Dual Starvations Induce Pyroptosis for Orthotopic Pancreatic Cancer Therapy through Simultaneous Deprivation of Glucose and Glutamine.

Pancreatic cancer is a highly fatal disease, and existing treatment methods are ineffective, so it is urgent to develop new effective treatment strategies. The high dependence of pancreatic cancer cells on glucose and glutamine suggests that disrupting this dependency could serve as an alternative strategy for pancreatic cancer therapy. We identified the vital genes glucose transporter 1 (GLUT1) and alanine-serine-cysteine transporter 2 (ASCT2) through bioinformatics analysis, which regulate glucose and glutamine metabolism in pancreatic cancer, respectively. Human serum albumin nanoparticles (HSA NPs) for delivery of GLUT1 and ASCT2 inhibitors, BAY-876/V-9302@HSA NPs, were prepared by a self-assembly process. This nanodrug inhibits glucose and glutamine uptake of pancreatic cancer cells through the released BAY-876 and V-9302, leading to nutrition deprivation and oxidative stress. The inhibition of glutamine leads to the inhibition of the synthesis of the glutathione, which further aggravates oxidative stress. Both of them lead to a significant increase in reactive oxygen species, activating caspase 1 and GSDMD and finally inducing pyroptosis. This study provides a new effective strategy for orthotopic pancreatic cancer treatment by dual starvation-induced pyroptosis. The study for screening metabolic targets using bioinformatics analysis followed by constructing nanodrugs loaded with inhibitors will inspire future targeted metabolic therapy for pancreatic cancer.

The Effect of Perioperative Dexamethasone on Postoperative Complications After Pancreaticoduodenectomy: A Multicenter Randomized Controlled Trial.

OBJECTIVE: To evaluate the effect of perioperative dexamethasone on postoperative complications after pancreaticoduodenectomy. BACKGROUND: The glucocorticoid dexamethasone has been shown to improve postoperative outcomes in surgical patients, but its effects on postoperative complications after pancreaticoduodenectomy are unclear. METHODS: This multicenter, double-blind, randomized controlled trial was conducted in four Chinese high-volume pancreatic centers. Adults undergoing elective pancreaticoduodenectomy were randomized to receive either 0.2 mg/kg dexamethasone or a saline placebo as an intravenous bolus within 5 minutes after anesthesia induction. The primary outcome was the Comprehensive Complication Index (CCI) score within 30 days after the operation, analyzed using the modified intention-to-treat principle. RESULTS: Among 428 patients for eligibility, 300 participants were randomized and 265 were included in the modified intention-to-treat analyses. One hundred thirty-four patients received dexamethasone and 131 patients received a placebo. The mean (SD) CCI score was 14.0 (17.5) in the dexamethasone group and 17.9 (20.3) in the placebo group (mean difference: -3.8; 95% CI: -8.4 to 0.7; P = 0.100). The incidence of major complications (Clavien-Dindo grade ≥III; 12.7% vs 16.0%, risk ratio: 0.79; 95% CI: 0.44 to 1.43; P = 0.439) and postoperative pancreatic fistula (25.4% vs 31.3%, risk ratio: 0.81; 95% CI: 0.55 to 1.19; P = 0.286) were not significantly different between the two groups. In the stratum of participants with a main pancreatic duct ≤3 mm (n = 202), the CCI score was significantly lower in the dexamethasone group (mean difference: -6.4; 95% CI: -11.2 to -1.6; P = 0.009). CONCLUSIONS: Perioperative dexamethasone did not significantly reduce postoperative complications within 30 days after pancreaticoduodenectomy.

Sketch-Supervised Histopathology Tumour Segmentation: Dual CNN-Transformer With Global Normalised CAM.

