Identifying drug candidates for pancreatic ductal adenocarcinoma based on integrative multiomics analysis.

Background: Due to a lack of early diagnosis methods and effective drugs, pancreatic ductal adenocarcinoma (PDAC) has an extremely poor prognosis. DNA methylation, transcriptome expression and gene copy number variation (CNV) have critical relationships with development and progression of various diseases. The purpose of the study was to screen reliable early diagnostic biomarkers and potential drugs based on integrative multiomics analysis. Methods: We used methylation, transcriptome and CNV profiles to build a diagnostic model for PDAC. The protein expression of three model-related genes were externally validated using PDAC samples. Then, potential therapeutic drugs for PDAC were identified by interaction information related to existing drugs and genes. Results: Four significant differentially methylated regions (DMRs) were selected from 589 common DMRs to build a high-performance diagnostic model for PDAC. Then, four hub genes, PHF12, FXYD3, PRKCB and ZNF582, were obtained. The external validation results showed that PHF12, FXYD3 and PRKCB protein expression levels were all upregulated in tumor tissues compared with adjacent normal tissues (P<0.05). Promising candidate drugs with activity against PDAC were screened and repurposed through gene expression analysis of online datasets. The five drugs, including topotecan, PD-0325901, panobinostat, paclitaxel and 17-AAG, with the highest activity among 27 PDAC cell lines were filtered. Conclusions: Overall, the diagnostic model built based on four significant DMRs could accurately distinguish tumor and normal tissues. The five drug candidates might be repurposed as promising therapeutics for particular PDAC patients.

The Role of C-reactive Protein and Procalcitonin in Predicting the Occurrence of Pancreatic Fistula in Patients who Underwent Laparoscopic Pancreaticoduodenectomy: a Retrospective Study.

The occurrence of postoperative pancreatic fistula following laparoscopic pancreaticoduodenectomy (LPD) is a significant concern, yet there is currently a lack of consensus on reliable predictive methods for this complication. Therefore, the aim of this study was to assess the clinical significance of C-reactive protein (CRP) and procalcitonin (PCT) values and their reliability in early predicting the development of clinically relevant pancreatic fistula (CRPF) following LPD.A retrospective analysis was conducted using data from 120 patients who had LPD between September 2019 and December 2021. Preoperative assessment data, standard patients' demographic and clinicopathological characteristics, intra- and postoperative evaluation, as well as postoperative laboratory values on postoperative days (PODs) 1, 3, and 7, including white blood cells (WBCs), CRP, and PCT, were prospectively recorded on a dedicated database. Two clinicians separately collected and cross-checked all of the data.Among 120 patients [77 men (64%), 43 women (36%], CRPF occurred in 15 patients (11 grade B and 4 grade C fistulas). The incidence rate of CRPF was 12.3%. A comparison of the median values of WBCs, PCT, and CRP across the two groups revealed that the CRPF group had higher values on most PODs than the non-CRPF group. Receiver operating characteristic (ROC) analysis was used to calculate the area under the curve (AUC) and cutoff values. It was discovered that POD 3 has the most accurate and significant values for WBCs, CRP, and PCT. According to the ROC plots, the AUC for WBCs was 0.842, whereas the AUC for PCT was 0.909. As for CRP, the AUC was 0.941 (95% CI 0.899-0.983, p < 0.01) with a cutoff value of 203.45, indicating a sensitivity of 93.3% and specificity of 91.4%.Both CRP and PCT can be used to predict the early onset of CRPF following LPD, with CRP being slightly superior on POD 3.

Feasibility and tolerability of sintilimab plus anlotinib as the second-line therapy for patients with advanced biliary tract cancers: An open-label, single-arm, phase II clinical trial.

