Publications by authors named "Si Shi"

134 Publications

Construction of a novel risk model based on the random forest algorithm to distinguish pancreatic cancers with different prognoses and immune microenvironment features.

Bioengineered 2021 Dec;12(1):3593-3602

Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.

Immune-related long noncoding RNAs (irlncRNAs) are actively involved in regulating the immune status. This study aimed to establish a risk model of irlncRNAs and further investigate the roles of irlncRNAs in predicting prognosis and the immune landscape in pancreatic cancer. The transcriptome profiles and clinical information of 176 pancreatic cancer patients were retrieved from The Cancer Genome Atlas (TCGA). Immune-related genes (irgenes) downloaded from ImmPort were used to screen 1903 immune-related lncRNAs (irlncRNAs) using Pearson's correlation analysis (R > 0.5; p < 0.001). Random survival forest (RSF) and survival tree analysis showed that 9 irlncRNAs were highly correlated with overall survival (OS) according to the variable importance (VIMP) and minimal depth. Next, Cox regression analysis was used to establish a risk model with 3 irlncRNAs (LINC00462, LINC01887, RP11-706C16.8) that was evaluated by Kaplan-Meier analysis, the areas under the curve (AUCs) of the receiver operating characteristics and the C-index. Additionally, we performed Cox regression analysis to establish the clinical prognostic model, which showed that the risk score was an independent prognostic factor (p < 0.001). A nomogram and calibration plots were drawn to visualize the clinical features. The Wilcoxon signed-rank test and Pearson's correlation analysis further explored the irlncRNA signatures and immune cell infiltration, as well as the immunotherapy response.
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http://dx.doi.org/10.1080/21655979.2021.1951527DOI Listing
December 2021

Head-to-head comparison between FOLFIRINOX and gemcitabine plus nab-paclitaxel in the neoadjuvant chemotherapy of localized pancreatic cancer: a systematic review and meta-analysis.

Gland Surg 2021 May;10(5):1564-1575

Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.

Background: The benefits of neoadjuvant chemotherapy (NCT) in pancreatic cancer (PC) have been realized and gradually accepted. FOLFIRINOX and gemcitabine and nab-paclitaxel (GA) are the two most widely used regimens for PC NCT.

Methods: The literature was systematically reviewed by searching MEDLINE, EMBASE, Web of Science and the Cochrane Library for studies published until September 2020.

Results: Eight studies were eligible for the meta-analysis. Compared to GA, neoadjuvant FOLFIRINOX significantly prolonged overall survival [hazard ratio (HR) =0.65, 95% confidence interval (95% CI): 0.55-0.77; P<0.001]. FOLFIRINOX provided better survival benefits in the first three years after surgery; however, the 4- and 5-year survival probabilities of the two strategies were similar based on a conservative estimation in the random effect model. The perioperative parameters analysed included perineural invasion (PNI), lymphovascular invasion (LVSI), R0 status, postoperative complications and resection rate. The PNI rate was marginally elevated in the GA group compared with the FOLFIRINOX cohort [79.8% 70.5%, odds ratio (OR) =0.70, 95% CI: 0.47-1.06, P=0.09], which may account for the potential survival benefits of FOLFIRINOX.

Conclusions: The results of our meta-analysis suggest that FOLFIRINOX is non-inferior to GA in patients who are FOLFIRINOCX capable.
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http://dx.doi.org/10.21037/gs-21-16DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8184396PMC
May 2021

Overcoming chemoresistance by targeting reprogrammed metabolism: the Achilles' heel of pancreatic ductal adenocarcinoma.

Cell Mol Life Sci 2021 Jul 15;78(14):5505-5526. Epub 2021 Jun 15.

Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, 270 Dong'An Road, Shanghai, 200032, People's Republic of China.

Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer-related death due to its late diagnosis that removes the opportunity for surgery and metabolic plasticity that leads to resistance to chemotherapy. Metabolic reprogramming related to glucose, lipid, and amino acid metabolism in PDAC not only enables the cancer to thrive and survive under hypovascular, nutrient-poor and hypoxic microenvironments, but also confers chemoresistance, which contributes to the poor prognosis of PDAC. In this review, we systematically elucidate the mechanism of chemotherapy resistance and the relationship of metabolic programming features with resistance to anticancer drugs in PDAC. Targeting the critical enzymes and/or transporters involved in glucose, lipid, and amino acid metabolism may be a promising approach to overcome chemoresistance in PDAC. Consequently, regulating metabolism could be used as a strategy against PDAC and could improve the prognosis of PDAC.
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http://dx.doi.org/10.1007/s00018-021-03866-yDOI Listing
July 2021

Applications of single-cell sequencing in cancer research: progress and perspectives.

J Hematol Oncol 2021 Jun 9;14(1):91. Epub 2021 Jun 9.

Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, No. 270 Dong'An Road, Shanghai, 200032, China.

Single-cell sequencing, including genomics, transcriptomics, epigenomics, proteomics and metabolomics sequencing, is a powerful tool to decipher the cellular and molecular landscape at a single-cell resolution, unlike bulk sequencing, which provides averaged data. The use of single-cell sequencing in cancer research has revolutionized our understanding of the biological characteristics and dynamics within cancer lesions. In this review, we summarize emerging single-cell sequencing technologies and recent cancer research progress obtained by single-cell sequencing, including information related to the landscapes of malignant cells and immune cells, tumor heterogeneity, circulating tumor cells and the underlying mechanisms of tumor biological behaviors. Overall, the prospects of single-cell sequencing in facilitating diagnosis, targeted therapy and prognostic prediction among a spectrum of tumors are bright. In the near future, advances in single-cell sequencing will undoubtedly improve our understanding of the biological characteristics of tumors and highlight potential precise therapeutic targets for patients.
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http://dx.doi.org/10.1186/s13045-021-01105-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8190846PMC
June 2021

Association between IL-6 and severe disease and mortality in COVID-19 disease: a systematic review and meta-analysis.

Postgrad Med J 2021 Jun 3. Epub 2021 Jun 3.

The Respiratory Department, Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China

Background: So far, SARS-CoV-2 is the seventh coronavirus found to infect humans and cause disease with quite a strong infectivity. Patients diagnosed as severe or critical cases are prone to multiple organ dysfunction syndrome, acute respiratory distress syndrome and even death. Proinflammatory cytokine IL-6 has been reported to be associated with the severity of disease and mortality in patients with COVID-19.

Objective: This systematic review and meta-analysis were carried out to evaluate the association between IL-6 and severe disease and mortality in COVID-19 disease.

Methods: A systematic literature search using China National Knowledge Infrastructure, Wanfang databases, China Science and Technology Journal Database, Chinese Biomedical Literature, Embase, PubMed and Cochrane Central Register of Controlled Trials was performed from inception until 16 January 2021.