Deep learning methods are frequently used in segmenting histopathology images with high-quality annotations nowadays. Compared with well-annotated data, coarse, scribbling-like labelling is more cost-effective and easier to obtain in clinical practice. The coarse annotations provide limited supervision, so employing them directly for segmentation network training remains challenging. We present a sketch-supervised method, called DCTGN-CAM, based on a dual CNN-Transformer network and a modified global normalised class activation map. By modelling global and local tumour features simultaneously, the dual CNN-Transformer network produces accurate patch-based tumour classification probabilities by training only on lightly annotated data. With the global normalised class activation map, more descriptive gradient-based representations of the histopathology images can be obtained, and inference of tumour segmentation can be performed with high accuracy. Additionally, we collect a private skin cancer dataset named BSS, which contains fine and coarse annotations for three types of cancer. To facilitate reproducible performance comparison, experts are also invited to label coarse annotations on the public liver cancer dataset PAIP2019. On the BSS dataset, our DCTGN-CAM segmentation outperforms the state-of-the-art methods and achieves 76.68 % IOU and 86.69 % Dice scores on the sketch-based tumour segmentation task. On the PAIP2019 dataset, our method achieves a Dice gain of 8.37 % compared with U-Net as the baseline network.

Secondary Metabolites from the Genus Eurotium and Their Biological Activities.

Eurotium is the teleomorph genus associated with the section Aspergillus. Eurotium comprises approximately 20 species, which are widely distributed in nature and human environments. Eurotium is usually the key microorganism for the fermentation of traditional food, such as Fuzhuan brick tea, Liupao tea, Meju, and Karebushi; thus, Eurotium is an important fungus in the food industry. Eurotium has been extensively studied because it contains a series of interesting, structurally diverse, and biologically important secondary metabolites, including anthraquinones, benzaldehyde derivatives, and indol diketopiperazine alkaloids. These secondary metabolites have shown multiple biological activities, including antioxidative, antimicrobial, cytotoxic, antitumor, insecticidal, antimalarial, and anti-inflammatory activities. This study presents an up-to-date review of the phytochemistry and biological activities of all Eurotium species. This review will provide recent advances on the secondary metabolites and their bioactivities in the genus Eurotium for the first time and serve as a database for future research and drug development from the genus Eurotium.

Early postsurgical lethal outcome due to splenic littoral cell angioma: A case report.

BACKGROUND: Littoral cell angioma (LCA) is a rare benign vascular tumor of the spleen. Given its rarity, standard diagnostic and therapeutic recommendations have yet to be developed for reported cases. Splenectomy is the only method of obtaining a pathological diagnosis and providing treatment to obtain a favorable prognosis. CASE SUMMARY: A 33-year-old female presented with abdominal pain for one month. Computed tomography and ultrasound revealed splenomegaly with multiple lesions and two accessory spleens. The patient underwent laparoscopic total splenectomy and accessory splenectomy, and splenic LCA was confirmed by pathology. Four months after surgery, the patient presented with acute liver failure, was readmitted, rapidly progressed to multiple organ dysfunction syndrome and died. CONCLUSION: Preoperative diagnosis of LCA is challenging. We systematically reviewed online databases to identify the relevant literature and found a close relationship between malignancy and immunodysregulation. When a patient suffers from both splenic tumors and malignancy or immune-related disease, LCA is possible. Due to potential malignancy, total splenectomy (including accessory spleen) and regular follow-up after surgery are recommended. If LCA is diagnosed after surgery, a comprehensive postoperative examination is needed.

A modified single-needle continuous suture of duct-to-mucosa pancreaticojejunostomy in pancreaticoduodenectomy.

Background: The pancreatic reconstruction technique decides the incidence of postoperative pancreatic fistulas (POPF) in pancreaticoduodenectomy (PD). This study aims to evaluate the safety of modified single-needle continuous suture (SNCS) of duct-to-mucosa and compare the efficacy with double-layer continuous suture (DLCS) of duct-mucosa pancreaticojejunostomy (PJ) in open PD (OPD). Methods: A total of 266 patients that received PD between January 2019 and May 2023 were retrospectively analyzed. Among them, 130 patients underwent DLCS, and 136 patients underwent SNCS [73 OPD and 63 laparoscopic PD (LPD)]. The primary outcome was clinically relevant POPF (CR-POPF) according to the definition of the revised 2016 International Study Group of Pancreatic Fistula (ISGPF). Propensity score matching (PSM) was conducted to reduce confounding bias. Results: A total of 66 pairs were successfully matched using PSM in OPD. No significant difference was observed in the occurrence of CR-POPF between the two groups (9.1% vs. 21.2%, P=0.052). However, the median duration of operation and PJ was shorter in the SNCS group. The incidence of CR-POPF in LPD was 9.5%. Furthermore, regarding the alternative fistula risk score (a-FRS), the CR-POPF rate were 2.1%, 10.5%, and 15.6% in low-, intermediate-, and high-risk groups (P=0.067). Conclusions: The SNCS is a facile, safe, and effective PJ technique and does not increase the incidence of POPF, regardless of a-FRS stratification, pancreatic texture, and main pancreatic duct (MPD) size.