Patients with biliary tract cancer (BTC) were associated with poor prognosis and limited therapeutic options after first-line therapy currently. In this study, we sought to evaluate the feasibility and tolerability of sintilimab plus anlotinib as the second-line treatment for patients with advanced BTC. Eligible patients had histologically confirmed locally advanced unresectable or metastatic BTC and failed after the first-line treatment were recruited. The primary endpoint was overall survival (OS). Simultaneously, association between clinical outcomes and genomic profiling and gut microbiome were explored to identify the potential biomarkers for this regimen. Twenty patients were consecutively enrolled and received study therapy. The trail met its primary endpoint with a median OS of 12.3 months (95% CI: 10.1-14.5). Only four (20%) patients were observed of the grade 3 treatment-related adverse events (TRAEs) and no grade 4 or 5 TRAEs were detected. Mutation of AGO2 was correlated with a significantly longer OS. Abundance of Proteobacteria was associated with inferior clinical response. Therefore, sintilimab plus anlotinib demonstrated encouraging anti-tumor activity with a tolerable safety profile and deserved to be investigated in larger randomized trials for patients with advanced BTC subsequently.

SOX21-AS1 activated by STAT6 promotes pancreatic cancer progression via up-regulation of SOX21.

BACKGROUND: Pancreatic cancer (PC) is a highly malignant tumor which threatens human's health. Long non-coding RNAs (lncRNAs) are implicated in many cancers, including PC, but their mechanisms in PC have not yet been entirely clarified. We focused on revealing the potential function of lncRNA SOX21-AS1 in PC. METHODS: Functional assays assessed SOX21-AS1 function on PC progression. Bioinformatics analysis, along with mechanism assays were taken to unmask the regulatory mechanism SOX21-AS1 may exert in PC cells. RESULTS: SOX21-AS1 possessed a high expression level in PC cells. SOX21-AS1 absence suppressed PC cell proliferation, migration, stemness and epithelial-mesenchymal transition (EMT) while elevated cell apoptosis. SOX21-AS1 positively regulated its nearby gene SRY-box transcription factor 21 (SOX21) at post-transcriptional level. Through mechanism assays, we uncovered that SOX21-AS1 sponged SOX21-AS1 to elevate SOX21 mRNA and recruited ubiquitin-specific peptidase 10 (USP10) to deubiquitinate and stabilize SOX21 protein. Moreover, signal transducer and activator of transcription 6 (STAT6) could transcriptionally activate SOX21-AS1 and SOX21 expression. CONCLUSIONS: SOX21-AS1 aggravated the malignant development of PC, which might provide the utility value for PC treatment.

Novel Nomogram Based on Inflammatory Markers for the Preoperative Prediction of Microvascular Invasion in Solitary Primary Hepatocellular Carcinoma.

Purpose: We aimed to develop and to validate a novel nomogram based on inflammatory markers to preoperatively predict microvascular invasion (MVI) in patients with solitary primary hepatocellular carcinoma (HCC). Patients and Methods: Data from 658 patients with solitary primary HCC who underwent hepatectomy at the First Affiliated Hospital of Zhengzhou University from June 2018 to October 2021 were retrospectively analyzed. Patients were divided into training (n=441) and validation (n=217) cohorts according to surgical data. Independent risk factors for MVI were identified via univariate and multivariate logistic regression analyses in the training cohort. A novel nomogram was developed based on the independent risk factors identified. Its accuracy was evaluated using a calibration curve and concordance index (C-index). The predictive value was evaluated using the receiver operating characteristic (ROC) curve and decision curve analysis (DCA). Results: Preoperative alpha-fetoprotein >969 µg/L (P<0.001), tumor size (P=0.002), neutrophil >1.8×109/L (P=0.002), gamma-glutamyl transpeptidase-to-platelet ratio (GPR) >0.32 (P=0.001), aspartate aminotransferase-to-platelet ratio (APR) >0.18 (P<0.001), gamma-glutamyl transpeptidase-to-albumin ratio (GAR) >2.30 (P=0.001), and gamma-glutamyl transpeptidase-to-lymphocyte ratio >29.58 (P<0.001) were identified as preoperative independent risk factors for MVI and were used to establish the nomogram. The C-index of the training and validation cohorts were 0.788 (95% confidence interval [CI]: 0.744-0.831) and 0.735 (95% CI: 0.668-0.802), respectively. The calibration curve analysis revealed that the standard curve fit well with the predicted curve. ROC curve analysis demonstrated high efficiency of the nomogram. DCA verified that the nomogram had notable clinical value. Conclusion: Preoperative GPR >0.32, APR >0.18, and GAR >2.30 were independent risk factors for MVI in patients with solitary primary HCC, suggesting their utility as preoperative predictors of MVI. The novel nomogram developed and validated in this study may aid in determining optimal therapeutic approaches for patients with solitary HCC at risk for MVI.