Results: 12 studies reported the value of IL-6 for predicting the severe disease in patients with COVID-19. The pooled area under the curve (AUC) was 0.85 (95% CI 0.821 to 0.931). 5 studies elaborated the predictive value of IL-6 on mortality. The pooled sensitivity, specificity and AUC were 0.15 (95% CI 0.13 to 0.17, I=98.9%), 0.73 (95% CI 0.65 to 0.79, I=91.8%) and 0.531 (95% CI 0.451 to 0.612), respectively. Meta-regression analysis showed that country, technique used, cut-off, sample, study design and detection time did not contribute to the heterogeneity of mortality.

Conclusion: IL-6 is an adequate predictor of severe disease in patients infected with the COVID-19. The finding of current study may guide clinicians and healthcare providers in identifying potentially severe or critical patients with COVID-19 at the initial stage of the disease. Moreover, we found that only monitoring IL-6 levels does not seem to predict mortality and was not associated with COVID-19's mortality.

Prospero Registration Number: CRD42021233649.
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http://dx.doi.org/10.1136/postgradmedj-2021-139939DOI Listing
June 2021

A Novel Validated Recurrence Stratification System Based on F-FDG PET/CT Radiomics to Guide Surveillance After Resection of Pancreatic Cancer.

Front Oncol 2021 12;11:650266. Epub 2021 May 12.

Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.

Objective: Despite the heterogeneous biology of pancreatic cancer, similar surveillance schemas have been used. Identifying the high recurrence risk population and conducting prompt intervention may improve prognosis and prolong overall survival.

Methods: One hundred fifty-six resectable pancreatic cancer patients who had undergone F-FDG PET/CT from January 2013 to December 2018 were retrospectively reviewed. The patients were categorized into a training cohort (n = 109) and a validation cohort (n = 47). LIFEx software was used to extract radiomic features from PET/CT. The risk stratification system was based on predictive factors for recurrence, and the index of prediction accuracy was used to reflect both the discrimination and calibration.

Results: Overall, seven risk factors comprising the rad-score and clinical variables that were significantly correlated with relapse were incorporated into the final risk stratification system. The 1-year recurrence-free survival differed significantly among the low-, intermediate-, and high-risk groups (85.5, 24.0, and 9.1%, respectively; p < 0.0001). The C-index of the risk stratification system in the development cohort was 0.890 (95% CI, 0.835-0.945).

Conclusion: The F-FDG PET/CT-based radiomic features and clinicopathological factors demonstrated good performance in predicting recurrence after pancreatectomy in pancreatic cancer patients, providing a strong recommendation for an adequate adjuvant therapy course in all patients. The high-risk recurrence population should proceed with closer follow-up in a clinical setting.
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http://dx.doi.org/10.3389/fonc.2021.650266DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8149949PMC
May 2021

Nuclear exosome HMGB3 secreted by nasopharyngeal carcinoma cells promotes tumour metastasis by inducing angiogenesis.

Cell Death Dis 2021 May 28;12(6):554. Epub 2021 May 28.

Department of Otolaryngology Head and Neck Surgery, Affiliated Hospital of Nantong University, Xisi Road 20, Nantong, 226001, Jiangsu Province, China.

Distant metastasis accompanied by angiogenesis is the main cause of nasopharyngeal carcinoma (NPC)-related death. Nuclear exosomes (nEXOs) are potential tumour biomarkers. High mobility group box 3 (HMGB3), a nuclear protein, is known to be overexpressed in cancers. However, its role in NPC has not been elucidated. Here, we explore for the first time the function of nEXO HMGB3 in tumour angiogenesis involved in NPC metastasis using a series of in vitro experiments with NPC cell lines and clinical specimens and in vivo experiments with tumour xenograft zebrafish angiogenesis model. We found a high expression of HMGB3 in NPC, accompanied by the formation of micronuclei, to be associated with metastasis. Furthermore, the NPC-secreted HMGB3 expression was associated with tumour angiogenesis. Moreover, HMGB3-containing nEXOs, derived from the micronuclei of NPC cells, were ingested by the human umbilical vein endothelial cells (HUVECs), and accelerated angiogenesis in vitro and in vivo. Importantly, western blotting and flow cytometry analysis showed that circulating nEXO HMGB3 positively correlated with NPC metastasis. In summary, nEXO HMGB3 can be a significant biomarker of NPC metastasis and provide a novel basis for anti-angiogenesis therapy in clinical metastasis.
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http://dx.doi.org/10.1038/s41419-021-03845-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8163785PMC
May 2021

From the Immune Profile to the Immunoscore: Signatures for Improving Postsurgical Prognostic Prediction of Pancreatic Neuroendocrine Tumors.

Front Immunol 2021 23;12:654660. Epub 2021 Apr 23.

Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.

Objective: Immune infiltration plays an important role in tumor development and progression and shows promising prognostic value in numerous tumors. In this study, we aimed to identify the role of immune infiltration in pancreatic neuroendocrine tumors (Pan-NETs) and to establish an Immunoscore system to improve the prediction of postsurgical recurrence-free survival.

Methods: To derive transcriptional signatures and deconvolute specific immune populations, two GEO datasets containing 158 Pan-NET patients were reanalyzed to summarize the immune infiltration landscape and identify immune-related signatures. Using real-time reverse transcription-polymerase chain reaction, immunofluorescence and immunochemistry methods, candidate signatures were further detected. The least absolute shrinkage and selection operator (LASSO) logistic regression model used statistically significant survival predicators in the training cohort (n=125) to build an Immunoscore system. The prognostic and predictive accuracy was validated in an external independent cohort of 77 patients.

Results: The immune infiltration profile in Pan-NETs showed significant heterogeneity, among which accumulated immune cells, T lymphocytes and macrophages were predominant. Fourteen statistically significant immune-related signatures were further identified in the screening cohort. The Immunoscore system for Pan-NETs (ISpnet) consisting of six immune features (CCL19, IL-16, CD163, IRF4, CD8 and CD8) was constructed to classify patients as high and low risk in the training cohort (cutoff value = 2.14). Low-risk patients demonstrated longer 5-year recurrence-free survival (HR, 0.061; 95% CI, 0.026 to 0.14; p < 0.0001), with fewer recurrences and better prognoses. To predict the individual risk of recurrence, a nomogram incorporating both immune signatures and clinicopathological characteristics was developed.

