myc dependent transcription (Figure 2). Furthermore, the synergistic cytotoxicity of TC was rescued by overexpression of eIF4E or c-Myc. TGR-1202, but not other PI3Kd inhibitors, was active against casein kinase-1 (CK1) epsilon (Figure 3). Targeting CK1e using a selective chemical inhibitor or shRNA complements the effects of idelalisib, as a single agent or in combination with carfilzomib, in repressing phosphorylation of 4E-BP1 and the protein level of c-Myc. Conclusion: These results suggest that TGR-1202 is a first-in-class dual PI3Kd/CK1e inhibitor, which may in part explain the preliminary clinical activity of TGR-1202 in aggressive lymphoma not found with idelalisib. Targeting CK1e should become an integral part of therapeutic strategies targeting translation of oncogenes such as c-Myc. Disclosures Lentzsch: BMS: Consultancy; Foundation One: Consultancy; Celgene: Consultancy, Honoraria. O'Connor:Seattle Genetics: Research Funding; Mundipharma: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Research Funding; Spectrum: Research Funding; Spectrum: Research Funding; Mundipharma: Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Research Funding; TG Therapeutics: Research Funding; Bristol Myers Squibb: Research Funding; Bristol Myers Squibb: Research Funding; Celgene: Research Funding; Celgene: Research Funding.
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k, Kalaiarasi, Sumathi M, and Mary Henrietta H. "Optimization of Fuzzy Inventory EOQ Model Using Kuhn-Tucker Method." Journal of Advanced Research in Dynamical and Control Systems 11, no. 0009-SPECIAL ISSUE (September 25, 2019): 595–99. http://dx.doi.org/10.5373/jardcs/v11/20192610.
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Chireh, Arvin, Mikael Sandell, Rikard Grankvist, Victoria Lövljung, Jonathan al-Saadi, Fabian Arnberg, Johan Lundberg, Magnus Settergren, and Staffan Holmin. "Safety evaluation of high-risk myocardial micro-biopsy in a swine model." Heart and Vessels 37, no. 4 (November 23, 2021): 697–704. http://dx.doi.org/10.1007/s00380-021-01995-9.
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AbstractThe objective of the study was to investigate the safety profile of high-risk micro-endomyocardial biopsy (micro-EMB) compared to conventional EMB in a large animal model. Twenty pigs were subjected to a maximum of 30 consecutive biopsies, including sampling from the free ventricular wall, with either micro-EMB (n = 10) or conventional EMB (n = 10). There were no major complications in the micro-EMB group (0/10), compared to six major complications in the EMB group (6/10; p = 0.003). Survival analysis further highlighted these differences (p = 0.004). There were significantly higher volumes of pericardial effusion in the EMB group (p = 0.01). The study shows a safety advantage of micro-EMB compared to standard EMB in the experimental high-risk circumstances investigated in this animal study. These results indicate enhanced possibilities to collect samples from sensitive areas by using the micro-EMB technique instead of standard EMB.
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Deng, Changchun, Mark Lipstein, Luigi Scotto, Yun Hao, Nicholas P. Tatonetti, Michael Mangone, Shirong Li, et al. "Disruption of the mTOR-eIF4F Axis By Selectively Targeting PI3Kdelta and Proteasome Potently Inhibits Cap Dependent Translation of c-Myc in Aggressive Lymphomas." Blood 126, no. 23 (December 3, 2015): 593. http://dx.doi.org/10.1182/blood.v126.23.593.593.
