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BRAF mutations are frequently observed in melanoma and hairy‐cell leukemia. Currently approved rapidly accelerated fibrosarcoma (RAF) kinase inhibitors targeting oncogenic BRAF V600 mutations have shown remarkable efficacy in the clinic, but their therapeutic benefits are occasionally hampered by acquired resistance due to RAF dimerization–dependent reactivation of the downstream MAPK pathway, which is known as paradoxical activation. There is also a concern that paradoxical activation of the MAPK pathway may trigger secondary cancer progression. In this study, we developed chimeric compounds, proteolysis targeting chimeras (PROTACs), that target BRAFV600E protein for degradation. CRBN(BRAF)‐24, the most effective chimera, potently degraded BRAFV600E in a ubiquitin‐proteasome system (UPS)‐dependent manner and inhibited the proliferation of BRAFV600E‐driven cancer cells. In BRAF wild‐type cells, CRBN(BRAF)‐24 induced neither BRAFWT degradation nor paradoxical activation of the MAPK pathway. Biochemical analysis revealed that CRBN(BRAF)‐24 showed more potent and sustained suppression of MAPK signaling than a BRAFV600E inhibitor, PLX‐8394, in BRAFV600E‐driven cancer cells. Targeted degradation of BRAFV600E by CRBN(BRAF)‐24 could be a promising strategy to evade paradoxical activation of the RAF‐MAPK pathway. [ABSTRACT FROM AUTHOR]

We propose a method to print four-dimensional (4D) stimuli-responsive hydrogel structures with internal gaps. Our 4D structures are fabricated by printing an N-isopropylacrylamide-based stimuli-responsive pre-gel solution (NIPAM-based ink) and an acrylamide-based non-responsive pre-gel solution (AAM-based ink) in a supporting viscous liquid (carboxymethyl cellulose solution) and by polymerizing the printed structures using ultraviolet (UV) light irradiation. First, the printed ink position and width were investigated by varying various parameters. The position of the printed ink changed according to physical characteristics of the ink and supporting liquid and printing conditions including the flow rates of the ink and the nozzle diameter, position, and speed. The width of the printed ink was mainly influenced by the ink flow rate and the nozzle speed. Next, we confirmed the polymerization of the printed ink in the supporting viscous liquid, as well as its responsivity to thermal stimulation. The degree of polymerization became smaller, as the interval time was longer after printing. The polymerized ink shrunk or swelled repeatedly according to thermal stimulation. In addition, printing multi-hydrogels was demonstrated by using a nozzle attached to a Y shape connector, and the responsivity of the multi-hydrogels to thermal-stimulation was investigated. The pattern of the multi-hydrogels structure and its responsivity to thermal-stimulation were controlled by the flow ratio of the inks. Finally, various 4D structures including a rounded pattern, a spiral shape pattern, a cross point, and a multi-hydrogel pattern were fabricated, and their deformations in response to the stimuli were demonstrated. [ABSTRACT FROM AUTHOR]

BRAF mutations are frequently observed in melanoma and hairy-cell leukemia. Currently approved rapidly accelerated fibrosarcoma (RAF) kinase inhibitors targeting oncogenic BRAF V600 mutations have shown remarkable efficacy in the clinic, but their therapeutic benefits are occasionally hampered by acquired resistance due to RAF dimerization-dependent reactivation of the downstream MAPK pathway, which is known as paradoxical activation. There is also a concern that paradoxical activation of the MAPK pathway may trigger secondary cancer progression. In this study, we developed chimeric compounds, proteolysis targeting chimeras (PROTACs), that target BRAF V600E protein for degradation. CRBN(BRAF)-24, the most effective chimera, potently degraded BRAF V600E in a ubiquitin-proteasome system (UPS)-dependent manner and inhibited the proliferation of BRAF V600E -driven cancer cells. In BRAF wild-type cells, CRBN(BRAF)-24 induced neither BRAF WT degradation nor paradoxical activation of the MAPK pathway. Biochemical analysis revealed that CRBN(BRAF)-24 showed more potent and sustained suppression of MAPK signaling than a BRAF V600E inhibitor, PLX-8394, in BRAF V600E -driven cancer cells. Targeted degradation of BRAF V600E by CRBN(BRAF)-24 could be a promising strategy to evade paradoxical activation of the RAF-MAPK pathway., (© 2022 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

We report the case ofa 76-year-old man who had bacteremia due to Edwardsiella tarda during the course ofchemotherapy, including ponatinib, for the treatment of recurrent Philadelphia-positive acute lymphoblastic leukemia. Treatment with cefepime improved his general condition. The number ofreported cases ofbacteremia due to Edwardsiella tarda is limited. Further accumulation ofcases is necessary to obtain accurate data such as the risk factors of Edwardsiella tarda bacteremia.

Here, we report a case of a 67-year-old man who had septic shock due to Citrobacter braakii infection during the course of chemotherapy with high-dose cytosine arabinoside for acute myeloid leukemia. Treatment with cefepime rapidly improved his condition. The number of reported cases of sepsis due to Citrobacter braakii is limited. Further accumulation of cases is necessary to obtain accurate data such as the risk factors for Citrobacter braakii infections.