ABSTRACT
BACKGROUND: After initially responding to empiric radio-chemotherapy, most advanced thymomas (TH) and thymic carcinomas (TC) become refractory and require second-line therapy. The multi-target receptor tyrosine kinase (RTK) inhibitor, sunitinib, is one of the few options, especially in patients with thymic carcinomas, and has resulted in partial remissions and prolonged overall survival. However, sunitinib shows variable activity in thymomas, and not all patients benefit equally. A better understanding of its mode of action and the definition of predictive biomarkers would help select patients who profit most. METHODS: Six cell lines were treated with sunitinib in vitro. Cell viability was measured by MTS assay and used to define in vitro responders and non-responders. A quantitative real-time assay simultaneously measuring the phosphorylation of 144 tyrosine kinase substrates was used to correlate cell viability with alterations of the phospho-kinome, calculate a sunitinib response index (SRI), and impute upstream tyrosine kinases. Sunitinib was added to protein lysates of 29 malignant TH and TC. Lysates were analyzed with the same phosphorylation assay. The SRI tentatively classified cases into potential clinical responders and non-responders. In addition, the activation patterns of 44 RTKs were studied by phospho-RTK arrays in 37 TH and TC. RESULTS: SRI application separated thymic epithelial tumors (TET) in potential sunitinib responders and resistant cases. Upstream kinase prediction identified multiple RTKs potentially involved in sunitinib response, many of which were subsequently shown to be differentially overexpressed in TH and TC. Among these, TYRO3/Dtk stood out since it was exclusively present in metastatic TH. The function of TYRO3 as a mediator of sunitinib resistance was experimentally validated in vitro. CONCLUSIONS: Using indirect and direct phosphoproteomic analyses to predict sunitinib response in malignant TET, we have shown that TH and TC express multiple important sunitinib target RTKs. Among these, TYRO3 was identified as a potent mediator of sunitinib resistance activity, specifically in metastatic TH. TYRO3 may thus be both a novel biomarker of sunitinib resistance and a potential therapeutic target in advanced thymomas and thymic carcinomas.
ABSTRACT
Covid-19 has profoundly impacted social work and has exposed the existing inequities in the health care system in the United States. Social workers play a critical role in the pandemic response for historically marginalized communities and for those who find themselves needing support for the first time. Innovative approaches to care management, including the Center for Health and Social Care Integration (CHaSCI) Bridge Model of transitional care provides a foundation from which social workers can rise to meet these new challenges.
Subject(s)
COVID-19/epidemiology , Delivery of Health Care/organization & administration , Multiple Chronic Conditions/epidemiology , Patient Care Management/organization & administration , Social Work/organization & administration , Aged , Aged, 80 and over , Humans , Interinstitutional Relations , Mental Health Services/organization & administration , Pandemics , Patient-Centered Care/organization & administration , SARS-CoV-2 , Self-Management , Telemedicine/organization & administration , United States/epidemiologyABSTRACT
The hospital experience is taxing and confusing for patients and their families, particularly those with limited economic and social resources. This complexity often leads to disengagement, poor adherence to the plan of care, and high readmission rates. Novel approaches to addressing the complexities of transitional care are emerging as possible solutions. The Bridge Model is a person-centered, social work-led, interdisciplinary transitional care intervention that helps older adults safely transition from the hospital back to their homes and communities. The Bridge Model combines 3 key components-care coordination, case management, and patient engagement-which provide a seamless transition during this stressful time and improve the overall quality of transitional care for older adults, including reducing hospital readmissions. The post Affordable Care Act (ACA) and managed care environment's emphasis on value and quality support further development and expansion of transitional care strategies, such as the Bridge Model, which offer promising avenues to fulfil the triple aim by improving the quality of individual patient care while also impacting population health and controlling per capita costs.
