In the last years, several studies have empirically demonstrated the presence of a specific pattern of therapist responses that are related to different patient personality disorders. Other works showed how the effects of the therapist's technique depend on the emotional context in which they are delivered and in particular countertransference experiences. Moreover, researchers suggest that the therapist's emotional responses occur across all kinds of therapy and are independent of the therapist's theoretical preferences.
Purpose: Approximately 20% of patients with RAS wild-type metastatic colorectal cancer (mCRC) experience objective responses to the anti-EGFR antibody cetuximab, but disease eradication is seldom achieved. The extent of tumor shrinkage correlates with long-term outcome. We aimed to find rational combinations that potentiate cetuximab efficacy by disrupting adaptive dependencies on anti-apoptotic molecules (BCL2, BCL-XL, MCL1). Experimental Design: Experiments were conducted in patient-derived xenografts (PDXs) and organoids (PDXOs). Apoptotic priming was analyzed by BH3 profiling. Pro- and anti-apoptotic protein complexes were evaluated by co-immunoprecipitation and electroluminescence sandwich assays. The effect of combination therapies was assessed by caspase activation in PDXOs and by monitoring PDX growth. Results: A population trial in 314 PDX cohorts, established from as many patients, identified 46 models (14.6%) with appreciable (>50% tumor shrinkage) but incomplete response to cetuximab. From these models, 14 PDXOs were derived. Cetuximab primed cells for apoptosis, but only concomitant blockade of BCL-XL precipitated cell death. Mechanistically, exposure to cetuximab induced upregulation of the pro-apoptotic protein BIM and its sequestration by BCL-XL. Inhibition of BCL-XL resulted in displacement of BIM, which was not buffered by MCL1 and thereby became competent to induce apoptosis. In 5 PDX models, combination of cetuximab and a selective BCL-XL inhibitor triggered apoptosis and led to more pronounced tumor regressions and longer time to relapse after treatment discontinuation than cetuximab alone. Conclusions: In mCRC tumors that respond to cetuximab, antibody treatment confers a synthetic-lethal dependency on BCL-XL. Targeting this dependency unleashes apoptosis and increases the depth of response to cetuximab.
Motivation The transition from evaluating a single time point to examining the entire dynamic evolution of a system is possible only in the presence of the proper framework. The strong variability of dynamic evolution makes the definition of an explanatory procedure for data fitting and clustering challenging. Results We developed CONNECTOR, a data-driven framework able to analyze and inspect longitudinal data in a straightforward and revealing way. When used to analyze tumor growth kinetics over time in 1599 patient-derived xenograft growth curves from ovarian and colorectal cancers, CONNECTOR allowed the aggregation of time-series data through an unsupervised approach in informative clusters. We give a new perspective of mechanism interpretation, specifically, we define novel model aggregations and we identify unanticipated molecular associations with response to clinically approved therapies. Availability CONNECTOR is freely available under GNU GPL license at https://qbioturin.github.io/connector and dx.doi.org/10.17504/protocols.io.8epv56e74g1b/v1. Supplementary information Supplementary data are available at Bioinformatics online.
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