Objective. Patients with type 2 diabetes are encouraged to lose weight, but excessive weight loss in older adults may be a marker of poor health and subsequent mortality. We examined weight changes during the post-intervention period of Look AHEAD, a randomized trial comparing intensive lifestyle intervention (ILI) and diabetes support and education (DSE; control) in individuals with overweight/obesity and type 2 diabetes and sought to identify predictors of excessive post-intervention weight loss and its association with mortality. <p>Research Design and Methods. These secondary analyses compared post-intervention weight change (year-8 to final visit [median 16 years]) in ILI and DSE in 3999 Look AHEAD participants. Using empirically derived trajectory categories, we compared four subgroups: Weight Gainers (N= 307), Weight Stable (N=1561), Steady Losers (N=1731) and Steep Losers (N=380) on post-intervention mortality, demographic variables and health status at randomization and year-8.</p> <p>Results. Post-intervention weight change averaged -3.7 ±9.5%, with greater weight loss in DSE than ILI. The steep weight loss trajectory subgroup lost on average 17.7 + 6.6%.; 30% of Steep Losers died during post-intervention follow-up vs 10-18% in other trajectories (p<. 0001). The following variables distinguished Steep Losers from Weight Stable: <i>Baseline </i>- older; longer diabetes duration; higher BMI; greater multimorbidity; <i>Intervention </i>– randomization to control group; less weight loss in years 1-8; <i>Year 8 </i>- higher prevalence of frailty, multimorbidity and depressive symptoms; lower use of weight control strategies. </p> <p>Conclusion. Steep weight losses post-intervention were associated with increased risk of mortality. Older individuals with longer duration diabetes and multi-morbidity should be monitored for excessive, unintentional weight loss. </p>

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Background: Anaplastic thyroid cancer (ATC) is a rare cancer with poor prognosis and few treatment options. The objective of this study was to investigate new immune-associated therapeutic targets by identifying ATCderived, human leukocyte antigen (HLA) class II-presenting peptides. One protein that generated multiple peptides in ATC was chondroitin sulfate-proteoglycan-4 (CSPG4), a transmembrane proteoglycan with increased expression in multiple aggressive cancers, but not yet investigated in ATC. Methods: We applied autologous peripheral blood T cells to ATC patient-derived xenografted mice to examine whether ATC induces a tumor-specific T cell response. We then identified peptide antigens eluted from the HLA-DQ complex in ATC patient-derived cells using mass spectrometry, detecting abundant CSPG4-derived peptides specific to the ATC sample. Next, we analyzed the surface expression level of CSPG4 in thyroid cancer cell lines and primary cell culture using flow cytometry. In addition, we used immunohistochemistry to compare the expression level and localization of the CSPG4 protein in ATC, papillary thyroid cancer, and normal thyroid tissue. We then investigated the correlation between CSPG4 expression and clinicopathological features of patients with thyroid cancer. Results: We found that ATC tissue had a high level of HLA-DQ expression and that the patient's CD4 + T cells showed activation when exposed to ATC. By eluting the HLA-DQ complex of ATC tissue, we found that CSPG4 generated one of the most abundant and specific peptides. CSPG4 expression at the cell surface of thyroid cancer was also significantly high when determined by flow cytometry, with the majority of ATC cell lines exhibiting *10-fold higher mean fluorescence intensity. Furthermore, most ATC patient cases expressed CSPG4 in the cytoplasm or membrane of the tumor cells. CSPG4 expression was correlated with tumor size, extrathyroidal extension, and intercellular adhesion molecule-1 (ICAM-1) circumferential expression. CSPG4 mRNA overexpression was associated with worse overall survival in patients with ATC and poorly differentiated thyroid cancer. Conclusions: CSPG4 expression is significantly elevated in aggressive thyroid cancers, with a strong correlation with a poor prognosis. The vast number of HLA-DQ eluted CSPG4 peptides was identified in ATC, demonstrating the potential of CSPG4 as a novel immunotherapeutic target for ATC.

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A subset of thyroid cancers, recurrent differentiated thyroid cancers and anaplastic thyroid cancer (ATC), are difficult to treat by thyroidectomy and systemic therapy. A common mutation in thyroid cancer, BRAFV600E, has targetable treatment options; however, the results have been disappointing in thyroid cancers compared with BRAFV600E melanoma, as thyroid cancers quickly become resistant to BRAFV600E inhibitor (BRAFi). Here, we studied the molecular pathway that is induced in BRAFV600E thyroid cancer cells and patient-derived tumor samples in response to BRAFi, vemurafenib, using RNA-sequencing and molecular analysis. Both inducible response to BRAFi and acquired BRAFi resistance in BRAFV600E thyroid cancer cells showed significant activation of the JAK/STAT pathway. Functional analyses revealed that the combination of BRAFi and inhibitors of JAK/STAT pathway controlled BRAFV600E thyroid cancer cell growth. The Cancer Genome Atlas data analysis demonstrated that potent activation of the JAK/STAT signaling was associated with shorter recurrence rate in patients with differentiated thyroid cancer. Analysis of tumor RNA expression in patients with poorly differentiated thyroid cancer and ATC also support that enhanced activity of JAK/STAT signaling pathway is correlated with worse prognosis. Our study demonstrates that JAK/STAT pathway is activated as BRAFV600E thyroid cancer cells develop resistance to BRAFi and that this pathway is a potential target for anticancer activity and to overcome drug resistance that commonly develops to treatment with BRAFi in thyroid cancer. Implications: Dual inhibition of BRAF and JAK/STAT signaling pathway is a potential therapeutic treatment for anticancer activity and to overcome drug resistance to BRAFi in thyroid cancer.

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