ORM 1 as a biomarker of increased vascular invasion and decreased sorafenib sensitivity in hepatocellular carcinoma

This study aimed to clarify the role of Orosomucoid 1 (ORM1) in the development and therapy resistance in hepatocellular carcinoma (HCC). The mRNA expression level of ORM1 was analyzed via integrative analysis of Gene Express Omnibus (GEO) and The Cancer Genome Atlas (TCGA) datasets. The protein expression level of ORM1 in our cohort was determined using immunohistochemistry. Correlation analysis was used to investigate the relationship between ORM1 expression and clinical parameters. The Cell Counting Kit-8 assay was used to clarify the role of ORM1 in HCC malignant behaviors, including cell growth and sorafenib sensitivity, in vitro. The results indicated that ORM1 was significantly downregulated in the hepatic cancer cells compared to that in the non-cancerous cells. However, it was upregulated in microvascular invasion samples, especially in the cancer embolus compared to that in the surrounding tumor cells. Though Kaplan-Meier analysis did not show an association of ORM1 expression with the overall survival rates of HCC patients, univariate analysis indicated that ORM1 expression was highly correlated with tumor grade and stage. An in vitro assay also revealed that downregulation of ORM1 led to the suppression of tumor growth and enhancement of sorafenib sensitivity without epithelial-to-mesenchymal transition (EMT) alteration, which was consistent with our bioinformatic analysis. Hence, ORM1 played a key role in HCC tumorigenesis and may serve as a potential target for the development of therapeutics against HCC in the future

Response of zooplankton to warming in a low-salinity, eutrophic bay

Warming and eutrophication are universal threats to bay ecosystems. However, the response of zooplankton varies due to diverse environmental settings and species composition. As a long and narrow semi-enclosed bay with low salinity (18–27) in the East China Sea, Xiangshan Bay (XSB) is jointly affected by global warming and the thermal drainage, which makes it an appropriate region for ascertaining the response of zooplankton to warming under low-salinity background. We examined the long-term changes in the abundance, biomass and dominant species of large mesozooplankton (LMZ; >505 μm) over four decades in XSB, and found downward trends in the annual abundance and biomass, and the biomass peak shifting from summer to spring since 2010. In addition, the relative abundance of cold-temperate species decreased, while that of warm-temperate/warm-water species and small-sized zooplankton increased. The decreased LMZ abundance and biomass in XSB were supposed to be related to low gelatinization compared with the other semi-enclosed bays in China, Jiaozhou Bay (JZB) in the Yellow Sea and Daya Bay (DYB) in the South China Sea, where the LMZ biomass and abundance increased or fluctuated mainly linked to the increase in gelatinous zooplankton. Salinity, temperature, and nutrient concentration are important factors affecting gelatinization. By comparing the background salinity and magnitudes of temperature and nutrient increases among the three bays, we speculated that the lower salinity (XSB: 18–27, JZB: 30–32, DYB: 30–34) influenced by freshwater input of the Changjiang River might be a potential factor causing the low gelatinization in XSB, as the similar upward trends in both nutrient concentration and temperature were observed in the three bays. This study suggests that miniaturization with low gelatinization and a decrease in cold-temperate species were the main responses of zooplankton to warming in the low-salinity bay in the East China Sea, which may lead to a specific pelagic ecosystem evolution

Rethinking Reverse Distillation for Multi-Modal Anomaly Detection

In recent years, there has been significant progress in employing color images for anomaly detection in industrial scenarios, but it is insufficient for identifying anomalies that are invisible in RGB images alone. As a supplement, introducing extra modalities such as depth and surface normal maps can be helpful to detect these anomalies. To this end, we present a novel Multi-Modal Reverse Distillation (MMRD) paradigm that consists of a frozen multi-modal teacher encoder to generate distillation targets and a learnable student decoder targeting to restore multi-modal representations from the teacher. Specifically, the teacher extracts complementary visual features from different modalities via a siamese architecture and then parameter-freely fuses these information from multiple levels as the targets of distillation. For the student, it learns modality-related priors from the teacher representations of normal training data and performs interaction between them to form multi-modal representations for target reconstruction. Extensive experiments show that our MMRD outperforms recent state-of-the-art methods on both anomaly detection and localization on MVTec-3D AD and Eyecandies benchmarks. Codes will be available upon acceptance

Establishment and Investigation of a Multiple Gene Expression Signature to Predict Long-Term Survival in Pancreatic Cancer

