Loss of SMAD4 Is Associated With Poor Tumor Immunogenicity and Reduced PD-L1 Expression in Pancreatic Cancer

Transforming Growth Factor β (TGFβ) is a key mediator of immune evasion in pancreatic ductal adenocarcinoma (PDAC), and the addition of TGFβ inhibitors in select immunotherapy regimens shows early promise. Though the TGFβ target SMAD4 is deleted in approximately 55% of PDAC tumors, the effects of SMAD4 loss on tumor immunity have yet to be fully explored. Using a combination of genomic databases and PDAC specimens, we found that tumors with loss of SMAD4 have a comparatively poor T-cell infiltrate. SMAD4 loss was also associated with a reduction in several chemokines with known roles in T-cell recruitment, which was recapitulated using knockdown of SMAD4 in PDAC cell lines. Accordingly, JURKAT T-cells were poorly attracted to conditioned media from PDAC cells with knockdown of SMAD4 and lost their ability to produce IFNγ. However, while exogenous TGFβ modestly reduced PD-L1 expression in SMAD4-intact cell lines, SMAD4 and PD-L1 positively correlated in human PDAC samples. PD-L1 status was closely related to tumor-infiltrating lymphocytes, particularly IFNγ-producing T-cells, which were more abundant in SMAD4-expressing tumors. Low concentrations of IFNγ upregulated PD-L1 in tumor cells in vitro, even when administered alongside high concentrations of TGFβ. Hence, while SMAD4 may have a modest inhibitory effect on PD-L1 in tumor cells, SMAD4 indirectly promotes PD-L1 expression in the pancreatic tumor microenvironment by enhancing T-cell infiltration and IFNγ biosynthesis. These data suggest that pancreatic cancers with loss of SMAD4 represent a poorly immunogenic disease subtype, and SMAD4 status warrants further exploration as a predictive biomarker for cancer immunotherapy

Mechanical collision simulation of potato tubers

This paper presents the results of an investigation on internal stress progression and the explicit dynamics simulation of the bruising behavior of potato tubers under dynamic mechanical collision. Physical measurements, mechanical tests, advanced solid modeling, and engineering simulation techniques were utilized in the study. The tuber samples used in the simulation were reverse engineered and finite element analysis (FEA) was set up to simulate the collision-based bruising behavior of the potato tubers. The total number of identical tuber models used in the simulation was 17. The numerical data of the FEA results revealed useful stress distribution and mechanical behavior visuals. These results are presented in a frame that can be used to describe bruise susceptibility value on potato-like agricultural crops. The modulus of elasticity was calculated from compression test data as 3.12 MPa. Structural stresses of 1.40 and 3.13 MPa on the impacting (hitting) and impacted (hit) tubers (respectively) were obtained. These stress values indicate that bruising is likely to occur on the tubers. This research paper provides a useful how-to-do strategy to further research on complicated bruising investigations of solid-like agricultural products through advanced engineering simulation techniques. Practical applications: This research aims to simulate realistic dynamic deformation of potato tubers during mechanical collision, which is very hard to achieve through physical or analytical expressions. This is attractive because related food processing industries have shown their interest in determining the physical properties and bruising behavior of food/agricultural products using experimental, numerical, and engineering simulation methods so that it can be used in their food processing technology. Very limited data have been found available in the literature about the subject of FEM-based explicit dynamics simulation of solid-like agricultural crops such as the self-collision case of potato tubers (which is very important for indoor or outdoor potato processing). Comparative investigations on determination of modulus of elasticity are very limited as well. Most of the research focused on single calculation theory and linear static loading assumption-based FEM simulation solutions. Here, we report a “how-to-do” case study for dynamic self-collision simulation of potato tubers

TGFβ Signaling in the Pancreatic Tumor Microenvironment

Pancreatic ductal adenocarcinoma (PDAC) is associated with poor clinical outcomes, largely attributed to incomplete responses to standard therapeutic approaches. Recently, selective inhibitors of the Transforming Growth Factor β (TGFβ) signaling pathway have shown early promise in the treatment of PDAC, particularly as a means of augmenting responses to chemo- and immunotherapies. However, TGFβ is a potent and pleiotropic cytokine with several seemingly paradoxical roles within the pancreatic tumor microenvironment (TME). Although TGFβ signaling can have potent tumor-suppressive effects in epithelial cells, TGFβ signaling also accelerates pancreatic tumorigenesis by enhancing epithelial-to-mesenchymal transition (EMT), fibrosis, and the evasion of the cytotoxic immune surveillance program. Here, we discuss the known roles of TGFβ signaling in pancreatic carcinogenesis, the biologic consequences of the genetic inactivation of select components of the TGFβ pathway, as well as past and present attempts to advance TGFβ inhibitors in the treatment of PDAC patients