A cumulative sum (CUSUM) analysis studying operative times and complications for a surgeon transitioning from laparoscopic to robot-assisted pediatric pyeloplasty: Defining proficiency and competency.

INTRODUCTION: The transition from laparoscopic to robot-assisted procedures leads to potential increase in operative times and health care costs. Cumulative sum (CUSUM) analysis can objectively study the learning curve to detect significant changes in operative timing and monitor complication rates. OBJECTIVE: The objective of this study is to investigate the total and step-specific times for pediatric robot-assisted pyeloplasty (RAP) to investigate the learning curve of a single surgeon transitioning from laparoscopic to RAP. STUDY DESIGN: This prospective cohort study included 50 consecutive RAP procedures performed since the inception of our robotic program from June 2013 to January 2019. The CUSUM of RAP total operative time (OT) was calculated to determine the breakpoints between learning phases using piecewise linear regression. Cumulative-observed-minus-expected failure chart with 80% and 95% reassurance boundary lines was constructed using 5% acceptable and 10% unacceptable complication rates. Step-specific operative times were prospectively recorded by an independent observer for port placement, dissection and hitch stitch placement, pelvis dismemberment and spatulation, suturing and port removal. RESULTS: Piecewise linear regression for OT identified breakpoints at case 13 and 29 suggesting transition at these points between Learning to Proficiency, and Proficiency to Competency. The overall mean OT was 142.2 ± 46.0 min. There was a significant difference in the mean OT between Learning (203.9 ± 35.3 min, the initial 13 cases), Proficiency (159.2 ± 18.6 min, the middle 16 cases), and Competency (126.6 ± 19.7 min, the last 21 cases) phases (p < 0.001). The complication rate for RAP stabilized around the acceptable level of 5% up to case 41 before finalizing at 8% overall. The step-specific analysis suggested that suturing entered the Competency phase at case 27, with a 50% decrease in suturing time from Learning to Proficiency and Competency. DISCUSSION: Our study suggests that by case 30 a surgeon transitioning to RAP can achieve a significant decrease in OT. Complication rates remained within acceptable limits throughout, indicating that RAP can be safely adopted, even in low volume RAP centres. Suturing competency seems to be a significant advantage of the robotic platform as suggested by early significant decrease in suturing times noted between the Learning and Proficiency phases. CONCLUSION: Future studies can confirm these findings and establish reference operative times to aid surgeons and trainees transitioning from laparoscopic pyeloplasty to RAP. Moreover, total OT decreases significantly and relatively soon after transition to RAP.

Acinar Cell-Derived Extracellular Vesicle MiRNA-183-5p Aggravates Acute Pancreatitis by Promoting M1 Macrophage Polarization Through Downregulation of FoxO1.

