SIRT7 knockdown promotes gemcitabine sensitivity of pancreatic cancer cell via upregulation of GLUT3 expression.

Gemcitabine serves as a first-line chemotherapeutic treatment for pancreatic cancer (PC), but it is prone to rapid drug resistance. Increasing the sensitivity of PC to gemcitabine has long been a focus of research. Fasting interventions may augment the effects of chemotherapy and present new options. SIRT7 is known to link metabolism with various cellular processes through post-translational modifications. We found upregulation of SIRT7 in PC cells is associated with poor prognosis and gemcitabine resistance. Cross-analysis of RNA-seq and ATAC-seq data suggested that GLUT3 might be a downstream target gene of SIRT7. Subsequent investigations demonstrated that SIRT7 directly interacts with the enhancer region of GLUT3 to desuccinylate H3K122. Our group's another study revealed that GLUT3 can transport gemcitabine in breast cancer cells. Here, we found GLUT3 KD reduces the sensitivity of PC cells to gemcitabine, and SIRT7 KD-associated gemcitabine-sensitizing could be reversed by GLUT3 KD. While fasting mimicking induced upregulation of SIRT7 expression in PC cells, knocking down SIRT7 enhanced sensitivity to gemcitabine through upregulating GLUT3 expression. We further confirmed the effect of SIRT7 deficiency on the sensitivity of gemcitabine under fasting conditions using a mouse xenograft model. In summary, our study demonstrates that SIRT7 can regulate GLUT3 expression by binding to its enhancer and altering H3K122 succinylation levels, thus affecting gemcitabine sensitivity in PC cells. Additionally, combining SIRT7 knockdown with fasting may improve the efficacy of gemcitabine. This unveils a novel mechanism by which SIRT7 influences gemcitabine sensitivity in PC and offer innovative strategies for clinical combination therapy with gemcitabine.

Magneto-Thermo-Elastic Theoretical Solution for Functionally Graded Thick-Walled Tube under Magnetic, Thermal and Mechanical Loads Based on Voigt Method.

In this study, the mechanical responses of a functionally graded thick-walled tube simultaneously under magnetic, thermal and mechanical loads are studied. Based on the assumption that the volume fraction of each phase material is distributed as a power function, the Voigt method is used to obtain the stress-strain relationship of the functionally graded materials (FGMs). The influences of the relevant material parameters including volume fraction, thermal expansion coefficient, and Poisson's ratio on the magneto-thermo-elastic theoretical solution are deeply studied and discussed. Furthermore, when some of the parameters are set as special values, the research results can be degenerated to two coupled loads which are consistent with the existing researches. The results of this paper provide theoretical support for the practical design and application of the FGM tube under the combined action of magnetic, thermal and mechanical loads.

Role and mechanism underlying FoxO6 in skeletal muscle in vitro and in vivo.

Skeletal muscle atrophy is a common feature of patients suffering with chronic infection and other systemic diseases, including acquired immunodeficiency syndrome, chronic kidney disease and cancer. Therefore, understanding the molecular basis of muscle loss is of importance. The majority of members of the forkhead box O (FoxO) family can induce skeletal muscle atrophy; however, the effect of FoxO6 on skeletal muscle is not completely understood. The present study investigated the role of FoxO6 in vitro and in vivo. Compared with the small interfering RNA (si)­negative control (NC) group, C2C12 cell proliferation (Cell Counting Kit­8 assay), myotube differentiation and myotube production were significantly decreased by FoxO6 knockdown, which was different from the known functions of other FoxO members. The immunofluorescence assay results demonstrated that si­FoxO6 clearly downregulated the expression levels of myosin heavy chain (MyHC) in C2C12 myotubes compared with si­NC. The western blotting results indicated that compared with the si­NC group, FoxO6 knockdown induced C2C12 myotube atrophy by notably downregulating myoblast determination protein 1 (MyoD), mTOR and MyHC expression levels, and by markedly upregulating ubiquitin ligase (atrogin1) and muscle RING­finger protein­1 (MURF1) expression levels. Similarly, in an in vitro model of TNF­α­induced myotube atrophy, the western blotting results indicated that FoxO6 expression levels were decreased, whereas atrogin1, MURF1, FoxO1 and FoxO3a expression levels were increased compared with the control group. Therefore, the results indicated that, unlike FoxO1 or FoxO3a, FoxO6 maintained C2C12 myotubes and protected against atrophy. Consistent with the in vitro data, similar results were observed in vivo. Collectively, the results of the present study suggested that FoxO6 served a critical role in muscle cell metabolism in vitro and in vivo, and might serve as a promising therapeutic target for ameliorating skeletal muscle atrophy.

Neutralization of PD-L2 is Essential for Overcoming Immune Checkpoint Blockade Resistance in Ovarian Cancer.

PURPOSE: Ovarian cancer represents a major clinical hurdle for immune checkpoint blockade (ICB), with reported low patient response rates. We found that the immune checkpoint ligand PD-L2 is robustly expressed in patient samples of ovarian cancers and other malignancies exhibiting suboptimal response to ICB but not in cancers that are ICB sensitive. Therefore, we hypothesize that PD-L2 can facilitate immune escape from ICB through incomplete blockade of the PD-1 signaling pathway. EXPERIMENTAL DESIGN: We engineered a soluble form of the PD-1 receptor (sPD-1) capable of binding and neutralizing both PD-L2 and PD-L1 with ×200 and ×10,000 folds improvement in binding affinity over wild-type PD-1 leading to superior inhibition of ligand-mediated PD-1 activities. RESULTS: Both in vitro and in vivo analyses performed in this study demonstrated that the high-affinity sPD-1 molecule is superior at blocking both PD-L1- and PD-L2-mediated immune evasion and reducing tumor growth in immune-competent murine models of ovarian cancer. CONCLUSIONS: The data presented in this study provide justification for using a dual targeting, high-affinity sPD-1 receptor as an alternative to PD-1 or PD-L1 therapeutic antibodies for achieving superior therapeutic efficacy in cancers expressing both PD-L2 and PD-L1.