The Asher-McDade scale has been used to evaluate cleft lift repairs but is limited due to its subjective nature. The basal view scale grades these repairs by using a scale of progressive columellar shortening and alar flaring/slumping, which provides an opportunity for quantification and standardization. Our results show that the basal view correlates with the Asher-McDade scale among raters, thus providing an objective and validated measure of cleft lip repair.
Cancer cells undergo phenotypic cell state transitions in response to chemotherapy as a mechanism that can confer transient resistance. However, such cell state transitions can also unlock unique vulnerabilities that can be exploited using temporally-sequenced combination chemotherapy. Here, utilizing a primary breast cancer ex-vivo functional assay that captures tumor heterogeneity, we report that in response to a chemotherapeutic agent, a subset of cancer cells can mount an acutely-induced phenotypic adaptive resistance to future cytotoxic pressure via the transient acquisition of a unique metabolic state defined by augmented glycolysis together with mitochondrial proficiency. These cells activate two complex, temporally-interdependent pathways that enable a glucose shunt towards the pentose phosphate pathway (PPP), which confers an adaptive cross-tolerance to different chemotherapeutic agents. Mathematically modeling these pathways, and simulating drug schedules, we define a rationally-designed 3-drug combination therapy of metabolic inhibitors and cytotoxic agents, which results in improved cancer survival. Our findings highlight a new bioenergetics-based adaptive resistance mechanism through which cancer cells can survive combinations of chemotherapy. Administration of metabolic inhibitors in rational, temporal sequence with existing chemotherapy can emerge as a new paradigm in the treatment of cancer.
Citation Format: Goldman A, Majumder B, Dhawan A, Kohandel M, Majumder P, Sengupta S. An ex-vivo platform predicts anti-tumor outcome of metabolically-targeted, algorithm-driven combination therapy in triple-negative breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P3-03-18.
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