Biology subjects

Weston, C.

Publications and source records attributed to Weston, C..

4 recordsLinked to original sources

bioRxiv2026

mSWI/SNF complex inhibition sensitizes KRAS-mutant lung cancers to targeted therapies via epithelial-mesenchymal subversion

Targeted therapies for KRAS-mutant non-small lung cancer (NSCLC) have shown promising clinical results, however, incomplete tumoral responses and the inevitable emergence of therapeutic resistance remain critical challenges. Here we identify mSWI/SNF chromatin remodeling complexes as critical determinants of (EMT)-mediated KRAS inhibitor inefficacy and resistance in KRAS G12C lung cancers. Treatment with the clinical-grade SMARCA4/2 inhibitor, FHD-286, dampens EMT-mediated acquired resistance in drug-responsive models and similarly resensitizes drug-refractory models by rewiring mSWI/SNF chromatin localization and activities that modulate epithelial transcriptional programs and cell state. Further, synergistic mSWI/SNF and KRAS inhibitor combination treatment sensitizes non-G12C KRAS-mutant NSCLC cells to pan-RAS and G12D-specific inhibitors. Finally, FHD-286 and sotorasib combination treatment results in potent anti-tumor efficacy in both G12Ci-resistant and - sensitive organoid models and in vivo patient-derived xenograft (PDX) systems. These data nominate mSWI/SNF inhibition as a combination strategy to improve KRAS inhibitor efficacy, response duration, and to mitigate emergence of resistance.

cancer biology↗

bioRxiv2024

Whole Genome 3D Blood Biopsy Profiling of Canine Cancers: Development and Validation of EpiSwitch Multi-Choice Array-Based Diagnostic Test.

Veterinary oncology has a critical need for an accurate, specific, and sensitive non-invasive (blood) biomarker assay to assess multiple canine oncological indications early to better inform therapeutic interventions. Extended from clinical applications in human oncology, here we report on a novel 3D genomics approach to identify systemic blood biomarkers for canine diffuse large B-cell lymphoma (DLBCL), T-zone lymphoma (TZL), hemangiosarcoma (HSA), histiocytic sarcoma, osteosarcoma, and canine malignant melanoma, in a single assay format that encompasses multiple classes and phenotypes of cancer. In the validation of the independent test cohort the 3D whole-genome profiling in peripheral blood demonstrated high sensitivity and specificity for lymphomas and sarcomas as a class, with accuracy >80%; and high sensitivity and specificity for individual indications, with accuracy >89%. This study demonstrates a 3D genomic approach can be used to develop a non-invasive, blood-based test for multiple choice diagnosis of canine oncological indications. The modular EpiSwitch(R) Specific Canine Blood (EpiSwitch SCB) test promises to help veterinary specialists to diagnose the disease, make more informed treatment decisions, better utilize alternative effective treatments, minimize or avoid unnecessarily toxicity, and efficiently manage costs and resources.

molecular biology↗

bioRxiv2018

Factors Affecting Electroconvulsive Therapy Ictal Outcomes: Duration and Postictal Suppression

Electroconvulsive therapy (ECT) is an effective and rapid treatment for severe depression, however predictors of therapeutic outcomes remain insufficiently understood. Ictal duration and postictal suppression are two outcomes that may be correlated with patient response, yet patient and treatment variables which may influence these outcomes have not been thoroughly explored. We collected ECT stimulus metrics, EEG parameters, patient demographics, primary diagnosis, and anesthesia type for retrospective ECTs. Univariate and multivariate mixed-effects linear regression models were used to identify variables associated with ictal duration and postictal suppression index. For both outcomes, multivariate models which included all variables resulted in the best fit, reflecting the complex influences of a variety of factors on the ictal response. These results are an important step forward in elucidating patterns in retrospective ECT clinical data which may lead to new clinical knowledge of modifiable factors to optimize ECT treatment outcomes.

neuroscience↗

bioRxiv2017

Depression Linked to Frequent Emergency Department Use in Large 10-year Retrospective Analysis of an Integrated Health Care System

We evaluated general patient features related to depression and frequency of Emergency Department (ED) use in a large integrated health care system. Electronic Health Records of 287,281 adults from a general patient population were studied retrospectively over a 10-year period. Patients with a history of depression were more likely to be seen in the ED and at higher frequency than those without. Frequent ED users were more likely to have a history of depression or psychiatric medication orders than infrequent users. ED visits by depression patients and frequent users have highly correlated complaints and discharge diagnoses with other ED users, often related to pain. Poorly managed depression may be playing a role in frequent ED utilization which may be addressed by universal screening for depression, evaluation of barriers to treatment, and other novel interventions to improve care coordination.

epidemiology↗