Conclusion: Our model, ISpnet, captures immune feature-associated prognostic indicators in Pan-NETs and represents the first immune feature-based score for the postsurgical prognostic prediction. The nomogram based on the ISpnet and independent clinical risk factors might facilitate decision-making regarding early recurrence risk monitoring, identify high-risk patients in need of adjuvant therapy, and provide auxiliary guidance for patients with Pan-NETs that may benefit from immunotherapy in clinical trials.
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http://dx.doi.org/10.3389/fimmu.2021.654660DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8102869PMC
April 2021

Identification of the Roles of a Stemness Index Based on mRNA Expression in the Prognosis and Metabolic Reprograming of Pancreatic Ductal Adenocarcinoma.

Front Oncol 2021 12;11:643465. Epub 2021 Apr 12.

Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.

Background: Cancer stem cells (CSCs) are widely thought to contribute to the dismal prognosis of pancreatic ductal adenocarcinoma (PDAC). CSCs share biological features with adult stem cells, such as longevity, self-renewal capacity, differentiation, drug resistance, and the requirement for a niche; these features play a decisive role in cancer progression. A prominent characteristic of PDAC is metabolic reprogramming, which provides sufficient nutrients to support rapid tumor cell growth. However, whether PDAC stemness is correlated with metabolic reprogramming remains unknown.

Method: RNA sequencing data of PDAC, including read counts and fragments per kilobase of transcript per million mapped reads (FPKM), were collected from The Cancer Genome Atlas-Pancreatic Adenocarcinoma (TCGA-PAAD) database. Single-sample gene set enrichment analysis (GSEA) was used to calculate the relative activities of metabolic pathways in each PDAC sample. Quantitative real-time PCR was performed to validate the expression levels of genes of interest.

Results: The overall survival (OS) of patients with high mRNA expression-based stemness index (mRNAsi) values was significantly worse than that of their counterparts with low mRNAsi values ( = 0.003). This survival disadvantage was independent of baseline clinical characteristics. Gene ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis and GSEA showed that the differentially expressed genes between patients with high and low mRNAsi values were mainly enriched in oncogenic and metabolic pathways. Weighted gene coexpression network analysis (WGCNA) revealed 8 independent gene modules that were significantly associated with mRNAsi and 12 metabolic pathways. Unsupervised clustering based on the key genes in each module identified two PDAC subgroups characterized by different mRNAsi values and metabolic activities. Univariate Cox regression analysis identified 14 genes beneficial to OS from 95 key genes selected from the eight independent gene modules from WGCNA. Among them, MAGEH1, MAP3K3, and PODN were downregulated in both pancreatic tissues and cell lines.

Conclusion: The present study showed that PDAC samples with high mRNAsi values exhibited aberrant activation of multiple metabolic pathways, and the patients from whom these samples were obtained had a poor prognosis. Future studies are expected to investigate the underlying mechanism based on the crosstalk between PDAC stemness and metabolic rewiring.
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http://dx.doi.org/10.3389/fonc.2021.643465DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8071957PMC
April 2021

Role of tumor mutation burden-related signatures in the prognosis and immune microenvironment of pancreatic ductal adenocarcinoma.

Cancer Cell Int 2021 Apr 7;21(1):196. Epub 2021 Apr 7.

Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, No. 270 Dong'An Road, Shanghai, 200032, China.

Background: High tumor mutation burden (TMB) has gradually become a sensitive biomarker for predicting the response to immunotherapy in many cancers, including lung, bladder and head and neck cancers. However, whether high TMB predicts the response to immunotherapy and prognosis in pancreatic ductal adenocarcinoma (PDAC) remained obscure. Hence, it is significant to investigate the role of genes related to TMB (TRGs) in PDAC.

Methods: The transcriptome and mutation data of PDAC was downloaded from The Cancer Genome Atlas-Pancreatic Adenocarcinoma (TCGA). Five independent external datasets of PDAC were chosen to validate parts of our results. qRT-PCR and immunohistochemical staining were also performed to promote the reliability of this study.

Results: The median overall survival (OS) was significantly increased in TMB_low group compared with the counterpart with higher TMB score after tumor purity adjusted (P = 0.03). 718 differentially expressed TRGs were identified and functionally enriched in some oncogenic pathways. 67 TRGs were associated with OS in PDAC. A prognostic model for the OS was constructed and showed a high predictive accuracy (AUC = 0.849). We also found TMB score was associated with multiple immune components and signatures in tumor microenvironment. In addition, we identified a PDAC subgroup featured with TMBMicrosatellite instability (MSI) was associated with prolonged OS and a key molecule, ANKRD55, potentially mediating the survival benefits.

Conclusion: This study analyzed the biological function, prognosis value, implications for mutation landscape and potential influence on immune microenvironment of TRGs in PDAC, which contributed to get aware of the role of TMB in PDAC. Future studies are expected to investigate how these TRGs regulate the initiation, development or repression of PDAC.
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http://dx.doi.org/10.1186/s12935-021-01900-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8028808PMC
April 2021

Emerging roles of the solute carrier family in pancreatic cancer.

Clin Transl Med 2021 03;11(3):e356

Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.

Pancreatic cancer is a gastrointestinal tumor with a high mortality rate, and advances in surgical procedures have only resulted in limited improvements in the prognosis of patients. Solute carriers (SLCs), which rank second among membrane transport proteins in terms of abundance, regulate cellular functions, including tumor biology. An increasing number of studies focusing on the role of SLCs in tumor biology have indicated their relationship with pancreatic cancer. The mechanism of SLC transporters in tumorigenesis has been explored to identify more effective therapies and improve survival outcomes. These transporters are significant biomarkers for pancreatic cancer, the functions of which include mainly proliferative signaling, cell death, angiogenesis, tumor invasion and metastasis, energy metabolism, chemotherapy sensitivity and other functions in tumor biology. In this review, we summarize the different roles of SLCs and explain their potential applications in pancreatic cancer treatment.
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http://dx.doi.org/10.1002/ctm2.356DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7989705PMC
March 2021

Deciphering the Prognostic Implications of the Components and Signatures in the Immune Microenvironment of Pancreatic Ductal Adenocarcinoma.

Front Immunol 2021 10;12:648917. Epub 2021 Mar 10.

Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.