Acute pancreatitis (AP) is a common cause of a clinically acute abdomen. Crosstalk between acinar cells and leukocytes (especially macrophages) plays an important role in the development of AP. However, the mechanism mediating the interaction between acinar cells and macrophages is still unclear. This study was performed to explore the role of acinar cell extracellular vesicles (EVs) in the crosstalk between acinar cells and macrophages involved in the pathogenesis of AP. EVs derived from caerulein-treated acinar cells induced macrophage infiltration and aggravated pancreatitis in an AP rat model. Further research showed that acinar cell-derived EV miR-183-5p led to M1 macrophage polarization by downregulating forkhead box protein O1 (FoxO1), and a dual-luciferase reporter assay confirmed that FoxO1 was directly inhibited by miR-183-5p. In addition, acinar cell-derived EV miR-183-5p reduced macrophage phagocytosis. Acinar cell-derived EV miR-183-5p promoted the pancreatic infiltration of M1 macrophages and increased local and systemic damage in vivo. Subsequently, miR-183-5p overexpression in macrophages induced acinar cell damage and trypsin activation, thus further exacerbating the disease. In clinical samples, elevated miR-183-5p levels were detected in serum EVs and positively correlated with the severity of AP. EV miR-183-5p might play an important role in the development of AP by facilitating M1 macrophage polarization, providing a new insight into the diagnosis and targeted management of pancreatitis. Graphical abstract of the present study. In our caerulein-induced AP model, miR-183-5p was upregulated in injured acinar cells and transported by EVs to macrophages. miR-183-5p could induce M1 macrophage polarization through downregulation of FoxO1 and the release of inflammatory cytokines, which could aggravate AP-related injuries. Therefore, a vicious cycle might exist between injured ACs and M1 macrophage polarization, which is fulfilled by EV-transported miR-183-5p, leading to sustainable and progressive AP-related injuries.

Comprehensive Analysis of Necroptosis in Pancreatic Cancer for Appealing its Implications in Prognosis, Immunotherapy, and Chemotherapy Responses.

Objective: Necroptosis represents a new target for cancer immunotherapy and is considered a form of cell death that overcomes apoptosis resistance and enhances tumor immunogenicity. Herein, we aimed to determine necroptosis subtypes and investigate the roles of necroptosis in pancreatic cancer therapy. Methods: Based on the expression of prognostic necroptosis genes in pancreatic cancer samples from TCGA and ICGC cohorts, a consensus clustering approach was implemented for robustly identifying necroptosis subtypes. Immunogenic features were evaluated according to immune cell infiltrations, immune checkpoints, HLA molecules, and cancer-immunity cycle. The sensitivity to chemotherapy agents was estimated using the pRRophetic package. A necroptosis-relevant risk model was developed with a multivariate Cox regression analysis. Results: Five necroptosis subtypes were determined for pancreatic cancer (C1∼C5) with diverse prognosis, immunogenic features, and chemosensitivity. In particular, C4 and C5 presented favorable prognosis and weakened immunogenicity; C2 had high immunogenicity; C1 had undesirable prognosis and high genetic mutations. C5 was the most sensitive to known chemotherapy agents (cisplatin, gemcitabine, docetaxel, and paclitaxel), while C4 displayed resistance to aforementioned agents. The necroptosis-relevant risk model could accurately predict prognosis, immunogenicity, and chemosensitivity. Conclusion: Our findings provided a conceptual framework for comprehending necroptosis in pancreatic cancer biology. Future work is required for evaluating its relevance in the design of combined therapeutic regimens and guiding the best choice for immuno- and chemotherapy.

Positive feedback regulation of lncRNA TPT1-AS1 and ITGB3 promotes cell growth and metastasis in pancreatic cancer.

Emerging evidence has indicated that long noncoding RNAs (lncRNAs) are potential biomarkers and play crucial roles in cancer development. However, the functions and underlying mechanisms of lncRNA TPT1-AS1 in pancreatic ductal adenocarcinoma (PDAC) remain elusive. RNAseq data of PDAC tissues and normal tissues were analyzed, and lncRNAs which were associated with PDAC prognosis were identified. The clinical relevance of TPT1-AS1 for PDAC patients was explored, and the effects of TPT1-AS1 in PDAC progression were investigated in vitro and in vivo. LncRNA TPT1-AS1 was highly expressed in PDAC, and high TPT1-AS1 levels predicted a poor prognosis. Moreover, functional experiments revealed that TPT1-AS1 promoted pancreatic cancer cell proliferation, migration, invasion, and epithelial-to-mesenchymal transition (EMT) process in vitro and in vivo. Mechanistically, TPT1-AS1 functioned as an endogenous sponge for miR-30a-5p, which increased integrin ß3 (ITGB3) level in pancreatic cancer cells. Conversely, our data revealed that ITGB3 could activate the transcription factor signal transducer and activator of transcription 3 (STAT3), which in turn bound directly to the TPT1-AS1 promoter and affected the expression of TPT1-AS1, thus forming a positive feedback loop with TPT1-AS1. Taken together, our results uncovered a reciprocal loop of TPT1-AS1 and ITGB3 which contributed to pancreatic cancer growth and development, and indicated that TPT1-AS1 might serve as a novel potential diagnostic biomarker and therapeutic target for PDAC patients.

