Kasia bodurka biography examples
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Abstract
Maintaining the body in a physiologically optimal state is a primary function of the mammalian nervous system. The neurovisceral architecture accomplishing such feats depends on the hierarchical central processing of peripheral internal body signals and operates hierarchically and across heterogenous time scales (Smith et al. 2017), automatically returning the internal state to a setpoint (i.e., homeostasis) (Cannon 1939) or shifting the internal state away from a setpoint in anticipation of future deviations (i.e. allostasis) (Sterling 2012). Importantly, these regulatory operations may depend on the unconscious as well as conscious monitoring of interoceptive states. Interoceptive sensations may even dominate awareness during significant physiological disturbances, motivating behaviors that restore bodily states to homeostatic equilibrium (Khalsa and Lapidus 2016) and forming the basis for emotional experience and numerous cognitive processes (Adolfi et al. 2017; Carvalho and Damasio 2021; Critchley and Garfinkel 2017; Uddin et al. 2014). In turn, dysfunctional interoception has been implicated in the pathophysiology of psychiatric (Bonaz et al. 2021; Khalsa et al. 2018) and neurological disorders (Birba et al. 2022; Drane et al. 2020), underscoring the importance
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Published in final edited form as: Clin Cancer Res. 2020 Nov 18;27(7):2011–2022. doi: 10.1158/1078-0432.CCR-20-3316
Abstract
Purpose:
Cisplatin-based chemotherapy is a first-line treatment for muscle-invasive and metastatic urothelial cancer. Approximately 10% of bladder urothelial tumors have a somatic missense mutation in the nucleotide excision repair (NER) gene, ERCC2, which confers increased sensitivity to cisplatin-based chemotherapy. However, a significant subset of patients is ineligible to receive cisplatin-based therapy due to medical contraindications, and no NER-targeted approaches are available for platinum-ineligible or platinum-refractory ERCC2-mutant cases.
Experimental Design:
We used a series of NER-proficient and NER-deficient preclinical tumor models to test sensitivity to irofulven, an abandoned anticancer agent. In addition, we used available clinical and sequencing data from multiple urothelial tumor cohorts to develop and validate a composite mutational signature of ERCC2 deficiency and cisplatin sensitivity.
Results:
We identified a novel synthetic lethal relationship between tumor NER deficiency and sensitivity to irofulven. Irofulven specifically targets cells with inactivation of the