The treatment modalities for pancreatic ductal adenocarcinoma (PDAC) are limited and unsatisfactory. Although many novel drugs targeting the tumor microenvironment, such as immune checkpoint inhibitors, have shown promising efficacy for some tumors, few of them significantly prolong the survival of patients with PDAC due to insufficient knowledge on the tumor microenvironment. A single-cell RNA sequencing (scRNA-seq) dataset and seven PDAC cohorts with complete clinical and bulk sequencing data were collected for bioinformatics analysis. The relative proportions of each cell type were estimated using the gene set variation analysis (GSVA) algorithm based on the signatures identified by scRNA-seq or previous literature. A meta-analysis of 883 PDAC patients showed that neutrophils are associated with worse overall survival (OS) for PDAC, while CD8+ T cells, CD4+ T cells, and B cells are related to prolonged OS for PDAC, with marginal statistical significance. Seventeen cell categories were identified by clustering analysis based on single-cell sequencing. Among them, CD8+ T cells and NKT cells were universally exhausted by expressing exhaustion-associated molecular markers. Interestingly, signatures of CD8+ T cells and NKT cells predicted prolonged OS for PDAC only in the presence of "targets" for pyroptosis and ferroptosis induction. Moreover, a specific state of T cells with overexpression of ribosome-related proteins was associated with a good prognosis. In addition, the hematopoietic stem cell (HSC)-like signature predicted prolonged OS in PDAC. Weighted gene co-expression network analysis identified 5 hub genes whose downregulation may mediate the observed survival benefits of the HSC-like signature. Moreover, trajectory analysis revealed that myeloid cells evolutionarily consisted of 7 states, and antigen-presenting molecules and complement-associated genes were lost along the pseudotime flow. Consensus clustering based on the differentially expressed genes between two states harboring the longest pseudotime span identified two PDAC groups with prognostic differences, and more infiltrated immune cells and activated immune signatures may account for the survival benefits. This study systematically investigated the prognostic implications of the components of the PDAC tumor microenvironment by integrating single-cell sequencing and bulk sequencing, and future studies are expected to develop novel targeted agents for PDAC treatment.
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http://dx.doi.org/10.3389/fimmu.2021.648917DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7987951PMC
March 2021

Hyperdense Pancreatic Ductal Adenocarcinoma: Clinical Characteristics and Proteomic Landscape.

Front Oncol 2021 25;11:640820. Epub 2021 Feb 25.

Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.

Purpose: Hypodensity of pancreatic ductal adenocarcinoma (PDAC) during contrast-enhanced computed tomography (CECT) examination is common, but a minority of PDAC patients exhibit hyperdense images. The present study examined the clinical characteristics and protein landscape of PDAC with hyperdensity.

Materials And Methods: A total of 844 pathologically confirmed PDAC patients who underwent CECT before surgery were included. During the parenchymal phase of CECT, patients were assigned to the hyperdense or hypodense group based on CT values. Clinical and CT characteristics for predicting relapse-free survival (RFS) and overall survival (OS) were analyzed using the Kaplan-Meier method and Cox proportional hazards model. The expression of the tumor angiogenesis marker CD31 and stroma-related protein CTHRC1 were analyzed using immunohistochemistry (IHC) assay to evaluate differences between the two groups. Proteomics was performed to compare the possible mechanisms underlying the differential enhancement on CT scans.

Results: Based on CECT, 43 and 801 PDAC patients had hyperdense and hypodense lesions, respectively. All 43 patients presented a hyperdense lesion in the parenchymal phase. The mean CECT values of the hyperdense group were higher than the hypodense group (102.5 ± 17.4 and 53.7 ± 18.7, respectively, 0.001). The hyperdense group had a better prognosis than the hypodense group (median RFS, 19.97 vs. 12.34 months, = 0.0176; median OS, 33.6 vs. 20.3 months, = 0.047). Multivariate analysis showed that age, higher CA19-9 levels (> 300 U/ml), tumor stage, tumor differentiation, tumor CT density, and adjuvant chemotherapy were significant independent prognostic factors for OS. CD31 immunohistochemical staining showed that the hyperdense PDACs had a higher microvessel density than the hypodense group ( 0.001). CTHRC1 expression was higher in the hypodense group ( = 0.019). Sixty-eight differentially expressed proteins were found using the tandem mass tag labeling-based quantification of the proteomes of PDAC tissue samples, and 7 proteins (POFUT1, PKP2, P0DOX4, ITPR1, HBG2, IGLC3, SAA2) were related to angiogenesis.

Conclusion: Patients who presented with a hyperdense mass on CECT had a higher microvessel density and better prognosis. Anti-angiogenic therapy may be suitable for these patients.
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http://dx.doi.org/10.3389/fonc.2021.640820DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7947874PMC
February 2021

ER resident protein 44 promotes malignant phenotype in nasopharyngeal carcinoma through the interaction with ATP citrate lyase.

J Transl Med 2021 02 16;19(1):77. Epub 2021 Feb 16.

Department of Otorhinolaryngology Head and Neck Surgery, Affiliated Hospital of Nantong University, Nantong, Jiangsu, China.

Background: Nasopharyngeal carcinoma (NPC) is one of the most common malignancy in head and neck. With the development of treatments, the prognosis has improved these years, but metastasis is still the main cause of treatment failure. The endoplasmic reticulum (ER) resident protein 44 is a UPR-induced ER protein of the protein disulphide isomerase (PDI) family. This study investigated the role of ERp44 in NPC progression.

Methods: Firstly, immunohistochemistry, western blot and qRT-PCR were used to investigate the expression of ERp44 in NPC samples and cell lines. We analyzed 44 NPC samples for ERp44 expression and investigated the association between its expression level with clinicopathologic parameters. Then we took CCK8, Transwell migration assay and used the zebrafish model to access the role of ERp44 on the malignant phenotype in NPC cells. Secondly, we used co-IP to gain the proteins that interact with ERp44 and took proteomic analysis. Furthermore, we successfully constructed the mutant variants of ERp44 and found the interaction domain with ATP citrate lyase(ACLY). Lastly, we subcutaneously injected NPC cells into nude mice and took immunohistochemistry to exam the expression of ACLY and ERp44. Then we used western blot to detect the expression level of epithelial-mesenchymal transition (EMT) markers.

Results: In the present study, we found ERp44 was elevated in NPC tissues and correlated with clinical stages and survive state of the patients. In vitro, the downregulation of ERp44 in NPC cells (CNE2, 5-8F) could suppress cells proliferation and migration. After that, we recognized that ACLY might be a potential target that could interact with ERp44. We further constructed the mutant variants of ERp44 and found the interaction domain with ACLY. The promotion of ERp44 on cell migration could be inhibited when ACLY was knocked down. More importantly, we also observed that the interaction of ERp44 with ACLY, especially the thioredoxin region in ERp44 play a vital role in regulating EMT. Lastly, we found ERp44 was positively correlated with the expression of ACLY and could promote NPC cells growth in nude mice.

Conclusion: Our data indicated that ERp44 participates in promoting NPC progression through the interaction with ACLY and regulation of EMT.
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http://dx.doi.org/10.1186/s12967-020-02694-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7887808PMC
February 2021

Development and multicenter validation of a nomogram for preoperative prediction of lymph node positivity in pancreatic cancer (NeoPangram).