Pancreatic cancer remains a lethal type of cancer with poor prognosis. Molecular classification enables in-depth, precise prognostic assessment. This study is aimed at identifying a robust and simple mRNA signature to predict the overall survival (OS) of pancreatic cancer (PC) patients. Differentially expressed genes (DEGs) between 45 paired pancreatic tumor samples and adjacent healthy tissues were selected. For risk determination, a LASSO Cox regression model with DEGs was used to generate the OS-associated risk score formula for the training cohort containing 177 PC patients. Another five independent datasets were used as the testing cohort to determine the predictive efficiency for further validation. In total, 441 DEGs were selected after considering the enrichment of classical pathways, such as EMT, cell cycle, cell adhesion, and PI3K-AKT. A five-gene signature for risk discrimination was established with high efficacy using LASSO Cox regression in the training group. External validation showed that patients identified by the gene expression signature to be in the high-risk group had poorer prognosis compared with the low-risk patients. Further investigation identified the differential epigenetic modification patterns of the five genes, which indicated their roles in tumor progression and their effect on therapy. In conclusion, we constructed a robust five-gene expression signature that could predict the OS of PC patients, offering a new insight for risk discrimination in daily clinical practice

Correlation between Macrophage Polarization and PD-L1-Related Tumor Microenvironmental Alteration and Metastasis in Pancreatic Ductal Adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy with a poor prognosis; nearly 80% patients have regional or distant metastasis when diagnosed. Tumor microenvironment (TME) alteration and epithelial-to-mesenchymal transition (EMT) have been reported to play a key role in cancer metastasis. However, the correlation between TME and EMT was poorly studied in PDAC. This study aims to explore the correlation between EMT markers and TME alteration, mainly including macrophage polarization and PD-L1 expression change, in primary and metastatic PDAC tissues by immunohistochemistry. The results indicated that macrophage polarization was found in metastases with the number of M1 macrophages (CD86+) decreased and M2 (CD163+) increased, though PD-L1 expression did not have a significant alteration. Compared to primary tumors, E-cadherin was significantly lower, while snail was higher, while no difference was found with N-cadherin and ZEB1. Correlation analysis indicated that snail, but not ZEB1, E-cadherin, or N-cadherin, was highly correlated with macrophage polarization. To conclude, the number of CD86+ M1 macrophages was increased while CD163+ M2 macrophages decreased in metastases, with no significant alteration of PD-L1 expression compared to primary tumors. EMT markers—Snail and E-cadherin—but not ZEB1 or N-cadherin, were found to be higher/lower in metastases, which mean that EMT played an important role in PDAC metastasis. Further analysis indicated that snail was highly correlated with M1 to M2 macrophage polarization, which prompted that EMT may be one reason for macrophage polarization induced TME alteration in PDAC metastasis

MEK inhibition targets cancer stem cells and impedes migration of pancreatic cancer cells in vitro and in vivo

Pancreatic ductal adenocarcinoma (PDAC) remains a devastating disease with a very poor prognosis. At the same time, its incidence is on the rise, and PDAC is expected to become the second leading cause of cancer-related death by 2030. Despite extensive work on new therapeutic approaches, the median overall survival is only 6-12 months after diagnosis and the 5-year survival is less than 7%. While pancreatic cancer is particularly difficult to treat, patients usually succumb not to the growth of the primary tumor, but to extensive metastasis; therefore, strategies to reduce the migratory and metastatic capacity of pancreatic cancer cells merit close attention. The vast majority of pancreatic cancers harbor RAS mutations. The outstanding relevance of the RAS/MEK/ERK pathway in pancreatic cancer biology has been extensively shown previously. Due to their high dependency on Ras mutations, pancreatic cancers might be particularly sensitive to inhibitors acting downstream of Ras. Herein, we use a genetically engineered mouse model of pancreatic cancer and primary pancreatic cancer cells were derived from this model to demonstrate that small-molecule MEK inhibitors functionally abrogate cancer stem cell populations as demonstrated by reduced sphere and organoid formation capacity. Furthermore, we demonstrate that MEK inhibition suppresses TGFβ-induced epithelial-to-mesenchymal transition and migration in vitro and ultimately results in a highly significant reduction in circulating tumor cells in mice.P.C.H. is supported by a Max Eder Fellowship of the German Cancer Aid (111746) and by a Hector Foundation Cancer Research grant (M65.1). P.C.H. and J.M. are supported by a Collaborative Research Centre grant of the German Research Foundation (316249678–SFB 1279). J.T.S. is supported by the European Union Framework Programme 7 for research, technological development, and demonstration (FP7/CAM-PaC) under grant agreement no. 602783, the German Cancer Consortium (DKTK), and the Deutsche Forschungsgemeinschaft (DFG; KFO337/SI 1549/3-1). B.S., Jr., was funded by a Rámon y Cajal Merit Award from the Ministerio de Economía y Competitividad, Spain, and a coordinated grant from the Fundación Asociación Española Contra el Cáncer (AECC, GC16173694BARB).Peer reviewe