A laparoscopic pancreaticoduodenectomy for pancreatic adenocarcinoma in a patient with situs inversus totalis.

Situs inversus totalis (SIT) is a congenital disorder in which the thoracic and abdominal viscera organs are mirrored from their normal anatomical position. Thus, the presence of any cancerous mass in one of the visceral organs of patients with SIT represents a great challenge due to the anatomical variation. We report a 52-year-old male with SIT who presented with obstructive jaundice and pancreatic-head mass. After preoperative examinations, it was decided to perform a laparoscopic pancreaticoduodenectomy. In this case, we aim to demonstrate the diagnosis and management of pancreatic cancer in an SIT patient, in addition to presenting the advantages and difficulties of laparoscopic surgery in this case.

Role of exosomes in pancreatic cancer.

Pancreatic cancer (PC) is a malignant tumour of the human digestive system that has a poor prognosis. Exosomes contain proteins and nucleic acids, and constitute a class of extracellular vesicles defined as membrane-bound nanovesicles of endocytic origin, with a diameter of 40-150 nm. Exosomes are potential diagnostic markers of PC; however, their roles in cancer initiation and progression remain unclear. Previous studies have focused on the molecular mechanisms and functions of exosomes that allow them to accelerate PC cell proliferation, migration and invasion. The present review discusses the interactions between exosomes and the pathophysiology of PC. The potential clinical applications of exosomes are also discussed.

Deep Heterogeneous Hashing for Face Video Retrieval.

Retrieving videos of a particular person with face image as query via hashing technique has many important applications. While face images are typically represented as vectors in Euclidean space, characterizing face videos with some robust set modeling techniques (e.g. covariance matrices as exploited in this study, which reside on Riemannian manifold), has recently shown appealing advantages. This hence results in a thorny heterogeneous spaces matching problem. Moreover, hashing with handcrafted features as done in many existing works is clearly inadequate to achieve desirable performance for this task. To address such problems, we present an end-toend Deep Heterogeneous Hashing (DHH) method that integrates three stages including image feature learning, video modeling, and heterogeneous hashing in a single framework, to learn unified binary codes for both face images and videos. To tackle the key challenge of hashing on manifold, a well-studied Riemannian kernel mapping is employed to project data (i.e. covariance matrices) into Euclidean space and thus enables to embed the two heterogeneous representations into a common Hamming space, where both intra-space discriminability and inter-space compatibility are considered. To perform network optimization, the gradient of the kernel mapping is innovatively derived via structured matrix backpropagation in a theoretically principled way. Experiments on three challenging datasets show that our method achieves quite competitive performance compared with existing hashing methods.

Overexpression of human telomerase reverse transcriptase promotes the motility and invasiveness of HepG2 cells in vitro.

Recent studies have indicated that telomerase activity promotes cancer invasion and metastasis, but the underlying mechanism remains unclear. Several studies have shown that expression of exogenous human telomerase reverse transcriptase (hTERT) can promote motility and invasiveness among telomerase-negative tumor cells, and inhibition of endogenous telomerase activity can reduce invasiveness in tumor cells. However, whether overexpression of hTERT can further enhance the motility and invasiveness of telomerase­positive tumor cells has yet to be determined. In the present study, we showed that stable overexpression of hTERT can increase telomerase activity and telomere length, which significantly promotes the invasive and metastatic potential of telomerase­positive HepG2 cells but does not affect cell proliferation. Further analysis suggested that enhanced invasiveness and metastasis may act through corresponding upregulation of mRNA and protein expression of matrix metalloproteinase 9 (MMP9) and Ras homolog gene family member C (RhoC). Our study indicated that exogenous expression of hTERT may promote invasiveness and metastasis through upregulation of MMP9 and RhoC.