Hepatobiliary Pancreat Dis Int 2021 Apr 5;20(2):163-172. Epub 2021 Jan 5.

Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Oncology, Shanghai Medical College of Fudan University, Shanghai 200032, China; Shanghai Pancreatic Cancer Institute, Shanghai 200032, China. Electronic address:

Background: Neoadjuvant therapy is associated with nodal downstaging and improved oncological outcomes in patients with lymph node (LN)-positive pancreatic cancer. This study aimed to develop and validate a nomogram to preoperatively predict LN-positive disease.

Methods: A total of 558 patients with resected pancreatic cancer were randomly and equally divided into development and internal validation cohorts. Multivariate logistic regression analysis was used to construct the nomogram. Model performance was evaluated by discrimination, calibration, and clinical usefulness. An independent multicenter cohort consisting of 250 patients was used for external validation.

Results: A four-marker signature was built consisting of carbohydrate antigen 19-9 (CA19-9), CA125, CA50, and CA242. A nomogram was constructed to predict LN metastasis using three predictors identified by multivariate analysis: risk score of the four-marker signature, computed tomography-reported LN status, and clinical tumor stage. The prediction model exhibited good discrimination ability, with C-indexes of 0.806, 0.742 and 0.763 for the development, internal validation, and external validation cohorts, respectively. The model also showed good calibration and clinical usefulness. A cut-off value (0.72) for the probability of LN metastasis was determined to separate low-risk and high-risk patients. Kaplan-Meier survival analysis revealed a good agreement of the survival curves between the nomogram-predicted status and the true LN status.

Conclusions: This nomogram enables the identification of pancreatic cancer patients at high risk for LN positivity who may have more advanced disease and thus could potentially benefit from neoadjuvant therapy.
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http://dx.doi.org/10.1016/j.hbpd.2020.12.020DOI Listing
April 2021

Circular RNA in pancreatic cancer: a novel avenue for the roles of diagnosis and treatment.

Theranostics 2021 1;11(6):2755-2769. Epub 2021 Jan 1.

Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.

Pancreatic cancer (PC), an important cause of cancer-related deaths worldwide, is one of the most malignant cancers characterized by a dismal prognosis. Circular RNAs (circRNAs), a class of endogenous ncRNAs with unique covalently closed loops, have attracted great attention in regard to various diseases, especially cancers. Compelling studies have suggested that circRNAs are aberrantly expressed in different cancer tissues and cell types, including PC. More specifically, circRNAs can modify the proliferation, progression, tumorigenesis and chemosensitivity of PC, and some circRNAs could serve as biomarkers for diagnosis and prognosis. Herein, we summarize what is currently known to be related to the biogenesis, functions and potential roles of human circRNAs in PC and their application prospects for PC clinical treatments.
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http://dx.doi.org/10.7150/thno.56174DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7806488PMC
July 2021

Prognostic value of circulating tumor DNA in pancreatic cancer: a systematic review and meta-analysis.

Aging (Albany NY) 2020 12 9;13(2):2031-2048. Epub 2020 Dec 9.

Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China.

Increasing evidence has revealed the potential correlation between circulating tumor DNA (ctDNA) and the prognosis of pancreatic cancer, but inconsistent findings have been reported. Therefore, a meta-analysis was performed to evaluate the prognostic value of ctDNA in pancreatic cancer. The Embase, MEDLINE, and Web of Science databases were searched for relevant articles published until April 2020. Articles reporting the correlation between ctDNA and the prognosis of pancreatic cancer were identified through database searches. The pooled hazard ratios (HRs) for prognostic data were calculated and analyzed using Stata software. A total of 2326 patients pooled from 25 eligible studies were included in the meta-analysis to evaluate the prognostic value of ctDNA in pancreatic cancer. Patients with mutations detected or high concentrations of ctDNA had a significantly poorer overall survival (OS) (univariate: HR = 2.54; 95% CI, 2.05-3.14; multivariate: HR = 2.07; 95% CI, 1.69-2.54) and progression-free survival (PFS) (univariate: HR = 2.18; 95% CI, 1.41-3.37; multivariate: HR = 2.20; 95% CI, 1.38-3.52). In conclusion, the present meta-analysis indicates that mutations detected or high concentrations of ctDNA are significant predictors of OS and PFS in patients with pancreatic cancer.
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http://dx.doi.org/10.18632/aging.202199DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7880399PMC
December 2020

The role of ferroptosis regulators in the prognosis, immune activity and gemcitabine resistance of pancreatic cancer.

Ann Transl Med 2020 Nov;8(21):1347

Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.

Background: Ferroptosis is a novel form of regulated cell death that can inhibit the progression of chemotherapy-resistant tumors. However, the types of cancer most susceptible to ferroptosis induction and the role of ferroptosis regulators in cancers, especially pancreatic cancer, remain unclear.

Methods: RNA sequencing data of 31 cancers were collected from The Cancer Genome Atlas (TCGA) and The Genotype-Tissue Expression (GTEx). A nomogram integrating patients' clinical information and risk scores based on the expression levels of ferroptosis regulators was depicted. Correlations among the activity levels of 29 immunity-associated gene sets, immune scores, infiltrating immune cells and key ferroptosis regulators were assessed.

Results: We performed a pan-cancer analysis and identified 14 distinct cancers that may show a robust response to ferroptosis inducers. Interestingly, the Xc-complex, which is the major target of ferroptosis induction, was upregulated in gemcitabine-resistant pancreatic cancer cells (P<0.05). Furthermore, we focused on the role of ferroptosis regulators in mediating the survival of patients with pancreatic cancer and constructed a prognostic model with good accuracy (AUC =0.713). We also correlated elevated sensitivity to ferroptosis with higher scores for CD8+ T cells (P<0.001), the type two interferon response (P<0.001) and immune checkpoints (P<0.05).

Conclusions: We hypothesized that the ferroptosis pathway plays an important role in the prognosis of pancreatic cancer. Immuno- and chemotherapy combined with a ferroptosis inducer is a feasible therapeutic approach for pancreatic cancer.
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http://dx.doi.org/10.21037/atm-20-2554aDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7723621PMC
November 2020

Copper mixed-triazolate frameworks featuring the thiophene-containing ligand towards enhanced photodegradation of organic contaminants in water.

J Hazard Mater 2021 03 9;406:124757. Epub 2020 Dec 9.

