The amount of patients receiving either medication with or without systemic corticosteroids (dexamethasone) was determined and lymphocyte counts before and under therapy assessed. Additionally, the number and severity of infections occurring in these groups was analyzed. Vemurafenib treatment led to a considerable decrease in lymphocyte cell counts, with 62.3% of patients having lymphopenia. Dabrafenib treated patients only rarely demonstrated lymphopenia (12.5%). Lymphopenias were observed in 84.6% of patients receiving vemurafenib and dexamethasone.ĭexamethasone co-administration further diminished lymphocyte counts. In our cohort, infections were noted in 9 patients, 4 of these were severe and 2 eventually fatal. All 9 cases with infections demonstrated lymphopenia, 8 of these had received dexamethasone and 7 of these a therapy with vemurafenib. Our findings demonstrate a significant lymphopenia in patients treated with the BRAF inhibitor vemurafenib, which is further augmented by dexamethasone and predisposes to infection. Targeting Autophagy Sensitizes BRAF-Mutant Thyroid Cancer to Vemurafenib If validated in other studies, risk of infection should be considered when applying corticosteroids in combination with BRAF inhibitors, in particular vemurafenib. Wang, Weibin Kang, Helen Zhao, Yinu Min, Irene Wyrwas, Brian Moore, Maureen Teng, Lisong Zarnegar, Rasa Jiang, XuejunĬontext: The RAF inhibitor vemurafenib has provided a major advance for the treatment of patients with BRAF-mutant metastatic melanoma. Anticancer therapy–induced autophagy can trigger adaptive drug resistance in a variety of cancer types and treatments. To date, role of autophagy during BRAF inhibition in thyroid cancer remains unknown. Objective: In this study, we investigate if autophagy is activated in vemurafenib-treated BRAF-mutant thyroid cancer cells, and whether autophagy inhibition improves or impairs the treatment efficacy of vemurafenib. Design: Autophagy level was determined by western blot assay and transmission electron microscopy. The combined effects of autophagy inhibitor and vemurafenib were assessed in terms of cell viability in vitro and tumor growth rate in vivo. Whether the endoplasmic reticulum (ER) stress was in response to vemurafenib-induced autophagy was also analyzed. Results: Vemurafenib induced a high level of autophagy in BRAF-mutant thyroid cancer cells. Inhibition of autophagy by either a pharmacological inhibitor or interfering RNA knockdown of essential autophagy genes augmented vemurafenib-induced cell death. Vemurafenib-induced autophagy was independent of MAPK signaling pathway and was mediated through the ER stress response. Finally, administration of vemurafenib with the autophagy inhibitor hydroxychloroquine promoted more pronounced tumor suppression in vivo. Conclusions: Our data demonstrate that vemurafenib induces ER stress response–mediated autophagy in thyroid cancer and autophagy inhibition may be a beneficial strategy to sensitize BRAF-mutant thyroid cancer to vemurafenib. Wang, Weibin Kang, Helen Zhao, Yinu Min, Irene Wyrwas, Brian Moore, Maureen Teng, Lisong Zarnegar, Rasa Jiang, Xuejun Fahey, Thomas J Targeting Autophagy Sensitizes BRAF-Mutant Thyroid Cancer to Vemurafenib. The RAF inhibitor vemurafenib has provided a major advance for the treatment of patients with BRAF-mutant metastatic melanoma. However, BRAF-mutant thyroid cancer is relatively resistant to vemurafenib, and the reason for this disparity remains unclear. In an apparent suicide, the photographer was found dead with a plastic bag over his head on Novemin Paris, France.Anticancer therapy-induced autophagy can trigger adaptive drug resistance in a variety of cancer types and treatments. In 2016, the photographer was accused of rape by four separate women who had served as former models. Similar to the work of Jock Sturges and Sally Mann, Hamilton’s erotic subject matter caused complaints of indecency over the decades. He published numerous photobooks during his life, The Age of Innocence (1995) being one of his most popular. In 1979, his film Laura was released in France-the movie blends melodrama with soft-core pornography, as wells as Hamilton’s hallmark soft focus. Born on Apin London, United Kingdom, the artist initially found work as an art director, then a commercial photographer in the 1950s and 60s in France. Using a photographic technique akin to painting, he has acknowledged the influence of Lucas Cranach on his style. Often controversial, the images evoke an effect of dreaminess through soft focus and varied grain. David Hamilton was a British photographer and film director known for his nude photographs of adolescent girls.
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