Aplasia Ras homologue member I overexpression induces apoptosis through inhibition of survival pathways in human hepatocellular carcinoma cells in culture and in xenograft.

The aim of the present study was to determine the effects of ARHI (aplasia Ras homologue member I; also known as DIRAS3), a member of the Ras superfamily, on HCC (hepatocellular carcinoma) cells and to define the molecular pathways involved. Stable transfection of ARHI into the HCC cell line Hep3B that lacks expression of this gene reduced cell proliferation significantly as compared with the transfection of empty vector (P<0.01). Moreover, the re-expression of ARHI induced significant apoptosis, whereas a few vector transfectants or non-transfected cells displayed apoptosis. Mechanistically, ARHI restoration impeded the activation of both Akt (also called protein kinase B) and NF-κB (nuclear factor κB). In vivo, restoring ARHI also exerted suppressive effects on xenograft tumour growth, which was coupled with increased apoptosis. Together, these results indicate that ARHI has pro-apoptotic effects on HCC cells, which is associated with the inactivation of both Akt and NF-κB survival pathways.

Simultaneous measurements of serum AFP, GPC-3 and HCCR for diagnosing hepatocellular carcinoma.

BACKGROUND/AIMS: Hepatocellular carcinoma (HCC) is a prevalent malignant tumor. Tumor markers are very useful in early diagnosis; however a single marker is rather limited. We launched a test to increase the diagnostic sensitivity through the combined detection. METHODOLOGY: Serum concentration of three tumor-markers, Glypican-3 (GPC-3), Human-Cervical-Cancer-Oncogene (HCCR) and a-fetoprotein (AFP), were determined in 189 samples: 101 cases of HCC, 40 cases of cirrhosis, 18 cases of hepatitis and 30 cases of control healthy donors. Every marker was evaluated for its diagnostic value by one-way-analysis-of-variance and receiver-operating-characteristics analysis. RESULTS: GPC-3 was the best marker with an area under the curve (AUC) of 0.892; using 26.8ng/mL as the cut-off for HCC diagnosis, GPC-3 has a sensitivity of 51.5% and maintains a specificity of 92.8%. HCCR, with an AUC of 0.831, can reach a sensitivity of 22.8% and maintain a specificity of 90.9% if the cut-off is set as 58.8mAU/mL. With an AUC of 0.827, the efficacy and sensitivity of AFP were 36.6% and 98.5% when using 199.3ng/mL as the cut-off. No significant correlation was found between these three markers. Simultaneously detecting three markers can significantly increases the sensitivity to 80.2%, much higher than AFP alone. CONCLUSIONS: GPC-3 and HCCR are useful tumor markers complementary to AFP for clinical diagnosis of HCC.

A novel system of artificial antigen-presenting cells efficiently stimulates Flu peptide-specific cytotoxic T cells in vitro.

Therapeutic numbers of antigen-specific cytotoxic T lymphocytes (CTLs) are key effectors in successful adoptive immunotherapy. However, efficient and reproducible methods to meet the qualification remain poor. To address this issue, we designed the artificial antigen-presenting cell (aAPC) system based on poly(lactic-co-glycolic acid) (PLGA). A modified emulsion method was used for the preparation of PLGA particles encapsulating interleukin-2 (IL-2). Biotinylated molecular ligands for recognition and co-stimulation of T cells were attached to the particle surface through the binding of avidin-biotin. These formed the aAPC system. The function of aAPCs in the proliferation of specific CTLs against human Flu antigen was detected by enzyme-linked immunospot assay (ELISPOT) and MTT staining methods. Finally, we successfully prepared this suitable aAPC system. The results show that IL-2 is released from aAPCs in a sustained manner over 30 days. This dramatically improves the stimulatory capacity of this system as compared to the effect of exogenous addition of cytokine. In addition, our aAPCs promote the proliferation of Flu antigen-specific CTLs more effectively than the autologous cellular APCs. Here, this aAPC platform is proved to be suitable for expansion of human antigen-specific T cells.