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Abstract Background: c-Myc is one of the most frequently altered genes across a vast array of human cancers. Overexpression of c-Myc is observed in up to 30% of cases of diffuse large B-cell lymphoma (DLBCL), the most common type of aggressive lymphoma. Although DLBCL can be cured in 60-70% patients, a substantial minority of patients with DLBCL still die from their lymphoma. There is emerging evidence that c-Myc expression is an adverse risk factor independent of the cell-of-origin classification. To date no drugs that directly target c-Myc have been approved for the treatment of any cancer. In fact, since c-Myc is involved in many normal cellular functions, direct c-Myc inhibitors may be associated with significant toxicity. The goal of our study is to develop novel strategies targeting c-Myc that will have an improved therapeutic index. The c-Myc protein has a very short half-life of less than 30 minutes, and its translation is highly dependent on the eukaryotic initiation factor 4F (eIF4F). eIF4F is activated by the mammalian target of rapamycin (mTOR), which is regulated not only by the PI3K-AKT pathway but also the proteasome pathway. These observations led us to hypothesize that if the proteasome and PI3K pathways cooperate in the activation of mTOR and its downstream target eIF4F, then combinations of proteasome and PI3K inhibitors should potently suppress eIF4F dependent translation of c-Myc and the growth of c-Myc dependent lymphoma. Methods: Cytotoxicity was studied in lymphoma cell lines and primary lymphoma cells using Cell TiterGlo. The Bliss additivism model was used to determine the expected inhibition of cell growth. The difference of the expected and observed levels of inhibition was used to calculate the excess over Bliss (EOB) values. EOB values above 0 indicate synergy, with higher values indicating higher levels of synergy. Mechanisms of synergy were determined through interrogation of PI3K/AKT/mTOR pathway and its downstream targets. Expression of c-Myc was investigated at the translation and transcription levels, using a combination of Western blot, qPCR, and a bi-cistronic luciferase reporter we developed to study cap dependent translation. Gene expression profiling (GEP) studies were conducted using RNAseq, and analyzed by the Fisher t-test and running enrichment score (RES) between different treatment groups. Results: We used a high-throughput platform to screen the cytotoxicity of two PI3Kdelta inhibitors (TGR-1202 & idelalisib/Cal-101), two proteasome inhibitors (bortezomib & carfilzomib), and four combination pairs using these drugs. We found that TGR-1202 and Cal-101 caused only minimal to mild inhibition of lymphoma cells, while bortezomib and carfilzomib caused potent inhibition as single agents. The combination of TGR-1202 and carfilzomib was consistently the most synergistic doublet, while the combination of Cal-101 and bortezomib the least synergistic in numerous lymphoma cell lines studied to date (Figure 1). TGR-1202 and carfilzomib were also highly synergistic in primary lymphoma cells, while Cal-101 and bortezomib were not. Importantly, normal lymphocytes were resistant to the combination of TGR-1202 and carfilzomib. At the molecular level, only the combination of TGR-1202 and carfilzomib potently inhibited mTORC1 dependent phosphorylation of 4E-BP1, leading to marked reduction of c-Myc protein (Figures 2 & 3). In contrast, the combination of TGR-1202 and carfilzomib produced no reduction of the mRNA level of c-Myc (Figures 3). A luciferase reporter demonstrated that the synergistic combination TGR-1202 and carfilzomib specifically inhibited the translation downstream of the 5'UTR of c-Myc (Figure 3). GEP studies confirmed that the canonical c-Myc target genes were potently downregulated at the level of transcription by the combination of TGR-1202 and carfilzomib (Figure 3). These results demonstrate that TGR-1202 and carfilzomib in combination potently inhibited the translation of c-Myc and the c-Myc transcriptional program, which appears to be primarily through disruption of the PI3Kdelta and proteasome pathways that converge on mTOR. Ongoing experiments are focused on confirmation of these observations in vivo. Further, a phase I/II clinical trial evaluating this combination regimen in aggressive c-Myc driven lymphomas is being planned. Disclosures Deng: TG Therapeutics: Research Funding; Gilead: Research Funding; Amgen/Onyx: Research Funding. Lentzsch:Celgene: Consultancy; BMS: Consultancy; Novartis: Consultancy; Janssen: Consultancy; Axiom: Honoraria. O'Connor:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Mundipharma: Consultancy, Research Funding; Acetylon: Consultancy, Other: Consultancy fee; Spectrum Pharmaceuticals: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb Company: Consultancy, Other: Consultancy fee; Takeda Millenium: Consultancy, Honoraria, Other: Consultancy fee, Research Funding; Novartis: Consultancy, Honoraria, Other: Consultancy fee; Seattle Genetics: Research Funding; Bayer: Consultancy, Honoraria.
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Chen, Lei, Sheema Matloob, Yang Sunlei, Sikandar Ali Qalati, Ali Raza, and Mónica Lorena Sánchez Limón. "A Moderated–Mediated Model for Eco-Conscious Consumer Behavior." Sustainability 15, no. 2 (January 4, 2023): 897. http://dx.doi.org/10.3390/su15020897.
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Using the Attitude‒Behavior‒Context theory, this research aims to investigate the impact of green marketing (GM) and green customer value (GCV) on eco-conscious consumer behavior (ECB) toward the consumption of green products. This study involved a survey technique that comprised 700 consumers through a self-administered questionnaire disseminated through enumerators in two metropolitan cities of Pakistan (namely, Lahore and Karachi), of which 349 were usable for the data analysis process. The hypothesized relationships were validated using partial least squares structural equation modeling through SmartPLS 4.0. The empirical findings showed a positive impact of GM and GCV on brand awareness (BA), environmental concern (EC), and ECB. The findings also revealed the partial mediating effect of BA and EC on the relationship between GM, GCV, and ECB. In addition, this study observed the moderating impact of felt obligation (FO) on the relationship between BA and ECB. The findings show that ECB is essential for a sustainable environment. This study’s results may guide managers and marketers in developing suitable GM strategies.
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Ilhan, Nevin, Solmaz Susam, Tuba Parlak Ak, and Burcu Gul Baykalir. "The antiiflammatory effect of Ginkgo biloba in lipopolysaccharide-induced rat sepsis model." LaboratoriumsMedizin 42, no. 1-2 (April 25, 2018): 45–49. http://dx.doi.org/10.1515/labmed-2017-0113.
