Overcoming resistance to chemotherapies remains a major unmet need for cancers, such as triple-negative breast cancer (TNBC). Therefore, mechanistic studies to provide insight for drug development are urgently needed to overcome TNBC therapy resistance. Recently, an important role of fatty acid β-oxidation (FAO) in chemoresistance has been shown. But how FAO might mitigate tumor cell apoptosis by chemotherapy is unclear. Here, we show that elevated FAO activates STAT3 by acetylation via elevated acetyl-coenzyme A (CoA). Acetylated STAT3 upregulates expression of long-chain acyl-CoA synthetase 4 (ACSL4), resulting in increased phospholipid synthesis. Elevating phospholipids in mitochondrial membranes leads to heightened mitochondrial integrity, which in turn overcomes chemotherapy-induced tumor cell apoptosis. Conversely, in both cultured tumor cells and xenograft tumors, enhanced cancer cell apoptosis by inhibiting ASCL4 or specifically targeting acetylated-STAT3 is associated with a reduction in phospholipids within mitochondrial membranes. This study demonstrates a critical mechanism underlying tumor cell chemoresistance.

To date, there are no inhibitors that directly and specifically target activated STAT3 and c-Myc in the clinic. Although peptide-based inhibitors can selectively block activated targets, their clinical usage is limited because of low cell penetration and/or serum stability. Here, we generated cell-penetrating acetylated (acet.) STAT3, c-Myc, and Gp130 targeting peptides by attaching phosphorothioated (PS) polymer backbone to peptides. The cell-penetrating peptides efficiently penetrated cells and inhibited activation of the intended targets and their downstream genes. Locally or systemically treating tumor-bearing mice with PS-acet.-STAT3 peptide at low concentrations effectively blocked STAT3 in vivo, resulting in significant antitumor effects in 2 human xenograft models. Moreover, PS-acet.-STAT3 peptide penetrated and activated splenic CD8 ⁺ T cells in vitro. Treating immune-competent mice bearing mouse melanoma with PS-acet.-STAT3 peptide inhibited STAT3 in tumor-infiltrating T cells, downregulating tumor-infiltrating CD4 ⁺ T regulatory cells while activating CD8 ⁺ T effector cells. Similarly, systemic injections of the cell-penetrating c-Myc and Gp130 peptides prevented pancreatic tumor growth and induced antitumor immune responses. Taken together, we have developed therapeutic peptides that effectively and specifically block challenging cancer targets, resulting in antitumor effects through both direct tumor cell killing and indirectly through antitumor immune responses.

With the increasing acceptance of cloud computing in various fields, Field Programmable Gate Arrays(FPGA), as one of the core computing power due to its programmable, low power consumption and low characteristics, has been widely deployed in data center. Therefore, how to deploy and use FPGA devices in the cloud computing system of ultra large-scale data center has become a research topic for many units. Traditionally, the deployment of FPGA in the data center is directly inserted in the PCIE slot of server, which belongs to the FPGA-CPU binding method, and The number of FPGA boards supported by single host is limited by the server slot. We propose to change the CPU-FPGA mode by decoupling the FPGA from the CPU and connecting the FPGA to the data center network as an independent resource. This solution solves the scalability problem of FPGA deployment, making it easier for FPGA to deploy and schedule on a large scale. Based on the above FPGA, this paper proposes a solution for large-scale deployment of FPGA devices in kubernetes platform. The scheme adopts container based and kubernetes container deployment management technology. The experimental results proved that the prototype has good throughput, lower communication latency between cards and better scalability compared with the deployment in the way of PCIE.