Green Catalysis Center and College of Chemistry, Zhengzhou University, 450001 Zhengzhou, Henan, PR China. Electronic address:

By using a thiophene-containing triazole ligand -3,5-di(thiophen-2-yl)-1H-1,2,4-triazole (3,5-Th-tzH) and 3,5-diphenyl-1H-1,2,4-triazole (3,5-Ph-tzH) in different molar ratio in the reactant, copper(I) mixed-triazolate frameworks CuMtz-1 {[Cu(3,5-Ph-tz)(3,5-Th-tz)](BF)(CHOH)} (x = 0.5 for CuMtz-1a and 1.1 for CuMtz-1b) were firstly synthesized and characterized by PXRD, IR, H NMR, SEM, TG and UV-vis DRS. They have been evaluated as photocatalysts for the degradation of organic pollutants in water. It was found that the rate constants towards the degradation of both traditional and emerging organic contaminants over CuMtz-1b were significantly improved, i.e. by 160% for methyl orange, 210% for rhodamine B, 80% for methyl blue and 180% for sulfasalazine in comparison with that catalyzed over the parent MOF CuTz-1 {[Cu(3,5-Ph-tz)](BF)(CHOH)} under Xe lamp irradiation in the absence of HO. More importantly, the degradation efficiency of methyl orange and sulfasalazine by CuMtz-1b without the addition of HO was quite comparable with that by CuTz-1 with the addition of HO under both Xe lamp irradiation and natural sunlight. The enhancement on the degradation efficiency can be attributed to the increased light absorption ability and the change of the band structure caused by the incorporation of thiophene-containing triazole ligand.
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http://dx.doi.org/10.1016/j.jhazmat.2020.124757DOI Listing
March 2021

Coicis semen protects against focal cerebral ischemia-reperfusion injury by inhibiting oxidative stress and promoting angiogenesis via the TGFβ/ALK1/Smad1/5 signaling pathway.

Aging (Albany NY) 2020 11 16;13(1):877-893. Epub 2020 Nov 16.

Department of Neurology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201620, China.

Background: Ischemic stroke is a devastating disease that causes long-term disability. However, its pathogenesis is unclear, and treatments for ischemic stroke are limited. Recent studies indicate that oxidative stress is involved in the pathological progression of ischemic stroke and that angiogenesis participates in recovery from ischemic stroke. Furthermore, previous studies have shown that Coicis Semen has antioxidative and anti-inflammatory effects in a variety of diseases. In the present study, we investigated whether Coicis Semen has a protective effect against ischemic stroke and the mechanism of this protective effect.

Results: Coicis Semen administration significantly decreased the infarct volume and mortality and alleviated neurological deficits at 3, 7 and 14 days after MCAO. In addition, cerebral edema at 3 days poststroke was ameliorated by Coicis Semen treatment. DHE staining showed that ROS levels in the vehicle group were increased at 3 days after reperfusion and then gradually declined, but Coicis Semen treatment reduced ROS levels. The levels of GSH and SOD in the brain were increased by Coicis Semen treatment, while MDA levels were reduced. Furthermore, Coicis Semen treatment decreased the extravasation of EB dye in MCAO mouse brains and elevated expression of the tight junction proteins ZO-1 and Occludin. Double immunofluorescence staining and western blot analysis showed that the expression of angiogenesis markers and TGFβ pathway-related proteins was increased by Coicis Semen administration. Consistent with the , cytotoxicity assays showed that Coicis Semen substantially promoted HUVEC survival following OGD/RX . Additionally, though LY2109761 inhibited the activation of TGFβ signaling in OGD/RX model animals, Coicis Semen cotreatment markedly reversed the downregulation of TGFβ pathway-related proteins and increased VEGF levels.

Methods: Adult male wild-type C57BL/6J mice were used to develop a middle cerebral artery occlusion (MCAO) stroke model. Infarct size, neurological deficits and behavior were evaluated on days 3, 7 and 14 after staining. In addition, changes in superoxide dismutase (SOD), GSH and malondialdehyde (MDA) levels were detected with a commercial kit. Blood-brain barrier (BBB) permeability was assessed with Evans blue (EB) dye. Western blotting was also performed to measure the levels of tight junction proteins of the BBB. Additionally, ELISA was performed to measure the level of VEGF in the brain. The colocalization of CD31, angiogenesis markers, and Smad1/5 was assessed by double immunofluorescent staining. TGFβ pathway-related proteins were measured by western blotting. Furthermore, the cell viability of human umbilical vein endothelial cells (HUVECs) following oxygen-glucose deprivation/reoxygenation (OGD/RX) was measured by Cell Counting Kit (CCK)-8 assay.

Conclusions: Coicis Semen treatment alleviates brain damage induced by ischemic stroke through inhibiting oxidative stress and promoting angiogenesis by activating the TGFβ/ALK1 signaling pathway.
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http://dx.doi.org/10.18632/aging.202194DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7835068PMC
November 2020

Prevalence and factors associated with postpartum depression during the COVID-19 pandemic among women in Guangzhou, China: a cross-sectional study.

BMC Psychiatry 2020 11 25;20(1):557. Epub 2020 Nov 25.

Department of rehabilitation, Nanhai Hospital, Southern Medical University, 28#Liguan Road, Lishui County, Foshan City, Guangdong Province, China.

Background: The 2019 coronavirus disease (COVID-19) is a public health emergency of international concern. To date, there are limited studies that have investigated the impact of COVID-19 pandemic on mental health among female population. Therefore, the study aims to investigate the prevalence of postpartum depression (PPD) and it's related factors among women in Guangzhou, China, during the COVID-19 pandemic.

Methods: A cross-sectional study was performed from 30th March 2020 to 13th April 2020 using anonymous online questionnaire among 864 women at 6-12 weeks postpartum. The Chinese version of Edinburgh Postnatal Depression Scale and a questionnaire regarding associated factors were administered to all participants. Multivariate logistic regression was used to determine factors that were significantly associated with PPD.

Results: The prevalence of PPD among women at 6-12 weeks postpartum was 30.0%. A multivariate logistic regression model identified significant factors as: immigrant women, persistent fever, poor social support, concerns about contracting COVID-19 and certain precautionary measures.

Conclusions: The findings suggest the need for policies and interventions to not only mitigate the psychological impacts but also target disadvantaged sub-groups of women following childbirth during the COVID-19 pandemic.
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http://dx.doi.org/10.1186/s12888-020-02969-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7686811PMC
November 2020

The value of a metabolic reprogramming-related gene signature for pancreatic adenocarcinoma prognosis prediction.

Aging (Albany NY) 2020 11 20;12(23):24228-24241. Epub 2020 Nov 20.

Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most fatal malignancies worldwide. Extensive enhancement of glycolysis and reprogramming of lipid metabolism are both associated with the development and progression of PDAC. Previous studies have suggested that various gene signatures could convey prognostic information about PDAC. However, the use of these signatures has some limitations, perhaps because of a lack of knowledge regarding the genetic and energy supply backgrounds of PDAC. Therefore, we conducted multi-mRNA analysis based on metabolic reprogramming to identify novel signatures for accurate prognosis prediction in PDAC patients. In this study, a three-gene signature comprising MET, ENO3 and CD36 was established to predict the overall survival of PDAC patients. The three-gene signature could divide patients into high- and low-risk groups by disparities in overall survival verified by log-rank test in two independent validation cohorts and could differentiate tumors from normal tissues with excellent accuracy in four Gene Expression Omnibus (GEO) cohorts. We also found a positive correlation between the risk score of the gene signature and inherited germline mutations in PDAC predisposition genes. A glycolysis and lipid metabolism-based gene nomogram and corresponding calibration curves showed significant performance for survival prediction in the TCGA-PDAC dataset. The high-risk designation was closely connected with oncological signatures and multiple aggressiveness-related pathways, as determined by gene set enrichment analysis (GSEA). In summary, our study developed a three-gene signature and established a prognostic nomogram that objectively predicted overall survival in PDAC. The findings could provide a reference for the prediction of overall survival and could aid in individualized management for PDAC patients.
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http://dx.doi.org/10.18632/aging.104134DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7762467PMC
November 2020

The promising role of noncoding RNAs in cancer-associated fibroblasts: an overview of current status and future perspectives.

J Hematol Oncol 2020 11 19;13(1):154. Epub 2020 Nov 19.

Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, No. 270 Dong'An Road, Shanghai, 200032, China.

As the most important component of the stromal cell population in the tumor microenvironment (TME), cancer-associated fibroblasts (CAFs) are crucial players in tumor initiation and progression. The interaction between CAFs and tumor cells, as well as the resulting effect, is much greater than initially expected. Numerous studies have shown that noncoding RNAs (ncRNAs) play an irreplaceable role in this interplay, and related evidence continues to emerge and advance. Under the action of ncRNAs, normal fibroblasts are directly or indirectly activated into CAFs, and their metabolic characteristics are changed; thus, CAFs can more effectively promote tumor progression. Moreover, via ncRNAs, activated CAFs can affect the gene expression and secretory characteristics of cells, alter the TME and enhance malignant biological processes in tumor cells to contribute to tumor promotion. Previously, ncRNA dysregulation was considered the main mechanism by which ncRNAs participate in the crosstalk between CAFs and tumor cells. Recently, however, exosomes containing ncRNAs have been identified as another vital mode of interaction between these two types of cells, with a more direct and clear function. Gaining an in-depth understanding of ncRNAs in CAFs and the complex regulatory network connecting CAFs with tumor cells might help us to establish more effective and safer approaches for cancer therapies targeting ncRNAs and CAFs and offer new hope for cancer patients.
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http://dx.doi.org/10.1186/s13045-020-00988-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7678062PMC
November 2020

The role of m6A-related genes in the prognosis and immune microenvironment of pancreatic adenocarcinoma.

PeerJ 2020 28;8:e9602. Epub 2020 Sep 28.

Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.

Background: Pancreatic adenocarcinoma (PAAD) is among the most lethal diseases and has a dismal prognosis; however, efficient treatment is currently limited. Several studies have observed epigenetic variation during tumorigenesis, suggesting the potential role of RNA methylation, especially N6-methyladenosine (m6A) modification, as a novel epigenetic modification mediating PAAD prognosis.

Methods: The expression levels of m6A-related genes were downloaded from The Cancer Genome Atlas-Pancreatic Adenocarcinoma (TCGA) and Genotype-Tissue Expression (GTEx) projects, and the findings were validated in four Expression Omnibus (GEO) datasets. A predictive model was constructed using a lasso regression and evaluated by a survival analysis and receiver operating characteristic curve. Consensus clustering identified two distinct subgroups with different immune activity signatures based on the expression pattern of m6A-related genes. The relationship between the mutation state of m6A-related genes and infiltration of immune cells was established and visualized using Tumor Immune Estimation Resource (https://cistrome.shinyapps.io/timer/).

Results: Fourteen of twenty-one m6A-related genes were differentially expressed between PAAD and normal tissues in TCGA-GTEx cohort. Among these genes, and were further validated in four GEO datasets. Moreover, an m6A-based model exhibited moderate accuracy in predicting overall survival in PAAD samples. Additionally, potential m6A modification targets were screened by selecting genes from a set of 23,391 genes that not only harbored the most m6A-modified sites but also showed a robust correlation with PAAD survival. Moreover, we correlated the expression level of m6A-related genes with the immune microenvironment of pancreatic cancer for the first time. Specifically, both arm-level gain and deletion of decreased the infiltration of CD8+T cells ( < 0.05 and  < 0.01, respectively).

Conclusion: Collectively, our findings suggest a novel anticancer strategy for restoring balanced RNA methylation in tumor cells and guide clinical physicians in developing a new practical approach for considering the impact of related genes on prognosis.
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http://dx.doi.org/10.7717/peerj.9602DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7528816PMC
September 2020

Prediction of adverse clinical outcomes in patients with coronavirus disease 2019.

J Clin Lab Anal 2021 Jan 28;35(1):e23598. Epub 2020 Sep 28.

The Respiratory Department, The Second Affiliated Hospital of Harbin Medical University, Harbin, China.

Objective: This study aims to investigate blood and biochemical laboratory findings in patients with coronavirus disease (COVID-19) and analyze the potential predictors of poor outcome in patients with COVID-19.

Methods: The clinical, laboratory, and outcome data of 87 patients with COVID-19 were collected and retrospectively analyzed. Only data collected at the time of admission were used in the analysis for predictors of poor outcome. These patients were divided into two groups: the adverse prognosis group (36 patients) and the non-adverse prognosis group (51 patients). The adverse prognosis of COVID-19 patients was defined as admission to the intensive care unit or death.

Results: On the univariate analysis, age, white blood cell (WBC) count, neutrophil counts, lymphocytes count, neutrophils-to-lymphocytes ratio (NLR), interleukin-6, albumin-to-globulin ratio (AGR), albumin, lactate dehydrogenase, glutamyl transpeptidase, and blood glucose were found to be the significant predictors. On the multivariate analysis, the predictors of poor outcome of patients with COVID-19 were NLR (OR = 2.741, [95% CI = 1.02 ~ 7.35], P = .045) and IL-6 (OR = 1.405, [95% CI = 1.04 ~ 1.89, P = .025]). The receiver operating characteristic (ROC) curve revealed that the AUC of NLR, interleukin-6, pneumonia severity index (PSI) score, and Confusion-Urea-Respiratory Rate-Blood pressure-65 (CURB-65) score were 0.883, 0.852, 0.824, and 0.782, respectively.