Aberrant integration of Hepatitis B virus DNA promotes major restructuring of human hepatocellular carcinoma genome architecture.

Most cancers are characterized by the somatic acquisition of genomic rearrangements during tumour evolution that eventually drive the oncogenesis. Here, using multiplatform sequencing technologies, we identify and characterize a remarkable mutational mechanism in human hepatocellular carcinoma caused by Hepatitis B virus, by which DNA molecules from the virus are inserted into the tumour genome causing dramatic changes in its configuration, including non-homologous chromosomal fusions, dicentric chromosomes and megabase-size telomeric deletions. This aberrant mutational mechanism, present in at least 8% of all HCC tumours, can provide the driver rearrangements that a cancer clone requires to survive and grow, including loss of relevant tumour suppressor genes. Most of these events are clonal and occur early during liver cancer evolution. Real-time timing estimation reveals some HBV-mediated rearrangements occur as early as two decades before cancer diagnosis. Overall, these data underscore the importance of characterising liver cancer genomes for patterns of HBV integration.

Polyphenols from Fu Brick Tea Reduce Obesity via Modulation of Gut Microbiota and Gut Microbiota-Related Intestinal Oxidative Stress and Barrier Function.

Fu brick tea (FBT) is a microbial-fermented tea, which is produced by the solid-state fermentation of tea leaves. Previous studies have proved that FBT aqueous extracts could attenuate obesity and gut microbiota dysbiosis. However, the bioactive components in FBT that contribute to these activities remain unclear. In this study, we aimed to investigate the effects of FBT polyphenols (FBTPs) on obesity, gut microbiota, and gut microbiota-related intestinal oxidative stress and barrier function and to further investigate whether the antiobesity effect of FBTPs was dependent on the alteration of gut microbiota. The results showed that FBTP supplementation effectively attenuated obesity in high-fat diet (HFD)-fed rats. FBTP supplementation improved the intestinal oxidative stress and intestinal barrier function, including intestinal inflammation and the integrity of the intestinal barrier. Furthermore, FBTP intervention significantly attenuated HFD-induced gut microbiota dysbiosis, characterized by increased phylogenetic diversity and decreased Firmicutes/Bacteroidetes ratio. Certain core microbes, including Akkermansia muciniphila, Alloprevotella, Bacteroides, and Faecalibaculum, were also found to be improved by FBTPs. Moreover, the antiobesity effect of FBTPs was gut microbiota-dependent, as demonstrated by a fecal microbiota transplantation experiment. Collectively, we concluded that FBTPs reduced obesity by modulating the gut microbiota and gut microbiota-related intestinal oxidative stress and barrier function. Therefore, FBTPs may be used as prebiotic agents to treat obesity and gut microbiota dysbiosis in obese individuals.

Integrating Genetic and Transcriptomic Data to Reveal Pathogenesis and Prognostic Markers of Pancreatic Adenocarcinoma.

Pancreatic adenocarcinoma (PAAD) is one of the deadliest malignancies and mortality for PAAD have remained increasing under the conditions of substantial improvements in mortality for other major cancers. Although multiple of studies exists on PAAD, few studies have dissected the oncogenic mechanisms of PAAD based on genomic variation. In this study, we integrated somatic mutation data and gene expression profiles obtained by high-throughput sequencing to characterize the pathogenesis of PAAD. The mutation profile containing 182 samples with 25,470 somatic mutations was obtained from The Cancer Genome Atlas (TCGA). The mutation landscape was generated and somatic mutations in PAAD were found to have preference for mutation location. The combination of mutation matrix and gene expression profiles identified 31 driver genes that were closely associated with tumor cell invasion and apoptosis. Co-expression networks were constructed based on 461 genes significantly associated with driver genes and the hub gene FAM133A in the network was identified to be associated with tumor metastasis. Further, the cascade relationship of somatic mutation-Long non-coding RNA (lncRNA)-microRNA (miRNA) was constructed to reveal a new mechanism for the involvement of mutations in post-transcriptional regulation. We have also identified prognostic markers that are significantly associated with overall survival (OS) of PAAD patients and constructed a risk score model to identify patients' survival risk. In summary, our study revealed the pathogenic mechanisms and prognostic markers of PAAD providing theoretical support for the development of precision medicine.