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AbstractBackground:Sepsis is characterized dysregulated inflammatory response and is the leading cause of organ failure or injury and death in critical care units.Ginkgo bilobaextract 761 (EGb 761) is characterized by antioxidant activity. There is no clear data in the functional role of EGb 761 that inhibiting of proinflammatory cytokines exist in sepsis. The purpose of this study was to investigate the antiinflammatory effect of EGb 761 on the levels of vascular endothelial growth factor (VEGF), matrix metalloproteinase-9 (MMP-9) and inducible nitric oxide synthase (iNOS) in lipopolysaccharide (LPS) induced rat sepsis model.Methods:The animals were randomly divided into the following six groups: the control, LPS, flunixin meglumine (FM), EGb 761, LPS+FM and LPS+EGb 761 groups. Enzyme-linked immunosorbent assay (ELISA) analysis was applied to measure serum levels of VEGF, MMP-9, and iNOS.Results:Serum iNOs (p<0.05), VEGF (p<0.01) and MMP-9 (p<0.05) levels were significantly higher in the sepsis group. Treatment with EGb 761 decreased serum iNOs levels (p<0.01), VEGF and MMP-9 levels decreased significantly (p<0.05). Also, treatment with FM decreased iNOs (p<0.01), VEGF and MMP-9 levels significantly (p<0.05).Conclusions:It is suggested that sepsis may lead to increase serum iNOs, MMP-9, and VEGF levels and treatment of EGb 761 may have a potential antiinflammatory effect against LPS-induced sepsis.
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Zhang, Zhijie, Wen Qiu, Chang Liu, Muhan Wang, Yinghua Miao, Qingchao Ji, Rongchen Sun, Hongping Yin, and Meijia Yang. "Abstract 5572: T cell receptor modified with EDB-targeting ScFv and CD28 intracellular domain led to complete tumor regression in xenograft model." Cancer Research 82, no. 12_Supplement (June 15, 2022): 5572. http://dx.doi.org/10.1158/1538-7445.am2022-5572.
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Abstract We explored use of chimeric antigen receptor T cell (CAR-T) for treatment of solid tumors, aiming at efficient killing of tumor cells while minimizing on-target off-tumor toxicities. We designed CAR targeting the extra domain B (EDB)-containing fibronectin, which is an oncofetal antigen widely expressed in tumor stroma and on the surface of cancer cells. Unlike membrane-spanning antigens, EDB-containing fibronectin is embedded in the extracellular matrix, and is enriched in new vasculatures and stromal tissues of tumor tissues. First, we made a second-generation EDB CAR (2G-EDB CAR) that killed EDB+ cells (U87MG, A549, and HUVEC) and showed tumor suppression in a U87MG xenograft tumor model. However, while in vitro the 2G-EDB CAR T cells were sufficiently cytotoxic, the in vivo inhibition of the tumor growth was moderate. Next we designed an EDB CAR that contained CD3ε to create 3ε-EDB CAR. We show that the 3ε-EDB CAR was incorporated into the T cell receptor (TCR) structure. The 3ε-EDB CAR completely displaced the native CD3ε in the TCR based on immune precipitation and Western analysis. The 3ε-EDB CAR was capable of inducing T cell activation and proliferation in the presence of EDB-fibronectin antigen. Further, the 3ε-EDB CAR T cells killed tumor cells containing EDB-fibronectin. In vivo, the 3ε-EDB CAR T cells demonstrated improved inhibition when compared to the 2G-EDB CAR T cells. To further enhance the EDB-targeting CAR, we added intracellular domain of CD28 to the 3ε-EDB CAR to create 3ε28-EDB CAR, and showed the 3ε28-EDB CAR was still incorporated into the TCR complex. The 3ε28-EDB CAR co-opted TCR complex and provided co-stimulatory signal upon binding of EDB antigens. Upon transduction of the 3ε28-EDB CAR into primary T cells, we observed upregulation of T cell activation markers CD25, CD69 and granzyme B in presence of the EDB antigen. We show that 3ε28-EDB CAR triggered the phosphorylation of CD3ζ, suggesting that EDB antigen stimulated co-opted TCR and signaled through the TCR-CD3 complex. T cells transduced with 3ε28-EDB CAR demonstrated stronger proliferation when activated by U87MG cells compared to 2G or 3ε-EDB CARs. Furthermore, 3ε28-EDB CAR T cells inhibited in vivo tumor growth in a dose-dependent manner, and most of the treated mice had no evidence of residual tumors. In conclusion, our results suggest that 3ε28-EDB CAR has great potential for treatment of solid tumors. Citation Format: Zhijie Zhang, Wen Qiu, Chang Liu, Muhan Wang, Yinghua Miao, Qingchao Ji, Rongchen Sun, Hongping Yin, Meijia Yang. T cell receptor modified with EDB-targeting ScFv and CD28 intracellular domain led to complete tumor regression in xenograft model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5572.