Conclusion: High interleukin-6 (6 pg/mL, cuff value) and NLR (4.48, cuff value) can be used to predict poor outcomes in patients with COVID-19 on admission, thus can serve as a beneficial tool for timely identifying COVID-19 patients prone to poor outcome and reduce patient mortality through early intervention.
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http://dx.doi.org/10.1002/jcla.23598DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7536920PMC
January 2021

Neuroprotective Effects of Dexmedetomidine Preconditioning on Oxygen-glucose Deprivation-reoxygenation Injury in PC12 Cells via Regulation of Ca-STIM1/Orai1 Signaling.

Curr Med Sci 2020 Aug 29;40(4):699-707. Epub 2020 Aug 29.

Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, 430060, China.

Dexmedetomidine (DEX), a potent and highly selective agonist for α-adrenergic receptors (αAR), exerts neuroprotective effects by reducing apoptosis through decreased neuronal Ca influx. However, the exact action mechanism of DEX and its effects on oxygen-glucose deprivation-reoxygenation (OGD/R) injury in vitro are unknown. We demonstrate that DEX pretreatment reduced OGD/R injury in PC12 cells, as evidenced by decreased oxidative stress, autophagy, and neuronal apoptosis. Specifically, DEX pretreatment decreased the expression levels of stromal interaction molecule 1 (STIM1) and calcium release-activated calcium channel protein 1 (Orai1), and reduced the concentration of intracellular calcium pools. In addition, variations in cytosolic calcium concentration altered apoptosis rate of PC12 cells after exposure to hypoxic conditions, which were modulated through STIM1/Orai1 signaling. Moreover, DEX pretreatment decreased the expression levels of Beclin-1 and microtubule-associated protein 1A/1B-light chain 3 (LC3), hallmark markers of autophagy, and the formation of autophagosomes. In conclusion, these results suggested that DEX exerts neuroprotective effects against oxidative stress, autophagy, and neuronal apoptosis after OGD/R injury via modulation of Ca-STIM1/Orai1 signaling. Our results offer insights into the molecular mechanisms of DEX in protecting against neuronal ischemia-reperfusion injury.
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http://dx.doi.org/10.1007/s11596-020-2201-5DOI Listing
August 2020

The superiority of [Ga]-FAPI-04 over [F]-FDG PET/CT in imaging metastatic esophageal squamous cell carcinoma.

Eur J Nucl Med Mol Imaging 2021 04 28;48(4):1248-1249. Epub 2020 Aug 28.

Department of Nuclear Medicine, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, 200032, China.

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http://dx.doi.org/10.1007/s00259-020-04997-3DOI Listing
April 2021

Ferroptosis, necroptosis, and pyroptosis in anticancer immunity.

J Hematol Oncol 2020 08 10;13(1):110. Epub 2020 Aug 10.

Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, No. 270 Dong'An Road, Shanghai, China.

In recent years, cancer immunotherapy based on immune checkpoint inhibitors (ICIs) has achieved considerable success in the clinic. However, ICIs are significantly limited by the fact that only one third of patients with most types of cancer respond to these agents. The induction of cell death mechanisms other than apoptosis has gradually emerged as a new cancer treatment strategy because most tumors harbor innate resistance to apoptosis. However, to date, the possibility of combining these two modalities has not been discussed systematically. Recently, a few studies revealed crosstalk between distinct cell death mechanisms and antitumor immunity. The induction of pyroptosis, ferroptosis, and necroptosis combined with ICIs showed synergistically enhanced antitumor activity, even in ICI-resistant tumors. Immunotherapy-activated CD8+ T cells are traditionally believed to induce tumor cell death via the following two main pathways: (i) perforin-granzyme and (ii) Fas-FasL. However, recent studies identified a new mechanism by which CD8+ T cells suppress tumor growth by inducing ferroptosis and pyroptosis, which provoked a review of the relationship between tumor cell death mechanisms and immune system activation. Hence, in this review, we summarize knowledge of the reciprocal interaction between antitumor immunity and distinct cell death mechanisms, particularly necroptosis, ferroptosis, and pyroptosis, which are the three potentially novel mechanisms of immunogenic cell death. Because most evidence is derived from studies using animal and cell models, we also reviewed related bioinformatics data available for human tissues in public databases, which partially confirmed the presence of interactions between tumor cell death and the activation of antitumor immunity.
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http://dx.doi.org/10.1186/s13045-020-00946-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7418434PMC
August 2020

Comment on "Prognosis-Based Definition of Resectability in Pancreatic Cancer: A Road Map to New Guidelines".

Ann Surg 2020 Jul 24. Epub 2020 Jul 24.

Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China Pancreatic Cancer Multidisciplinary Center, Fudan University Shanghai Cancer Center, Shanghai, China Shanghai Pancreatic Cancer Institute, Shanghai, China Pancreatic Cancer Institute, Fudan University, Shanghai, China.

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http://dx.doi.org/10.1097/SLA.0000000000004291DOI Listing
July 2020

Dexmedetomidine pretreatment attenuates myocardial ischemia reperfusion induced acute kidney injury and endoplasmic reticulum stress in human and rat.

Life Sci 2020 Sep 2;257:118004. Epub 2020 Jul 2.

Department of Anesthesiology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, Anhui, China. Electronic address:

Background: Patients undergoing cardiopulmonary bypass (CPB) often develop acute kidney injury (AKI) caused by myocardial ischemia reperfusion (MI/R), and this renal injury can be resolved notably by dexmedetomidine. Endoplasmic reticulum (ER) stress was reported to get involved in organ injury including AKI.

Objectives: The current study aimed to address the correlation between MI/R induced AKI with ER stress and to assess the effects of dexmedetomidine pretreatment on AKI protection.

Method: Patients selected for heart valve replacement surgery were randomly assigned to NS group (pre-anesthesia with 0.9% NaCl) and DEX group (pre-anesthesia with dexmedetomidine). Rat MI/R model was induced by occluding coronary artery for 30 min followed by 48-hour reperfusion. Rats were randomized into Sham (0.9% NaCl), I/R (MI/R + 0.9% NaCl) and I/R + DEX (MI/R + dexmedetomidine). Organ function and ER stress condition were evaluated by blood chemistry, pathology, and molecular test.

Results: Clinical data indicated dexmedetomidine pretreatment attenuated AKI and oxidative stress as well as postischemic myocardial injury in patients. Accordingly animal results suggested dexmedetomidine reduced cellular injury and improved postischemic myocardial and renal function. Dexmedetomidine also reduced myocardial and renal cells apoptosis and down-regulated ER stress.

Conclusions: These results suggested that dexmedetomidine pretreatment attenuates MI/R injury-induced AKI by relieving the ER stress.
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http://dx.doi.org/10.1016/j.lfs.2020.118004DOI Listing
September 2020
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