Invadopodia: A potential target for pancreatic cancer therapy.

Dissemination of cancer cells is an intricate multistep process that represents the most deadly aspect of cancer. Cancer cells form F-actin-rich protrusions known as invadopodia to invade surrounding tissues, blood vessels and lymphatics. A number of studies have demonstrated the significant roles of invadopodia in cancer. Therefore, the specific cells and molecules involved in invadopodia activity can provide as therapeutic targets. In this review, we included a thorough overview of studies in invadopodia and discussed their functions in cancer metastasis. We then presented the specific cells and molecules involved in invadopodia activity in pancreatic cancer and analyzed their suitability to be effective therapeutic targets. Currently, drugs targeting invadopodia and relevant clinical trials are negligible. Here, we highlighted the significance of potential drugs and discussed future obstacles in implementing clinical trials. This review presents a new perspective on invadopodia-induced pancreatic cancer metastasis and may prosper the development of targeted therapeutics against pancreatic cancer.

Deep Learning Methods for Lung Cancer Segmentation in Whole-Slide Histopathology Images-The ACDC@LungHP Challenge 2019.

Accurate segmentation of lung cancer in pathology slides is a critical step in improving patient care. We proposed the ACDC@LungHP (Automatic Cancer Detection and Classification in Whole-slide Lung Histopathology) challenge for evaluating different computer-aided diagnosis (CADs) methods on the automatic diagnosis of lung cancer. The ACDC@LungHP 2019 focused on segmentation (pixel-wise detection) of cancer tissue in whole slide imaging (WSI), using an annotated dataset of 150 training images and 50 test images from 200 patients. This paper reviews this challenge and summarizes the top 10 submitted methods for lung cancer segmentation. All methods were evaluated using metrics using the precision, accuracy, sensitivity, specificity, and DICE coefficient (DC). The DC ranged from 0.7354 ±0.1149 to 0.8372 ±0.0858. The DC of the best method was close to the inter-observer agreement (0.8398 ±0.0890). All methods were based on deep learning and categorized into two groups: multi-model method and single model method. In general, multi-model methods were significantly better (p 0.01) than single model methods, with mean DC of 0.7966 and 0.7544, respectively. Deep learning based methods could potentially help pathologists find suspicious regions for further analysis of lung cancer in WSI.

Dark tea extracts: Chemical constituents and modulatory effect on gastrointestinal function.

Processing of dark tea varieties, such as Fu brick tea, Liupao tea, Qianliang tea, and Qing brick tea, includes solid-state fermentation involving microorganisms. In this study, we analyzed the major chemical constituents of dark tea extracts and evaluated their modulatory effect on the gastrointestinal function in normal mice, including the improvement of gastrointestinal transit and intestinal microbial, as well as the attenuation of intestinal microbial dysbiosis and intestinal pathological damage, and the adjustment of immune function in antibiotic-treated mice. Substantial differences in major chemical constituents, including total polyphenols, total organic acids, water extract content, 18 free amino acids, gallic acid, and six tea catechins, were observed among Fu brick tea, Qianliang tea, Qing brick tea, and Liupao tea extracts. Extracts from the four dark tea varieties significantly promoted gastrointestinal transit and colonization of beneficial Bifidobacterium and Lactobacillus, and inhibited the growth of harmful Escherichia coli and Enterococcus in normal mice. In addition, Qianliang tea, Qing brick tea, and Liupao tea extracts significantly accelerated the reversal of the ampicillin sodium-induced pathological damage in the ileum, intestinal bacterial dysbiosis (Bifidobacterium, Lactobacillus, E. coli, and Enterococcus), and low immunity.