A New Bliss Independence Model to Analyze Drug Combination Data

Zhao, Wei; Sachsenmeier, Kris F.; Zhang, Lanju; Sult, Erin; Hollingsworth, Robert E.; Yang, Harry

doi:10.1177/1087057114521867

Cited by 216 publications

(231 citation statements)

References 12 publications

(16 reference statements)

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“…Using assessments for Bliss independence, we determined that the bile acids function synergistically, with the activity of the combined acids being greater than the additive activity of the individual acids (see Text S1 in the supplemental material) (44,45). To evaluate the mechanism by which cholate and deoxycholate function synergistically, we reexamined the effect of bile acid solubility.…”

Section: Resultsmentioning

confidence: 99%

Bile Acids Function Synergistically To Repress Invasion Gene Expression in Salmonella by Destabilizing the Invasion Regulator HilD

et al. 2016

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bSalmonella spp. are carried by and can acutely infect agricultural animals and humans. After ingestion, salmonellae traverse the upper digestive tract and initiate tissue invasion of the distal ileum, a virulence process carried out by the type III secretion system encoded within Salmonella pathogenicity island 1 (SPI-1). Salmonellae coordinate SPI-1 expression with anatomical location via environmental cues, one of which is bile, a complex digestive fluid that causes potent repression of SPI-1 genes. The individual components of bile responsible for SPI-1 repression have not been previously characterized, nor have the bacterial signaling processes that modulate their effects been determined. Here, we characterize the mechanism by which bile represses SPI-1 expression. Individual bile acids exhibit repressive activity on SPI-1-regulated genes that requires neither passive diffusion nor OmpF-mediated entry. By using genetic methods, the effects of bile and bile acids were shown to require the invasion gene transcriptional activator hilD and to function independently of known upstream signaling pathways. Protein analysis techniques showed that SPI-1 repression by bile acids is mediated by posttranslational destabilization of HilD. Finally, we found that bile acids function synergistically to achieve the overall repressive activity of bile. These studies demonstrate a common mechanism by which diverse environmental cues (e.g., certain short-chain fatty acids and bile acids) inhibit SPI-1 expression. These data provide information relevant to Salmonella pathogenesis during acute infection in the intestine and during chronic infection of the gallbladder and inform the basis for development of therapeutics to inhibit invasion as a means of repressing Salmonella pathogenicity.

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Section: Resultsmentioning

confidence: 99%

Bile Acids Function Synergistically To Repress Invasion Gene Expression in Salmonella by Destabilizing the Invasion Regulator HilD

et al. 2016

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“…Some authors [18] pointed out that in some cases the identification procedure can rapidly become expensive as well as experimentally and computationally highly demanding, and makes the analysis of drug combination prohibitive. Hence, the Loewe additivity model becomes unusable when a doseeffect curve is not available or difficult to model [33]. This is the most common restriction for every unknown system.…”

Section: Practical Limitationsmentioning

confidence: 99%

Application of a Microfluidic Chip with Mechanical Stimuli for Culturing Mouse Embryos in vitro

Li¹,

Li²,

Wei³

et al. 2018

Int J Bioautomation

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“…Briefly, this method compares the observed response of the combination with the predicted response, which was obtained using the assumption that there is no effect from drug-drug interactions (26). Typically, the combination effect is declared synergistic if the observed response is greater than predicted response.…”

Section: Combination Analysesmentioning

confidence: 99%

Significant Therapeutic Efficacy with Combined Radioimmunotherapy and Cetuximab in Preclinical Models of Colorectal Cancer

et al. 2015

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Despite extensive efforts to improve the clinical management of patients with colorectal cancer, approved treatments for advanced disease offer limited survival benefit. Therefore, the identification of novel treatment strategies is essential. We evaluated the preclinical efficacy of combination radioimmunotherapy, using a humanized 131 Ilabeled anti-carcinoembryonic antigen antibody ( 131 I-huA5B7), with cetuximab in colorectal cancer (CRC). Methods: Three human CRC cell lines-SW1222, LoVo, and LS174T-were used to generate subcutaneous xenografts, and stably luciferase-transfected SW1222 cells were used to establish a model of hepatic metastases in immunocompromised mice. Imaging and biodistribution studies were conducted to confirm the selective tumor localization of 131 I-huA5B7. Efficacy was evaluated on the basis of tumor growth delay and survival, along with markers of DNA damage response, cell cycle, proliferation, and apoptosis. Results: Selective tumor targeting was achieved with 131 IhuA5B7 alone or in combination with cetuximab without observable toxicity. Compared with monotherapy, combining cetuximab with radioimmunotherapy significantly and synergistically reduced tumor growth and prolonged survival of mice in 2 of the subcutaneous and in the metastatic tumor model. Evidence of DNA damage, G2/M arrest, significantly decreased proliferation, and increased apoptosis were observed with radioimmunotherapy and the combination therapy. However, a significant decrease in DNA-protein kinase expression with the combination regimen suggests that the addition of cetuximab suppressed DNA repair. Conclusion: Our results demonstrate enhanced therapeutic efficacy with the combination of cetuximab and radioimmunotherapy in CRC, which could potentially translate into successful clinical outcomes. This strategy could improve the treatment of residual disease postoperatively and ultimately prevent or delay recurrence. Furthermore, other carcinoembryonic antigen-expressing malignancies could also benefit from this approach.

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A New Bliss Independence Model to Analyze Drug Combination Data

Cited by 216 publications

References 12 publications

Bile Acids Function Synergistically To Repress Invasion Gene Expression in Salmonella by Destabilizing the Invasion Regulator HilD

Bile Acids Function Synergistically To Repress Invasion Gene Expression in Salmonella by Destabilizing the Invasion Regulator HilD

Application of a Microfluidic Chip with Mechanical Stimuli for Culturing Mouse Embryos in vitro

Significant Therapeutic Efficacy with Combined Radioimmunotherapy and Cetuximab in Preclinical Models of Colorectal Cancer

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