CD200 is overexpressed in the pancreatic tumor microenvironment and predictive of overall survival.

Pancreatic cancer is an aggressive disease with a 5 year survival rate of 13%. This poor survival is attributed, in part, to limited and ineffective treatments for patients with metastatic disease, highlighting a need to identify molecular drivers of pancreatic cancer to target for more effective treatment. CD200 is a glycoprotein that interacts with the receptor CD200R and elicits an immunosuppressive response. Overexpression of CD200 has been associated with differential outcomes, depending on the tumor type. In the context of pancreatic cancer, we have previously reported that CD200 is expressed in the pancreatic tumor microenvironment (TME), and that targeting CD200 in murine tumor models reduces tumor burden. We hypothesized that CD200 is overexpressed on tumor and stromal populations in the pancreatic TME and that circulating levels of soluble CD200 (sCD200) have prognostic value for overall survival. We discovered that CD200 was overexpressed on immune, stromal, and tumor populations in the pancreatic TME. Particularly, single-cell RNA-sequencing indicated that CD200 was upregulated on inflammatory cancer-associated fibroblasts. Cytometry by time of flight analysis of PBMCs indicated that CD200 was overexpressed on innate immune populations, including monocytes, dendritic cells, and monocytic myeloid-derived suppressor cells. High sCD200 levels in plasma correlated with significantly worse overall and progression-free survival. Additionally, sCD200 correlated with the ratio of circulating matrix metalloproteinase (MMP) 3: tissue inhibitor of metalloproteinase (TIMP) 3 and MMP11/TIMP3. This study highlights the importance of CD200 expression in pancreatic cancer and provides the rationale for designing novel therapeutic strategies that target this protein.

Tomatidine targets ATF4-dependent signaling and induces ferroptosis to limit pancreatic cancer progression.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with high metastasis and therapeutic resistance. Activating transcription factor 4 (ATF4), a master regulator of cellular stress, is exploited by cancer cells to survive. Prior research and data reported provide evidence that high ATF4 expression correlates with worse overall survival in PDAC. Tomatidine, a natural steroidal alkaloid, is associated with inhibition of ATF4 signaling in multiple diseases. Here, we discovered that in vitro and in vivo tomatidine treatment of PDAC cells inhibits tumor growth. Tomatidine inhibited nuclear translocation of ATF4 and reduced the transcriptional binding of ATF4 with downstream promoters. Tomatidine enhanced gemcitabine chemosensitivity in 3D ECM-hydrogels and in vivo. Tomatidine treatment was associated with induction of ferroptosis signaling validated by increased lipid peroxidation, mitochondrial biogenesis, and decreased GPX4 expression in PDAC cells. This study highlights a possible therapeutic approach utilizing a plant-derived metabolite, tomatidine, to target ATF4 activity in PDAC.

A Critical Analysis of Industrial Human-Robot Communication and Its Quest for Naturalness Through the Lens of Complexity Theory.

Human-robot communication is one of the actively researched fields to enable efficient and seamless collaboration between a human and an intelligent industrial robotic system. The field finds its roots in human communication with the aim to achieve the "naturalness" inherent in the latter. Industrial human-robot communication pursues communication with simplistic commands and gestures, which is not representative of an uncontrolled real-world industrial environment. In addition, naturalness in communication is a consequence of its dynamism, typically ignored as a design criterion in industrial human-robot communication. Complexity Theory-based natural communication models allow for a more accurate representation of human communication which, when adapted, could also benefit the field of human-robot communication. This paper presents a perspective by reviewing the state of human-robot communication in industrial settings and then presents a critical analysis of the same through the lens of Complexity Theory. Furthermore, the work identifies research gaps in the aforementioned field, fulfilling which, would propel the field towards a truly natural form of communication. Finally, the work briefly discusses a general framework that leverages the experiential learning of data-based techniques and naturalness of human knowledge.

Exosomal Transfer of DNA Methyl-Transferase mRNA Induces an Immunosuppressive Phenotype in Human Monocytes.

INTRODUCTION: Survivors of sepsis exhibit persistent immunosuppression. Epigenetic events may be responsible for some of these immunosuppressive changes. During sepsis circulating exosomes contain large quantities of DNA methyltransferase (DNMT) mRNAs. We hypothesized that exosomes directly transfer DNMT mRNAs to recipient monocytes with resultant methylation events and immunosuppression. METHODS: Exosomes containing DNMT mRNA were generated by stimulating monocytes with LPS. Confocal microscopy was used to determine uptake kinetics in the presence of pharmacologic inhibition. Expression and packaging of specific DNMT mRNA was controlled using DNMT siRNAs. Whole genome and gene specific methylation was assessed using bisulfite sequencing. Ingenuity pathway analysis was performed to determine the biological function of significance of differentially methylated regions. RESULTS: Exosomes effectively transferred DNMT mRNA to recipient monocytes. Pharmacologic inhibition of exosome uptake prevented this increase in DNMT mRNA expression. Recipient monocytes exhibited hypermethylation changes and gene suppression. siRNAs decreased the packaging of DNMT mRNAs and prevented TNFα gene suppression, restoring immunocompetence. CONCLUSION: These data support a role for exosome-mediated transfer of DNMT mRNA with resultant methylation and gene silencing. Pharmacologic uptake inhibition or targeted siRNA mediated DNMT gene silencing prevented DNMT mRNA transfer and maintained the cell's ability to express TNFα in response to LPS. This highlights the potential therapeutic value of targeting these exosome-mediated epigenetic events to maintain the host immune response during sepsis.

Regulation of cellular immunity by activating transcription factor 4.

Activating transcription factor 4 (ATF4) is a DNA binding transcription factor belonging to the family of basic Leucine zipper proteins. ATF4 can be activated in response to multiple cellular stress signals including endoplasmic reticulum stress in the event of improper protein folding or oxidative stress because of mitochondrial dysfunction as well as hypoxia. There are multiple downstream targets of ATF4 that can coordinate the regulation between survival and apoptosis of a cell based on time and exposure to stress. ATF4, therefore, has a broad range of control that results in the modulation of immune cells of the innate and adaptive responses leading to regulation of the cellular immunity. Studies provide evidence that ATF4 can regulate immune cells such as macrophages, T cells, B cells, NK cells and dendritic cells contributing to progression of disease. Immune cells can be exposed to stressed environment in the event of a pathogen attack, infection, inflammation, or in the tumor microenvironment leading to increased ATF4 activity to regulate these responses. ATF4 can further control differentiation and maturation of different immune cell types becoming a determinant of effective immune regulation. Additionally, ATF4 has been heavily implicated in rendering effector immune cells dysfunctional that are used to target tumorigenesis. Therefore, there is a need to evaluate where the literature stands in understanding the overall role of ATF4 in regulating cellular immunity to identify therapeutic targets and generalized mechanisms for different disease progressions.

Soy-tomato enriched diet reduces inflammation and disease severity in a pre-clinical model of chronic pancreatitis.

Chronic pancreatitis (CP) is a fibro-inflammatory syndrome in individuals who develop persistent pathological responses to parenchymal injury or stress. Novel therapeutic or dietary interventions that could lessen inflammation in this disease could significantly improve quality of life in patients with CP. Complex dietary foods like soy and tomatoes are composed of active metabolites with anti-inflammatory effects. Data from our group reports that bioactive agents in soy and tomatoes can reduce pro-inflammatory cytokines and suppressive immune populations. Additionally, our team has developed a novel soy-tomato juice currently being studied in healthy individuals with no toxicities, and good compliance and bioavailability. Thus, we hypothesize that administration of a soy-tomato enriched diet can reduce inflammation and severity of CP. C57BL/6 mice were injected intraperitoneally with 50 µg/kg caeurlein (7 hourly injections, twice weekly) for 6 weeks to induce CP. After 4 weeks of caerulein injections, mice were administered a control or a soy-tomato enriched diet for 2 weeks. Disease severity was measured via immunohistochemical analysis of pancreata measuring loss of acini, fibrosis, inflammation, and necrosis. Serum lipase and amylase levels were analyzed at the end of the study. Inflammatory factors in the serum and pancreas, and immune populations in the spleen of mice were analyzed by cytokine multiplex detection, qRT-PCR, and flow cytometry respectively. Infra-red (IR) sensing of mice was used to monitor spontaneous activity and distress of mice. Mice fed a soy-tomato enriched diet had a significantly reduced level of inflammation and severity of CP (p = 0.032) compared to mice administered a control diet with restored serum lipase and amylase levels (p < 0.05). Mice with CP fed a soy-tomato diet had a reduction in inflammatory factors (TNF-α, IL-1ß, IL-5) and suppressive immune populations (myeloid-derived suppressor cells; MDSC) compared to control diet fed mice (p < 0.05). Infra-red sensing to monitor spontaneous activity of mice showed that soy-tomato enriched diet improved total activity and overall health of mice with CP (p = 0.055) and CP mice on a control diet were determined to spend more time at rest (p = 0.053). These pre-clinical results indicate that a soy-tomato enriched diet may be a novel treatment approach to reduce inflammation and pain in patients with CP.